understanding and treating heart failurethe effect of coenzyme q10 on morbidity and mortality in...

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Dialogues in Cardiovascular Medicine - Vol 21 . No. 1 . 2016

EditorialUnderstanding and treating heart failure: looking into the future - A. Vazir, K. Fox, R. Ferrari 3

Lead Article Understanding and treating heart failure: looking to the future - F. Ruschitzka 7

Expert Answers to Three Key Questions What is the role of the heart failure nurse? - J. P. Riley 27

What is the role of telemonitoring in heart failure? - M. R. Cowie 35

Gene therapy for heart failure: the end of the beginning? - A. C. Morley-Smith, C. Hayward, S. E. Harding, A. R. Lyon 45

Fascinoma Cardiologica Trails of Discovery: Angiotensin receptor antagonists - J. D. Fitzgerald 59

Summaries of Ten Seminal Papers - A. Vazir 67

Bibliography of One Hundred Key Papers 78

Telemonitoring or structured telephone support programmesfor patients with chronic heart failure: systematic review andmeta-analysis – R. A. Clark and others

Advanced heart failure treated with continuous-flow left ventricular assist device – M. S. Slaughter and others

Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study – K. Swedberg and others

Wireless pulmonary artery haemodynamic monitoring inchronic heart failure: a randomised controlled trial W. T. Abraham and others

Spironolactone for heart failure with preserved ejection fractionB. Pitt and others

Angiotensin–neprilysin inhibition versus enalapril in heart failure – J. J. McMurray and others

The effect of coenzyme Q10 on morbidity and mortality inchronic heart failure: results from Q-SYMBIO: a randomizeddouble-blind trial – S. A. Mortensen

Efficacy of β blockers in patients with heart failure plus atrialfibrillation: an individual-patient data meta-analysis – D. Kotecha

Adaptive servo-ventilation for central sleep apnea in systolicheart failure – M. R. Cowie and others

Coronary-artery bypass surgery in patients with ischemic cardiomyopathy – E. J. Velazquez

Understanding and Treating Heart Failure

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Anand I, MD Prof MedicineLa Jolla, CA, USA

Avkiran M, PhD Cardiovascular Research The Rayne InstituteSt Thomas’ HospitalLondon, UK

Bassand JP, MDDept of CardiologyUniversity Hospital Jean MinjozBesançon, France

Bertrand ME, MDHôpital CardiologiqueLille, France

Böhm M, MDSaarland University HospitalHomburg/Saar, Germany

Bolli R, MDDivision of CardiologyUniversity of LouisvilleLouisville, KY, USA

Borer JS, MDHoward Gilman Institute for Heart Valve DiseaseSchiavone Institute for Cardio-vascular Translational ResearchState University of New YorkDownstate Medical Center, New York, NY, USA

Cetin E, MDTurkey Yuksek Ihtisas Training & Research HospitalAnkara, Turkey

Coats A, MDFaculty of MedicineUniversity of SydneySydney, Australia

Cowie M, MD, PhDDept of Clinical CardiologyNational Heart & Lung InstituteLondon, UK

Danchin N, MDDept of CardiologyHôpital Européen Georges PompidouParis, France

Dargie HJ, MDCardiac ResearchWestern InfirmaryGlasgow, UK

Fox KA, MDDept of Cardiological ResearchUniversity of EdinburghEdinburgh, UK

Fuster V, MD, PhDCardiovascular InstituteMount Sinai Medical CenterNew York, NY, USA

Consulting Editors

Editors in ChiefFerrari R, MD, PhDChair of Cardiology University Hospital of Ferrara, Cona (Ferrara),Italy

Fox K, MD, FRCPNational Heart and Lung InstituteInstitute of Cardiovascular Medicine and ScienceRoyal Brompton Hospital, London, UK

Hasenfuss G, MDDept of CardiologyGeorg-August UniversitätGöttingen, Germany

Heusch G, MD, PhDWest German Heart and Vascular Centre EssenInstitute for Pathophysiology University of Essen MedicalSchoolEssen, Germany

Hori M, MD, PhDDept of Internal Medicine and TherapeuticsOsaka University Graduate School of MedicineOsaka, Japan

Hu D, MDHeart Institute Intervention Center People Hospital of PekingUniversity Beijing, China

Komajda M, MDDept of CadiologyCHU Pitié-SalpêtrièreParis, France

Libby P, MDCardiovascular MedicineBrigham & Women’s HospitalBoston, MA, USA

Lonn E, MDHamilton Health Sciences General SiteHamilton, Ontario, Canada

Lüscher T, MDDepartment of CardiologyUniversity Heart Center University Hospital Zürich, Switzerland

Lopez-Sendon JL, MDCCU Dept of CardiologyHospital University Gregorio MaranonMadrid, Spain

Maggioni AP, MDANMC Research CenterFirenze, Italy

Marber MS, MD, PhDCardiovascular Research The Rayne Institute St Thomas’ HospitalLondon, UK

Oktay E, MDDept Cardiology Dokuz Eylul University Faculty of Medicine İzmir, Turkey

Oto A, MDMedical Office, Hacettepe University School of MedicineAnkara, Turkey

Patrono C, MDDept of PharmacologyUniversity La SapienzaRome, Italy

Pepine CJ, MDDept of MedicineUniversity of FloridaGainesville, FL, USA

Pfeffer MA, MD, PhDDept MedicineBrigham and Women’s HospitalBoston, MA, USA

Pinto F, MDCardiology DepartmentFaculdade de MedicinaUniversidade de LisboaLisbon, Portugal

Rapezzi C, MDInstitute of CardiologyUniversity of BolognaBologna, Italy

Rosen MR, MDDept of Pharmacology & PediatricsColumbia University College of Physicians & SurgeonsNew York, NY, USA

Ryden L, MD, PhDDept of CardiologyKarolinska University Hospital SolnaStockholm, Sweden

Schneider MD, MDBaylor College of MedicineHouston, TX, USA

Seabra-Gomes RJ, MDInstituto do CoracaoHospital Santa CruzCarnaxide, Portugal

Shah A, MDCardiovascular DivisionJames Black CentreBritish Heart Foundation Centreof ExcellenceKing’s College London London, UK

Simoons ML, MDThoraxcenterErasmus University Medical CenterRotterdam, The Netherlands

Sipido K, MD, PhDDept Cardiovascular SciencesKatholieke Universiteit LeuvenLeuven, Belgium

Steg PG, MDDept of CardiologyHôpital Bichat–Claude BernardParis, France

Swedberg K, MD, PhDDept of MedicineSahlgrenska University Hospital OstraGöteborg, Sweden

Tardif JC, MDMontreal Heart InstituteMontreal, Quebec, Canada

Tavazzi L, MDDivision of CardiologyPoliclinico San Matteo IRCCSPavia, Italy

Tendera M, MD3rd Division of CardiologySilesian School of MedicineKatowice, Poland

Vanhoutte PM, MDDept of PharmacologyUniversity of Hong Kong Faculty of MedicineHong Kong, China

Widimsky P, MD, PhDVinohrady CardiocenterCharles University HospitalPrague, Czech Republic

Wijns WC, MDCardiovascular Center AalstOLV Hospital, Aalst, Belgium

Zamorano JL, MDUniversity Francisco deVitoria/Hospital Ramón y CajalMadrid, Spain


3

n 1933, Sir Thomas Lewis believed that “the very essence of cardiovascular prac-

tice is the early detection of heart failure,” which he defined as “a condition in

which the heart fails to discharge its contents adequately.” Since then, various

other definitions for heart failure have existed and have evolved, as have advance-

ments in treatments, based on our better understanding of the disease. The more

modern definition from the European Society of Cardiology describes heart failure as

an “abnormality of cardiac structure or function leading to failure of the heart to deliver

oxygen at a rate commensurate with the requirements of the metabolizing tissues,

despite normal filling pressures.”1

In the UK, over 800 000 patients have heart failure, and it constitutes a large burden

to the health care systems, costing close to £2 ($3) billion per year, with over 50% of

the cost being from hospitalization for heart failure.2 With the aging population and

rising prevalence of comorbidities, such as hypertension and diabetes mellitus, the

burden of heart failure is expected to worsen with escalating costs. The prognosis of

heart failure remains poor, with mortality being highest for those hospitalized. For

example, in the 2013-2014 National Heart Failure audit in England, 30-day mortality

for hospitalized patients was 15%, of whom, 10% had died in the hospital.3

On a more positive note, there has been some progress made in improving prognosis,

and much of this is associated with a better appreciation of the pathophysiology of

heart failure, in particular the importance of blocking the overactivated renin-angio-

tensin-aldosterone and sympathetic nervous systems with angiotensin-converting

enzyme inhibitors, b-blockers, and mineralocorticoid receptor antagonists. Furthermore,

heart rate has been identified as an important modifiable risk factor that can be low-

ered to improve outcomes.4 These strategies have been particularly useful in patients

categorized as having heart failure with reduced systolic function, resulting in reverse

left ventricular remodeling and improved survival and quality of life. Unfortunately, for

I

•••

Ali Vazir, MB, BS, PhD, FRCP, FESC

Kim Fox, MD, FRCP

Roberto Ferrari, MD, PhD

Editorial

UNDERSTANDING AND TREATINGHEART FAILURE: LOOKING INTO THE FUTURE

Copyright © 2016, AICH - Servier Research Group. All rights reserved www.dialogues-cvm.org

certain categories of heart failure, such as heart failure with preserved ejection fraction

(HFPEF) or acute heart failure, progress has been limited in developing effective treat-

ments that have a favorable impact on prognosis. There are multiple reasons that could

explain this; for example, both HFPEF and acute heart failure are characterized by

significant heterogeneity in patient populations, serving as a reason why trials of

potential treatments have failed to be of benefit.

Other than pharmacological and device therapy, the value of safeguarding and empow-

ering the heart failure patients by educating them about their disease and ensuring

that multidisciplinary teams and technologies are available to help monitor, support,

and reach out to these patients should not be underestimated, as these strategies

also have significant prognostic impact. As our understanding of heart failure improves,

we look to the future in an optimistic light, identifying potential treatment targets that

can improve quality of life and survival.

In this important issue of Dialogues in Cardiovascular Medicine, edited by Ali Vazir,Frank Ruschitztka, the current president of the Heart Failure Association of the European

Society of Cardiology, writes the lead article on understanding and treating heart fail-

ure, and offers a look into the future. He highlights the recent important advances in

pharmacotherapy of heart failure with reduced systolic function with the angiotensin-

neprylisin inhibitor sacubitril/valsartan, a new class of drug, which is associated with a

20% relative risk reduction in cardiovascular mortality compared with the angiotensin-

converting enzyme inhibitor enalapril.5 This sort of advancement has not been achieved

in a heart failure trial for at least a decade, especially when the comparator is an already

established and effective treatment as opposed to the comparator being placebo. He

also emphasizes the current challenges faced in managing HFPEF and acute heart failure

syndromes, but he reports on the improved phenotyping and improved trial designs

for new therapies that are on the horizon and are currently being investigated.

Jillian Riley is in a key position to discuss the multidisciplinary approach to managing

heart failure and the important role of the heart failure nurse in the patient’s journey

through acute admission, discharge, and patient education, follow-up, and monitoring,

all of which are associated with better outcomes. She also discusses the role of the heart

failure nurse in end of life care. Martin Cowie emphasizes the role, practicality, and

effectiveness of telemonitoring in the management of the increasing elderly population

living with heart failure. Finally, Andrew Morley-Smith, Carl Hayward, Sian Harding,

and Alexander Lyon report on the stimulating area of gene therapy for heart failure,

with the concept of replacing faulty genes with undamaged ones within the failing

cardiomyocyte. They discuss the neutral findings of the CUPID-2 trial and the potential

challenges in this translational field and look ahead to what is next in gene therapy

for heart failure.


Editorial - Vazir, Fox, Ferrari

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Editorial - Vazir, Fox, Ferrari

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1. McMurray JJ, Adamopoulos S, Anker SD, et al.

ESC guidelines for the diagnosis and treatment of acute and chronic heartfailure 2012.

Eur J Heart Fail. 2012;14:803-869.

2. British Heart Foundation.

Cardiovascular disease statistics 2014.

www.bhf.org.uk/research/heart-statistics. Accessed April 22, 2016.

3. British Society for Heart Failure.

National Heart Failure Audit 2012 to 2013.

www.ucl.ac.uk/nicor/audits/heartfailure/documents/annualreports/hfannual12-13.pdf. Accessed April 22, 2016.

4. Swedberg K, Komajda M, Böhm M, et al; SHIFT Investigators.

Ivabradine and outcomes in chronic heart failure (SHIFT): a randomisedplacebo-controlled study.

Lancet. 2010;376:875-885.

5. McMurray JJ, Packer M, Desai AS, et al; PARADIGM-HFInvestigators and Committees.

Angiotensin-neprilysin inhibition versus enalapril in heart failure.

N Engl J Med. 2014;371:993-1004.

REFERENCES

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Understanding and treating heart failure: looking to the futureFrank Ruschitzka, MD

University Heart Center - Zurich University Hospital - SWITZERLAND

Understanding heart failure

DEFINITION OF HEART FAILURE

In order to properly understand and effectively treatheart failure (HF), we must first define what it is.In HF, the heart is unable to pump enough bloodto meet metabolic demand because of a dimin-

ished capacity for ventricular filling or ejection.1,2 HFis an end stage of the cardiovascular disease continu-um that is characterized by the symptoms of dyspnea,fatigue, and fluid retention and signs of elevated jugu-lar venous pressure, pulmonary crackles, and displacedapex beat.3

Over time, the quality of life of the HF patient worsens,functional capacity declines, and death may occur viapump failure or ventricular arrhythmias. In the yearsto come, the challenge of affordably managing HF willbecome a priority for many countries with aging pop-ulations.1,2

Diagnosis of HF is based on history, physical examina-tion, and investigation of a possible cardiac cause (asmyocardial disease is usually responsible for systolicand/or diastolic ventricular dysfunction). The renin–an-giotensin–aldosterone system (RAAS) and sympatheticnervous system are activated in HF, causing a range ofdeleterious effects, including myocardial injury. Manykey HF treatments rely on the interruption of these twoimportant systems. HF is normally seen in its chronicform, but the clinical course is punctuated by episodesof acute HF, which are marked by worsening signs andsymptoms. The hearts of HF patients are particularlysusceptible, with even minor upsets capable of pro-voking an episode of acute decompensation.1,2

HF is commonly categorized according to whether ejec-tion fraction (EF) is maintained (HF with preserved EF[HFPEF]), or not (HF with reduced EF [HFREF]). EF iswidely used for classifying the diverse range of patientswith HF—who differ with regard to demographics,comorbidities, prognosis, and treatment affinity.1,2


Keywords: acute; classification; device; genetics; pharmacotherapy; pre-served ejection fraction; reduced ejection fraction; technology; therapeuticstrategy Address for correspondence:Prof Frank Ruschitzka, Cardiology Department, University Heart Center,Zurich University Hospital, Rämistrasse 100, CH-8091 Zürich,Switzerland(e-mail: [email protected])

Dialogues Cardiovasc Med. 2016;21:7-24

In the last 25 years, evidence-based treatment algo-rithms in international HF guidelines have helpedimprove the management and treatment of HF bypromoting the effective use of pharmacological anddevice therapies. However, the combination of agingpopulations and a marked rise in HF risk factors (ie,hypertension, obesity, and diabetes) has meant thatthe morbidity, mortality, and economic burden of HFare set to rise. Fortunately, new evidence from clinicaltrials and molecular, cellular, genetic, and electronicresearch is providing promising new avenues to im-prove the treatment of HFREF, HFPEF, and acuteHF. Examples of promising avenues include researchon the pathophysiology of HFPEF and HFPEF phe-notypes, the improvement in HFREF prognosis withvalsartan/sacubitril, and the development of novel drugand device therapies in acute and advanced HF. Car-diac metabolism and calcium cycling are excitingareas of HF research, and the replacement of cardio-myocytes using gene therapy, miRNA, and cell ther-apy holds great promise. In advanced HF, enhancedLVAD technology is making myocardial recovery aclinical objective. “The best way to predict the futureis to invent it,” according to Alan Kay, an eminentAmerican computer scientist. In HF, we have the in-teresting ideas and now the new tools to match.

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Understanding and treating heart failure - Ruschitzka

STUDY ACRONYMS

ALCADIA AutoLogous human CArdiac-Derived stem cell to treat Ischemic cArdiomyopathy [trial]

ALLSTAR ALLogeneic heart STem cells to Achieve myocardial Regeneration [trial]

ARIC Atherosclerosis Risk In Communities [study]

BENEFIT BENznidazole Evaluation For Interrupting Trypanosomiasis [study]

CHARM-Added Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity–Added [trial]

CONFIRM-HF COmparisoN of the use of FerrIc caRboxyMaltose with placebo in patients with chronic Heart Failure and iron deficiency [trial]

CONSENSUS COoperative North Scandinavian ENalapril SUrvival Study

CORONA COntrolled ROsuvastatin in multiNAtional trial heart failure

CUPID Calcium Upregulation by Percutaneous administration of gene therapy In cardiac Disease [trial]

DIG Digitalis Investigation Group [trial]

EchoCRT ECHOcardiography guided Cardiac Resynchronization Therapy [trial]

EMPA-REGEMPAgliflozin cardiovascular OUTCOME event trial in type 2 diabetes mellitus patients

OUTCOME

EXACT-HF xanthine oxidase inhibition for hyperuricemic heart failure patients [study]

EXAMINE EXAMINation of cardiovascular outcomes with alogliptin vs standard of care in patients with type 2 diabetes mellitus and acute coronary syndromE

FAIR-HF Ferric carboxymaltose Assessment in patients with IRon deficiency and chronic Heart Failure

GISSI-HF Gruppo Italiano per lo Studio della Streptochinasi nell’Infarto miocardico-Heart Failure

MADIT-CRT Multicenter Automatic Defibrillator Implantation Trial–Cardiac Resynchronization Therapy

MOOD-HF MOrbidity, mOrtality and mood in Depressed Heart Failure patients

NECTAR-HF NEural Cardiac TherApy foR Heart Failure [trial]

OPT-CHF OxyPurinol Therapy for Congestive Heart Failure [study]

PARADIGM-HF Prospective comparison of ARNI with ACE inhibitor to Determine Impact on Global Mortality and morbidity in Heart Failure [trial]

PARAGON-HF efficacy and safety of LCZ696 compared with valsartan, on morbidity and mortality in heart failure patients with preserved ejection fraction

Q-SYMBIO Coenzyme Q10 as adjunctive treatment of chronic heart failure: a randomised, double-blind, multicentre trial with focus on SYMptoms, BIomarker status (brain-natriuretic peptide), and long-term Outcome (hospitalizations/mortality)

RALES Randomized ALdactone Evaluation Study

RELAX SeRELAXin in acute heart failure patients with preserved left ventricular ejection fraction [study]

REMATCH Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart failure

SADHART-CHF Sertraline Against Depression and HeART disease in Chronic Heart Failure [trial]

SAVOR TIMI Saxagliptin Assessment of Vascular Outcomes Recorded in patients with diabetes mellitus– Thrombolysis In Myocardial Infarction

SERVE-HF treatment of sleep-disordered breathing with predominant central sleep apnoea with adaptive SERvo-VEntilation in patients with chronic Heart Failure [trial]

SHIFT Systolic Heart failure treatment with the If inhibitor ivabradine Trial

SUPPORT SUPPlemental benefit of an angiotensin receptor blocker in hypertensive patients with stable heart failure using OlmesaRTan [trial]

TECOS Trial Evaluating Cardiovascular Outcomes with Sitagliptin

TOPCAT Treatment Of Preserved CArdiac funcTion heart failure with an aldosterone antagonist [trial]

TRUE-AHF efficacy and safety of ularitide for the TReatment of acUtE decompensAted Heart Failure [study]

Val-HeFT Valsartan Heart Failure Trial

Heart failure with reduced ejection fraction

HFREF can be defined as a combination of the usualHF symptoms and signs plus reduced LVEF, and it isoften accompanied by LV enlargement with patholog-ical ventricular remodeling (dilatation and reducedcontractility). Those with LV systolic dysfunction regu-larly have elements of diastolic dysfunction as well.Coronary artery disease is the cause of half of the in-cident HF in the general population, but these arenot the only risk factors.1,2,4

Untreated systolic dysfunction, which may be symp-tomless to begin with, deteriorates progressively dueto additional myocyte death and neurohumoral activa-tion in particular, leading to increased LV enlargementand a reduction in EF.1,2 Compared with HFPEF pa-tients, HFREF patients are younger, more likely to bemen, and less likely to be obese. Importantly, the prog-nosis of patients with HFREF is worse than that ofHFPEF patients.

Heart failure with preserved ejection fraction

The diagnostic criteria proposed by the Heart FailureAssociations of the European Society of Cardiology todefine the syndrome of HFPEF share three features:(i) clinical signs or symptoms of HF; (ii) evidence ofnormal LV systolic function; and (iii) evidence of ab-normal LV diastolic dysfunction. Patients with HFPEFhave the usual symptoms and signs of HF, but unlikeHFREF, there is no LV dilation and LVEF is unaffectedor only mildly impaired. Structural heart disease, likeLV hypertrophy or left atrial enlargement, and/or dias-tolic dysfunction (determined by Doppler echocardio-graphy or cardiac catheterization), may be present.1,2

HF estimates indicate that about half of HF patientshave HFPEF, and its incidence appears to be on therise. While the number one cause of HFPEF is hyperten-sion, other causes, such as obesity, diabetes mellitus,hyperlipidemia, and atrial fibrillation, are also oftenobserved in HFPEF. Some HFPEF patients will havepreviously had HFREF, and the clinical characteristicsof this group are different from those of patients whohave only ever had HFREF or HFPEF,1,2 highlighting theobvious need for standardization of diagnostic criteriaand, in particular, the choice of EF cut-off levels forthe definition of HFPEF and HFREF.

Acute heart failure

The term “acute heart failure” describes HF symptomsand signs that occur or change suddenly. Episodes ofacute HF are frequently triggered by a cardiac abnor-mality, such as an arrhythmia in HFREF or severe hy-pertension in HFPEF. Despite the “acute” label, theseverity and duration of presenting symptoms varyconsiderably.1,2 Immediate medical attention and urgent hospital admission are required. In the shortterm, the principal objectives are to improve symptomsand stabilize hemodynamic status; in the long term,focus shifts toward the prevention of recurrences andimprovement in prognosis.

EPIDEMIOLOGY OF HEART FAILURE

Globally, nearly 40 million patients have a diagnosisof HF. Global population aging means the burden ofHF is likely to get worse, even in low- to middle-incomecountries where hypertension, obesity, and diabetescaused by sedentary Western lifestyles has begun toimpact population health.5-7 One negative upshot ofthe improved treatment of early cardiovascular diseasein recent years is the increased manifestation of late-

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SELECTED ABBREVIATIONS AND ACRONYMS

ACCF American College of Cardiology Foundation

ACE angiotensin-converting enzyme

AHA American Heart Association

ARB angiotensin receptor blocker

BMMNC bone marrow–derived mononuclear cell

CRT cardiac resynchronization therapy

DPP-4 dipeptidyl peptidase 4

EF ejection fraction

HF heart failure

HFPEF heart failure with preserved ejection fraction

HFREF heart failure with reduced ejection fraction

LVA left ventricular assistance

LVAD left ventricular assistance device

LVEF left ventricular ejection fraction

miRNA microribonucleic acid

MRA mineralocorticoid receptor antagonist

NYHA New York Heart Association

RyR2 type 2 ryanodine receptor

SERC2a sarcoplasmic-endoplasmic reticulum ATPase type 2a

SSRI selective serotonin reuptake inhibitor

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stage cardiovascular disease, like HF. The prevalenceof HF rises with age, growing from 1%-2% in the adultpopulation to ≥10% in those ≥70 years.8 The preva-lence of asymptomatic LV dysfunction (systolic or di-astolic) also rises with age, and estimates vary from6% to 21%. After the age of 40, the lifetime risk forAmericans of developing HF is 20%.1,2

Hypertension, diabetes mellitus, metabolic syndrome,and atherosclerotic disease are all common risk fac-tors for HF. Treatment of risk factors is valuable: anti-hypertensive treatment halves the risk of HF, whiletreatments that target components of metabolic syn-drome—such as diabetes mellitus, hypertension, anddyslipidemia—reduce the risk of developing HF.1,2

Treatments even exist for recently discovered HF riskfactors, such as elevated heart rate.9,10 In the US, theannual expenditure on HF surpasses $30 billion, withover half of these costs spent on hospitalizations.11

Most HF patients (83%) have been hospitalized andmany (43%) have been hospitalized several times (≥4times). Up to 1 in 4 patients hospitalized for HF willbe rehospitalized within 1 month.1,2

CAUSES OF HEART FAILURE

Heart failure is a progressive clinical syndrome withnumerous etiologies. In the ESC-HF Long-Term Registry,a prospective, observational study conducted in 211cardiology centers in 21 European and Mediterraneancountries, ischemic etiology accounted for 43% of thecases in patients with chronic HF.12 Less common, butimportant, causes of HF in order of decreasing preva-lence are cardiomyopathies, infections, particularly viralmyocarditis as well as alcohol, and cytotoxic drugs.

COMORBIDITIES IN HEART FAILURE

Diabetes

A wealth of new findings on HF comorbidities, such asdiabetes, has helped build a new understanding aboutthe relationship between these comorbidities and HF.Diabetes is highly prevalent in HF and its presence islinked with a negative prognosis. Albeit that HF itselfmay lead to insulin resistance through sympatheticnervous system activation, systemic blood flow impair-ment, and skeletal muscle mass reduction and a con-sequential sedentary lifestyle, regulatory agencies today now routinely demand information about thecardiovascular safety of new antidiabetic agents. Whilethe first-line antidiabetic agent metformin is now re-garded to be relatively safe in HF, the safety of other

antidiabetics in HF is a matter of ongoing debate. Inparticular, glitazones and some sulfonylureas may in-crease sodium and water retention and subsequentlymay increase the risk of HF. Similarly, the dipeptidylpeptidase 4 inhibitors (DPP-4) came under scrutinyafter saxagliptin was found to increase HF hospitaliza-tions by 27% without demonstrating other cardiovascu-lar benefits in SAVOR TIMI 53 (Saxagliptin Assessmentof Vascular Outcomes Recorded in patients with dia-betes mellitus–Thrombolysis In Myocardial Infarc-tion).13 Interestingly, another DPP-4 inhibitor, sitagliptin,did not increase HF hospitalizations, but failed todemonstrate cardiovascular benefit. In the EXAMINEtrial (EXAMINation of cardiovascular outcomes withalogliptin vs standard of care in patients with type 2diabetes mellitus and acute coronary syndromE),14

there was a nonsignificant signal for an increased riskof HF with another DPP-4 inhibitor, alogliptin, in dia-betic patients with acute coronary syndrome.15

The TECOS trial (Trial Evaluating Cardiovascular Out-comes with Sitagliptin) showed that the DPP-4 inhibitorsitagliptin did not increase the incidence of HF vs con-trol treatment (HR, 1.00; 95% CI, 0.83-1.20; P=0.98) in14 671 patients with type 2 diabetes mellitus, cardio-vascular disease, and a baseline HbA1c of 6.5% to 8% af-ter 3 years.16 There was no difference (HR, 0.98; 95% CI,0.88-1.09; P<0.001 for noninferiority) in the compositeend point (cardiovascular mortality, nonfatal myocardialinfarction, nonfatal stroke or hospitalization for unsta-ble angina). Taken together, although a DPP-4 inhib-itor class effect can be discounted on the basis of theseresults, ongoing vigilance is warranted for this class.

The recent EMPA-REG OUTCOME trial (EMPAgliflozincardiovascular OUTCOME event trial in type 2 diabetesmellitus patients) analyzed the effects of the sodium-glucose cotransporter 2 inhibitor empagliflozin vs place-bo on the rate of the primary composite cardiovascularoutcome and death from any cause when added tostandard care in patients with type 2 diabetes at highrisk for cardiovascular events.17 After 3.1 years, theprimary end point (death from cardiovascular causes,nonfatal myocardial infarction, or nonfatal stroke)(HR, 0.86; 95% CI, 0.74-0.99; P=0.04) and the second-ary end point (hospitalization for heart failure) (–35%;P=0.002) were significantly reduced empagliflozin.15

Depression

Sertraline did not reduce depression or improve cardiovascular status in HF patients with depressioncompared with placebo in the SADHART-CHF trial



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(Sertraline Against Depression and HeART disease inChronic Heart Failure).18 After 12 weeks, there was nobetween-group difference in the cardiovascular pro-files of patients ([worsened, improved, or unchanged]29.9%, 40.6%, and 29.5% for sertraline vs 31.1%, 43.8%,and 25.1% for placebo [P=0.78]). In HFREF patientswith major depression in the MOOD-HF trial [MOrbidity,mOrtality and mood in Depressed Heart Failure pa-tients],19 escitalopram did not reduce mortality or hos-pitalizations, nor did it reduce depression symptoms,compared with placebo. Selective serotonin reuptakeinhibitor (SSRI) antidepressants should be used inHFREF patients with caution, as in further analyses,mortality and hospitalization improved with escitalo-pram in patients with milder HF, but worsened in thosewith more severe HF. Depression may well be a naturalbyproduct of HF and, with the resolution of HF symp-toms, depression may disappear of its own accord. Itmay already be alleviated by regular patient contact,since depressive symptoms diminished over time withplacebo and SSRIs in both trials.18,19

Dyslipidemia

The CORONA (COntrolled ROsuvastatin in multiNA-tional trial heart failure) and GISSI-HF (Gruppo Italianoper lo Studio della Streptochinasi nell’Infarto miocardi-co-Heart Failure) trials showed that rosuvastatin didnot reduce mortality or coronary events in HFREF pa-tients.20,21 All the patients from CORONA and mostfrom GISSI-HF had HF of ischemic origin. Rosuvastatinlowered the number of repeat HF hospitalizations ina recent reanalysis of CORONA. One explanation isthat cholesterol may counteract the deleterious effectsof endotoxin in HF.

Sleep-disordered breathing

Half of HF patients have sleep-disordered breathing,which includes Cheynes-Stoke respiration, obstructivesleep apnea, and central sleep apnea.22 Central sleepapnea is associated with HF severity, mortality risk,and ventricular arrhythmias.23 A trial of continuous pos-itive airway pressure in central sleep apnea in HFREFpatients found no evidence of outcome benefits,24 soattention turned to adaptive servo-ventilation (ASV).

New findings show, however, that adding ASV to posi-tive airway pressure is detrimental in HFREF patientswith central sleep apnea.25 The SERVE-HF trial (treat-ment of sleep-disordered breathing with predominantcentral sleep apnea with adaptive SERvoVEntilationin patients with chronic Heart Failure) in 1325 patients

with moderate to severe HF, LVEF <45%, and predom-inant central sleep apnea showed that HF patientstreated with an ASV device on top of expiratory posi-tive airway pressure were at a greater risk of cardio-vascular death than control patients (HR, 1.34; 95%CI, 1.09-1.65; P=0.006). There was also a trend towardmore cases of all-cause mortality and HF hospitaliza-tions. Mortality risk increased as HF severity increased.If central sleep apnea is a compensatory mechanism,ASV may cause interference leading to problems. Al-ternatively, in certain sensitive HF patients positiveairway pressure may worsen cardiac function. Phrenicnerve stimulation is currently under investigation as a way of reducing Cheynes-Stokes respiration.

Gout

Uric acid levels are frequently elevated in HF patients,predict outcome, and correlate with gout risk, and ithas been speculated that increased xanthine oxidasemight affect the pathophysiology of HF. However, twostudies in HFREF, EXACT-HF (xanthine oxidase inhi-bition for hyperuricemic heart failure patients) withallopurinol and OPT-CHF (OxyPurinol Therapy for Con-gestive Heart Failure) with oxypurinol,26,27 failed toshow the benefit of xanthine oxidase inhibition on HFoutcomes. In EXACT-HF, treatment with allopurinol didnot improve the clinical status of HF patients comparedwith placebo ([worsened, unchanged and improved]45%, 42%, and 13% for allopurinol vs 46%, 34%, and19% for placebo, respectively; P=0.68) after 24 weeks.

Similar findings were obtained in OPT-CHF: treatmentwith oxypurinol did not improve the clinical status ofHF patients after 24 weeks. One reason may be thatdiminishing uric acid levels reduces a beneficial anti-oxidant effect. Nevertheless, treatment of gout in cer-tain types of HFREF patients may be worthwhile.

Iron deficiency

Intravenous iron improved the symptoms, functionalcapacity, and quality of life of 304 iron-deficient HFREFpatients, regardless of anemic status, in the CONFIRM-HF trial (COmparisoN of the use of FerrIc caRboxy-Maltose with placebo in patients with chronic HeartFailure and iron deficiency), a double-blind, placebo-controlled trial.28 Patients in CONFIRM-HF were ran-domized to treatment with iv ferric carboxymaltose orplacebo for 52 weeks. Intravenous iron also reducedthe risk of hospitalization for worsening HF (HR, 0.39;95% CI, 0.19-0.82; P=0.009). Over a third (40%) of HFREFpatients are iron deficient, and iron deficiency is asso-



12

ciated with increased symptom severity and outcomes.CONFIRM-HF corroborated the results of the FAIR-HFtrial (Ferric carboxymaltose Assessment in patientswith IRon deficiency and chronic Heart Failure).29 Nei-ther study, however, was able to show an effect on mor-tality because of their relatively small sizes.28

PROGNOSIS

HF mortality has declined in the last quarter of a cen-tury from 60%-70% within 5 years of diagnosis to lessthan 50%. Mortality rates after HF hospitalization inthe US in the ARIC study (Atherosclerosis Risk In Com-munities) were 10.4%, 22%, and 42.3% after 30 days, 1 year, and 5 years, respectively.30 Severe HF has a poorprognosis. The 5-year mortality rate of HF patients in-creases with the severity of HF (3%, 4%, 25%, and 80%for stages A, B, C, and D, respectively), with survivaldeclining rapidly in the later stages of HF.31 About 1 in5 patients hospitalized for HF die. Prognosis in HF isinfluenced by age, cause of HF, New York Heart Asso-ciation (NYHA) class, EF, comorbidities (renal, diabetic,anemic, or hyperuricemic), and natriuretic peptide.1,2

Current therapeutic strategies and targets for treating heart failure

Nonpharmacological

Exercise and the multidisciplinary management arerecommended as part of the holistic management ofchronic HF; the former has been shown to improvethe functional capacity and symptoms of HF patients,while the latter has been shown to reduce the risk ofhospitalization for HF.1

TREATMENT OF HFREF

Pharmacological

Modern international HF guidelines provide a robustevidence-based framework to direct prescribing in HF.1,2

Current guideline-recommended pharmacologicaltherapy of HFREF is effective at achieving the objec-tives of both clinicians and patients. For clinicians,these aims include the relief of symptoms and signs,prevention of hospitalization, and mortality reduction.Symptom relief is also important from a patient’s per-spective, but so too are quality of life and functionalcapacity. Indirectly, the pharmacological control of HFrisk factors is relevant and it should not be forgotten.Standard systolic HF treatments that block neurohor-



Table I. Timeline of therapeutic or research developments inheart failure in the late 20th and early 21st century.Abbreviations: ACE, angiotensin-converting enzyme; ARB, angiotensinreceptor blocker; MRA, mineralocorticoid receptor antagonist; RNA, ribonucleic acid.Modified from reference 32: Abraham and Staylor. Medscape Cardiology.© 2002, Medscape LLC.

Era and type of therapy/research

Pre-1980sNonpharmacological

Pharmacological

1980sPharmacological

1990sPharmacological

2000sDevice

2010sNonpharmacological

Pharmacological

Device

Cellular/genetic

Therapy or research

Bed restInactivityFluid restriction

DigitalisDiuretics

VasodilatorNitrateHydralazine

Positive inotropeb-adrenergic agonistPhosphodiesterase inhibitor

Neurohormonal interventionACE inhibitorARBb-BlockerMRA

Cardiac resynchronization therapy

Implantable cardioverter-defibrillator

Left ventricular assistance device

Total artificial heartCardiac reshaping deviceUltrafiltrationHeart valve repair/replacement

Multidisciplinary management

Heart rate reduction (ivabradine)

Dual angiotensin receptor neprilysin inhibition

Implant-based multiparametrictelemonitoring

Chronic vagal stimulationGene therapyCardiac metabolismCalcium cyclingMicroRNACell therapy

13

monal pathways include ACE inhibitors (or angiotensinreceptor blockers [ARBs]), b-blockers, and mineralo-corticoid receptor antagonists (MRAs) (Table I).32 Di-uretics are also regularly prescribed alongside theseto reduce congestive symptoms and signs.1 Betteroutcomes are obtained with higher doses,33-35 but inclinical practice titration to these target doses is chal-lenging. Loop diuretics are popular in HF, but in pa-tients with concomitant hypertension, particularly in-patients with a GFR >40 mL/min, thiazide diureticsmay be more appropriate.

All the main HFREF treatments improve prognosis.ACE inhibitors reduce the risk of death and hospital-ization in all HFREF patients, regardless of the severityof HF symptoms.36 Treatment with b-blockers in HFREFcan markedly improve EF, eliminate symptoms, anddecrease the risks of all-cause mortality and combinedall-cause mortality and hospitalization.37 It appearsbeneficial regardless of coronary artery disease or di-abetic status, race, sex, or treatment with ACE inhib-itors.1 b-Blockers do not, however, improve prognosisin HF patients with atrial fibrillation. A pooled analy-sis comparing b-blockers with placebo in HFREF in 18 254 patients found that b-blockers reduced all-causedeath (by 27%) in HFREF patients in sinus rhythm(n=13 946; HR, 0.73; 95% CI, 0.67-0.80; P<0.001), butnot in those with atrial fibrillation (n=3066; HR, 0.97;95% CI, 0.83-1.14; P=0.73).38

As regards outcome reduction with MRAs, all-causemortality was reduced by 30% (RR, 0.70; 95% CI, 0.60-0.82; P<0.001) after 24 months with spironolactone vsplacebo in 1663 HFREF patients with LVEF <35% inthe RALES study (Randomized ALdactone EvaluationStudy).39 Decreases in sudden cardiac death (RR, 0.71;95% CI, 0.54-0.95; P=0.02) and worsening HF hospital-izations (RR, 0.65; 95% CI, 0.54-0.77; P<0.001) werealso observed in this trial. In a more diverse range ofHFREF patients, eplerenone, another MRA, reducedall-cause mortality, cardiovascular mortality, and HFhospitalization.40,41

Hyperkalemia can be a limiting factor for the use ofMRA blockade in HFREF. Spironolactone and eplere-none can concentrate in the kidney, increasing localconcentrations of potassium. Finerenone, a nonsteroidalMRA distributed more equally in the heart and kidney,increased potassium levels less than spironolactonewith no difference in myocardial wall stress betweenthe two agents.42 Finerenone is also currently beingcompared with eplerenone in a phase 2b study.43 Twoshort-term studies showed that sodium zirconium cy-

closilicate and patiromer reduced elevated potassiumin hyperkalemic patients by binding potassium in thegastrointestinal tract,44,45 but their safety and efficacyin HF still need to be determined.

ACE inhibitors and MRAs (and probably ARBs) areuseful in HF patients with moderate (stage 3) kidneydisease (eGFR, 30-59 mL/min/1.73 m2), while limitedevidence suggests ACE inhibitors and ARBs may beuseful in HF patients with severe kidney disease (eGFR,<30 mL/min/1.73 m2).46 The resolution of venous con-gestion and prevention of HF decompensation by neu-rohormonal blockers helps preserve renal function.

Other treatments in systolic heart failureSome drugs have proven useful for reducing symptomsand/or HF hospitalizations, despite a lack of evidencefor an effect on all-cause mortality.1 The addition ofARBs to standard HF therapy has been shown to re-duce the risk of hospitalization for HF by 24% in theVal-HeFT trial (Valsartan Heart Failure Trial) and 17%in the CHARM-Added trial (Candesartan in Heart fail-ure: Assessment of Reduction in Mortality and morbid-ity–Added),47,48 making ARBs a useful alternative inpatients unable to take an ACE inhibitor. ARBs alsoimproved symptoms and quality of life in CHARM andVal-HeFT.

Heart rate is an independent prognostic factor in HFpatients.9 Ivabradine inhibits the If channel in the sinusnode leading to heart rate reduction in HF patients insinus rhythm. In the SHIFT trial (Systolic Heart failuretreatment with the If inhibitor ivabradine Trial),10 theaddition of ivabradine to standard HF treatment (in-cluding b-blockers) in symptomatic patients with LVEF≤35% and heart rate ≥70 bpm led to a reduction in theprimary composite end point of cardiovascular deathor hospital admission for worsening HF (HR, 0.82; 95%CI, 0.75-0.90; P<0.001) after 22.9 months. Substantialreductions in hospital admission for worsening HF(HR, 0.74; 95% CI, 0.66-0.83; P<0.0001) and HF death(HR 0.74; 95% CI, 0.58-0.94; P=0.014) were importantcontributors to the reduction in the primary end point.

Digoxin can be used in symptomatic HF patients insinus rhythm with LVEF ≤40%.1,49 Although it did notreduce all-cause mortality vs placebo in the DIG trial(Digitalis Investigation Group), it did reduce the riskof hospitalization for worsening HF by 28% (RR, 0.72;95% CI, 0.66-0.79; P<0.001). Digoxin is also a second-line alternative to b-blockers for reducing an elevatedventricular rate in patients with symptomatic HFREFand atrial fibrillation. In African-Americans patients



14

with HF, adding a combination of hydralazine and iso-sorbide dinitrate to standard HF therapy, including ACEinhibitors, b-blockers, and MRAs, not only improvedsymptoms, but reduced morbidity and mortality as well.Nevertheless, concerns about the study size and earlytermination have limited the impact of these results.1

GISSI-HF demonstrated that omega-3 polyunsaturat-ed fatty acids have a slight treatment effect vs placeboon all-cause mortality (adjusted HR, 0.91; 95% CI, 0.83-1.00; P=0.041), but no effect on HF hospitalization.50

Nonrecommended treatmentsCertain treatments cannot be recommended becauseeither there is no proof of benefit or, worse still, out-right proof of harm. Treatment in HFREF with statins,renin inhibitors, and oral anticoagulants lacks proof.Treatment with thiazolidinedione, calcium channelblockers, nonsteroidal anti-inflammatory drugs, andCOX-2 inhibitors, or the addition of an ARB or directrenin inhibitor to treatment with an ACE inhibitor andMRA, should be avoided as they can be harmful.1

Devices

Implantable cardioverter-defibrillatorVentricular arrhythmias (and occasionally bradycardiaand asystole) are responsible for much of the suddendeath of HF patients, in particular those with less se-vere symptoms. Prevention of sudden death, whichaccounts for half of HF deaths, is an important HF ob-jective. Although certain drugs can reduce the risk ofsudden death in HF, they do not eliminate it entirely.Therefore, implantable cardioverter-defibrillators (ICDs)are invaluable for reducing the risk of ventricular ar-rhythmia–related mortality.1

Cardiac resynchronization therapyCardiac resynchronization therapy (CRT) is useful insymptomatic HF patients by enhancing ventricularcontractility, diminishing secondary mitral regurgita-tion, reversing ventricular remodeling, and sustainingimprovement in LVEF. Patients with prolonged QRS(≥150 ms) should receive CRT if they are in sinus rhythm,their LVEF is low (≤30%), and they have a good func-tional status. Evidence for CRT is robust in left bundlebranch block, but less so in right bundle branch block,interventricular conduction delay, or atrial fibrillation.1

Length of QRS prolongation is an important determi-nant of which patients might benefit from CRT. In theEchoCRT trial (ECHOcardiography guided CardiacResynchronization Therapy),51 CRT therapy has been

found to increase all-cause mortality in HFREF pa-tients with a QRS <130 ms and signs of left ventricu-lar dyssynchrony (HR, 1.81; 95% CI, 1.11-2.93; P=0.02);guidelines recommend against using CRT with a QRS<120 ms. A meta-analysis in 3782 HFREF patients hassuggested a QRS cut-off >140 ms,52 a suggestion sup-ported by a subanalysis of EchoCRT that showed CRTwas of no value in patients with a QRS of 120-130 ms.53

A reduction in HF events helped CRT significantly re-duce all-cause death or HF compared with ICD therapyin 1820 patients with mild HFREF (NYHA classes I–II),QRS ≥130 ms, and LVEF ≤30% in the MADIT-CRT trial(Multicenter Automatic Defibrillator ImplantationTrial–Cardiac Resynchronization Therapy) after 2.4years.54 Mortality was significantly reduced by 41% after5.6 years in HFREF patients with left bundle branchblock (adjusted HR, 0.59; 95% CI, 0.43-0.80; P<0.001),but not in those without.55

TREATMENT OF HFPEF

HFPEF is currently treated based on observation andexperience, as there are no treatments that reducemorbidity and mortality in HFPEF.1,2 Drugs that workin HFREF do not necessarily work in HFPEF and, wor-ryingly, the prevalence of HFPEF is increasing. In HF-PEF, the relief of congestion and myocardial ischemiaand the reduction in blood pressure (and ventricularrate in atrial fibrillation) are important objectives. Likein HFREF, diuretics can be used to alleviate breath-lessness and edema. Unlike HFREF, calcium channelblockers that lower heart rate, like verapamil, are usefulin HFPEF by helping relieve symptoms and enhancingexercise capacity. They also decrease raised blood pres-sure, relieve myocardial ischemia, and, like b-block-ers, control ventricular rate in atrial fibrillation patients.Apart from heart-rate–lowering calcium channel block-ers, if a drug is unsuitable in HFREF it is also unsuit-able in HFPEF.1 Nonpharmacological treatment ap-proaches should not be ignored, as exercise and weightcontrol can improve diastolic function and physicalperformance in HFPEF patients.

As mentioned above, therapies shown to be of benefitin HFREF have failed to do the same in HFPEF, includ-ing ARBs, ACE inhibitors, and most recently MRAs.Treatment with spironolactone was unable to reducethe primary end point of cardiovascular death, HFhospitalization, and aborted cardiac arrest vs placebo(HR, 0.89; 95% CI, 0.77-1.04; P=0.14) in 3445 HFPEFpatients over 3.3 years in the TOPCAT trial (TreatmentOf Preserved CArdiac funcTion heart failure with an



15

aldosterone antagonist).56 A component of the pri-mary end point, HF hospitalization, was reduced withspironolactone (HR, 0.83; 95% CI, 0.69-0.99; P=0.04).The results do not preclude the possibility that spiro-nolactone may be useful in HF patients with mildlyreduced ejection fraction.

Combining treatments is no guarantee of reducingoutcomes in HFPEF either. When an ARB was addedto treatment with ACE inhibitors and/or b-blockers inHFPEF patients in the SUPPORT trial (SUPPlementalbenefit of an angiotensin receptor blocker in hyperten-sive patients with stable heart failure using Olme-saRTan),57 cardiovascular risk and the risk of renal dys-function increased. In this trial, the ARB olmesartanwas added to ACE inhibitors, b-blockers, or both. Meanejection fraction was 54% in the 1147 patients enrolled.The primary end point (all-cause death, nonfatal myo-cardial infarction, nonfatal stroke, and hospitalizationfor worsening HF) did not differ significantly (HR, 1.18;95% CI, 0.96-1.46; P=0.11). Outcomes were worse whenolmesartan was added to patients on both ACE inhib-itors and b-blockers: the primary end point (HR, 1.47;95% CI, 1.11-1.95; P=0.006), all-cause death (HR, 1.50;95% CI, 1.01-2.23; P=0.046), and renal dysfunction(HR, 1.85; 95% CI, 1.24-2.76; P=0.003) all increased.15

Success has also eluded other approaches to the treat-ment of HFPEF. In HFPEF, decreased bioavailability ofnitric oxide leads to decreased cyclic guanosine mono-phosphate (cGMP) levels in myocytes. The RELAXstudy (SeRELAXin in acute heart failure patients withpreserved left ventricular ejection fraction) was unableto show any benefit of treatment with the phosphodi-esterase type 5 inhibitor sildenafil in 216 elderly HFPEFpatients compared with placebo.58 No improvementwas observed in maximal exercise capacity (P=0.90),6-minute walking distance (P=0.92), clinical status(P=0.85), quality of life, left ventricular remodeling, ordiastolic function after 24 weeks of follow-up.15 Anoth-er study that compared sildenafil with placebo in 52patients with HFPEF and pulmonary hypertension failedto find a difference in pulmonary artery pressure, theprimary end point (–2.4 vs -4.7 mm Hg; P=0.14), orother invasive hemodynamic or clinical parameters af-ter 12 weeks.59 Some treatment benefits were obtainedusing a different approach focusing on cGMP produc-tion rather than preventing degradation. Althoughtreatment with soluble guanosine cyclase stimulatorriociguat did not reduce mean pulmonary artery pres-sure vs placebo in 21 HFPEF patients (P=0.6), it didimprove other hemodynamic and echocardiographicparameters like stroke volume (+9 mL; 95% CI, 0.4-17;

P=0.04), systolic blood pressure (–12 mm Hg; 95% CI,–22 to –1; P=0.03), and right ventricular end diastolicarea (–5.6 cm2; 95% CI, –11 to –0.3; P=0.04).60

It is now becoming clearer just how different HFPEFand HFREF are. Studies that help improve our under-standing of its pathophysiology and that give us aclearer idea of the phenotype of HFPEF patients arevital next steps. Coronary artery disease and mechan-ical dyssynchrony, for example, are found more com-monly in HFPEF patients than the general popula-tion. The need for better characterization of different HFPEF phenotypes was illustrated by the differencein primary end point reduction between HFPEF pa-tients from the Americas and those from Georgia andRussia in TOPCAT.56,61 Specific HFPEF diagnostic cri-teria are urgently needed.

TREATMENT OF ACUTE HEART FAILURE

Abnormal blood pressure, dyspnea, and hypoxemiaare key medical challenges during an acute episode ofHF and, as such, vasodilators, diuretics, and oxygenare key treatments. Due to its nature, diagnostic in-vestigation of acute HF often occurs at the same timeas treatment. Regular monitoring of systolic bloodpressure, heart rate, heart rhythm, oxygen saturation,and urine output is recommended in patients whohave not been stabilized.1,2

The treatment of abnormal blood pressure depends onwhether blood pressure is high or low. In hypertension,vasodilators, such as nitroglycerin and diuretics, areuseful; in hypotension, vasopressors (eg, noradrena-lin) or inotropes (eg, dobutamine) may be appropriate.Dopamine is an inotrope and has vasoconstrictiveproperties when used at a high dose (5 mg/kg/min).

Intravenous diuretics and the human brain natriureticpeptide nesiritide reduce dyspnea caused by pulmonaryedema. Diuretic dose appears not to affect HF symp-toms or serum creatinine, but a high-dose diureticmay be more effective than a low-dose diuretic at re-ducing dyspnea, although this is associated with anincrease in transient worsening renal function. In resist-ant peripheral edema, combination diuretic therapywith a loop diuretic and thiazide-like or thiazide-typediuretic may be required for a greater diuretic effect.Opiates are valuable for reducing dyspnea-inducedpatient anxiety and may, in addition, have a beneficialvenodilatory effect. Another option in dyspneic patientsis noninvasive ventilation. If breathing difficulties are



severe (eg, respiratory failure), then invasive or endo-tracheal intubation should be considered. Hypoxemia,which is associated with a greater risk of short-termmortality, can be alleviated with oxygen.1,2

In HFREF patients who are not already on standardHF treatments (ie, ARBs, b-blockers, and MRAs), thenthese should be initiated following stabilization ofacute HF. Digoxin can be given to HFREF patients withatrial fibrillation and uncontrolled ventricular rate.1

The risk of thromboembolism can be mitigated withanticoagulants, and low blood sodium levels treatedwith the selective, competitive vasopressin receptor 2antagonist tolvaptan.

Several other measures are available in acute HF inaddition to pharmacological management. If associat-ed with hypervolemia, the restriction of dietary sodiumto <2 g/day and fluid to <1.5 to 2.0 L/day is beneficial.Venovenous isolated ultrafiltration can also eliminateexcess fluid, particularly in diuretic-resistant patients.Where mechanical circulatory support is needed, intra-aortic balloon pumps are helpful in certain types ofcardiogenic shock or as a short-term solution until aventricular assist device is implanted.1,2

New therapeutic strategiesand targets for treating

heart failure

The latest developments in HF therapy or researchcover a wide range of categories, including nonphar-macological, pharmacological, device, and cellular biology/genetics (Table I).32

Dual angiotensin receptor and neprilysin inhibition

Excellent results from the PARADIGM-HF trial (Prospec-tive comparison of ARNI with ACE inhibitor to Deter-mine Impact on Global Mortality and morbidity inHeart Failure),62 which compared dual angiotensin receptor neprilysin inhibition with ACE inhibition inHFREF, led to the early termination of this trial. LCZ696,a combination of the ARB valsartan and the neprilysininhibitor sacubitril, reduced a composite of deathfrom cardiovascular causes or hospitalization for HFby 20% (HR, 0.80; 95% CI, 0.73-0.87; P<0.001) in 8442patients with HFREF vs the ACE inhibitor enalapril, agrade 1A guideline-recommended drug. All-cause mor-tality was reduced by 16% (HR, 0.84; 95% CI, 0.76-0.93;P<0.001). LCZ696 was well tolerated, and unlike thecombined ACE inhibitor/neprilysin inhibitor omapatrilat,

there was no significant increase in angioedema. Symp-tomatic hypotension was more frequently observedwith LCZ696, but worsening renal function less so. Thisis the first time in nearly 30 years that a drug performedbetter than enalapril in HF in the CONSENSUS study(COoperative North Scandinavian ENalapril SUrvivalStudy).63 The morbidity-mortality trial PARAGON-HF(efficacy and safety of LCZ696 compared to valsartan,on morbidity and mortality in HF patients with pre-served ejection fraction; NCT01920711) is ongoing todetermine the effect of LCZ696 in HFPEF.

Hormone therapy in acute heart failure

After many years in which there have been few con-crete developments in acute HF, there are good signsof progress. Serelaxin, a recombinant form of the hu-man vasoactive hormone relaxin-2 that prevents inflam-mation and fibrosis, causes vasodilation, and promotesangiogenesis, relieved dyspnea and reduced cardio-vascular mortality in 1161 acute HF patients in thephase 3 study RELAX-AHF.64 Serelaxin was associatedwith a significant reduction in mortality at day 180, butnot HF readmissions.

A follow-up study with a primary end point of cardio-vascular mortality in 6375 acute HF patients, RELAX-AHF 2 (EudraCT No. 2013-001498-25), will help deter-mine whether serelaxin is the first treatment to lowerthe risk of long-term mortality in acute HF. Other stud-ies have shown that, in acute HF, serelaxin can reducepulmonary capillary wedge pressure, is similarly effec-tive in HFREF and HFPEF, and is associated with lessdiuretic use.

Another study, TRUE-AHF (efficacy and safety of ulari-tide for the TReatment of acUtE decompensAted HeartFailure; NCT01661634), is investigating whether ulari-tide, a chemically synthesized form of the hormoneurodilatin that causes diuresis by increasing bloodflow in the kidney, is of value in acute HF. In preclinicalstudies, ularitide has been shown to have congestion-relieving and diuretic and kidney function–preservingproperties.61

.

Cardiac metabolism

Interest is reemerging in therapies that restore cardiacmetabolism in HF. A recent trial in 420 patients withmoderate-to-severe HF, the Q-SYMBIO trial (coen-zyme Q10 as adjunctive treatment of chronic HF: arandomized, double-blind, multicenter trial with fo-

16



cus on SYMptoms, BIomarker status [brain-natriureticpeptide], and long-term Outcome [hospitalizations/mortality]),65 has shown that, compared with placebo,coenzyme Q10 (100 mg tds) reduced mortality (all-cause [P=0.018] and cardiovascular [P=0.026]), HFhospitalizations (P=0.033), and NYHA class (P=0.028)after 2 years. The addition of coenzyme Q10 to stan-dard HF therapy reduced the risk of major adverse car-diovascular events by half (HR, 0.50; 95% CI, 0.32-0.80;P=0.003). Previously, studies had been too small anddiverse to draw firm conclusions about the morbidity-mortality benefits of coenzyme Q10.

A characteristic of HF is mitochondrial dysfunction,which can be caused by decreased cardiolipin.66 Car-diolipin, a mitochondrial membrane lipid, maintainsenergy production by maintaining the proper functionof the electron transport chain. A phase 2 HF study ofa tetrapeptide that binds to cardiolipin and reestab-lishes the function of the electron transport chain,Bendavia, is currently ongoing.67

Calcium cycling

Disruption of calcium cycling in cardiomyocytes, whichis essential for cardiac contraction and relaxation, maycause HF. Contraction is caused by an increase in in-tracytoplasmic calcium via the influx of calcium ionsthrough type 2 ryanodine receptors (RyR2), largetetrameric protein complexes.68,69 In cardiac relaxation,the sarcoplasmic-endoplasmic reticulum ATPase type2a (SERCA2a) pumps calcium ions back into the sar-coplasmic reticulum, which induces cardiomyocyterelaxation.69 Restoration of disrupted RyR2 or SERCA2acould, in theory, improve cardiac contraction and relaxation and thus HF symptoms.70 Other potentialcalcium-related therapeutic targets in HF include in-tracellular calcium-binding proteins, such as S100A,CaMKII, and PKA.

Another approach is to sensitize cardiac myosin to cal-cium to improve cardiac function in HFREF patients,and some progress has been made with this approach.Via increased activation of actin-myosin cross bridges,omecamtiv mecarbil increased stroke volume by pro-longing the duration of systolic ejection in a phase 2clinical trial in HFREF.71

Gene therapy

It is hoped that one day the replacement of faulty genesby undamaged, viral vector-delivered genes might cor-rect HF defects at a molecular level.69 The insertion of

the SERCA2a gene into isolated cardiomyocytes ob-tained from HFREF patients led to an improvement inmyocardial contractility in preclinical studies.72 Posi-tive phase 1 safety results led to the CUPID trial (Cal-cium Upregulation by Percutaneous administration ofgene therapy In cardiac Disease), a phase 2 random-ized, double-blind, placebo-controlled, dose-rangingstudy in 39 patients with advanced HFREF.73 Vector-delivered SERCA2a (intracoronary infusion of recom-binant adeno-associated virus serotype 1) reducedthe risk of prespecified recurrent cardiovascular eventsby 82% with high-dose treatment vs placebo after 3years (P=0.048), and no safety concerns were report-ed.61 Unfortunately, in CUPID 2 (NCT01643330), thephase 2b follow-up study in 243 patients with severeHF, transgene treatment did not reduce the primaryend point (recurrent HF hospitalizations and ambula-tory worsening HF in the presence of terminal events,including all-cause death or transplant) vs placebo(HR, 0.93; 95% CI, 0.53-1.65; P=0.81) or any secondaryend point. No safety issues were highlighted. Transgenedose, injection pathway, effect duration, and inade-quate vector, promoter, or target were cited as poten-tial reasons for failure.15

Other gene therapy targets associated with abnormalcalcium cycling that have been investigated includephospholamban (isolated failing human cardiomyocytesand sheep models) and S100A131 (isolated failinghuman cardiomyocytes and post–myocardial infarctionporcine HF model). Additional gene therapy HF targetsinclude b-adrenergic receptors (downregulated in HF),G protein–coupled receptor kinase 2 (GRK2, overex-pressed in HF), and b-adrenergic receptor kinases.69

MicroRNAs

MicroRNAs (miRNAs) are small noncoding RNA seg-ments that regulate gene transcription and proteinformation by silencing messenger RNA. Preclinical research into miRNAs has shown the influence thesemolecules have in calcium cycling, ventricular hyper-trophy, and HF.69,74 Genetic knockout and the use ofantagomirs, chemically engineered oligonucleotideantagonists of miRNAs, have allowed the function ofmiRNAs to be pinpointed. MiRNA25 prolongs calciumuptake in cardiomyocytes and is upregulated in HF. In-jection of miRNA25 antagomir reversed HF in a mousemodel. HF therapy could change the expression ofmiRNAs in the myocardium. Some miRNAs promotehypertrophy (miRNAs 23a, 208, and 499), while othersinhibit it (miRNAs 1, 9, 98, 133, and 378). Additionally,miRNAs might make useful biomarkers.

17



Cell therapy

Cardiomyocytes present an interesting therapeutic so-lution in HF at a cellular level. HF could be improvedby the implantation of stem cells into injured heartsto regenerate myocardium and improve cardiac func-tion. Allogeneic embryonic stem cells can differentiateinto cardiomyocytes,75 but immune suppression is re-quired to avoid rejection, risk of teratoma increases,and ethical considerations are fundamental. Inducedpluripotent stem cells can be generated from adultsomatic cells using specific transcription factors, andthese too can differentiate into cardiomyocytes.76

Ethical issues are bypassed, but the risk of teratomaremains. Research is also looking into how to programcardiac fibroblasts directly into cardiomyocytes.69

Bone marrow contains different stem cells and is nothard to acquire. Secretion of growth factors, cytokines,chemokines, and the induction of new capillaries byunfractionated autologous bone marrow-derived mono-nuclear cells (BMMNCs) appears to account for theirclinical efficacy.75,77 Results of BMMNC trials are mixed,but a large meta-analysis of 2625 patients with is-chemic heart disease showed that those who receivedBMMNCs had a statistically higher left ventricular ejec-tion fraction of 4.0% (95% CI, 2.90-5.02%; P<0.00001)than controls.78 In addition, infarct size, LV end-systolicvolume, and LV end-diastolic volume were smaller for bone marrow cell–treated patients (all P<0.0001). The first phase 3 trial of BMMNC cell therapy in acutemyocardial infarction (NCT01569178) is recruitingparticipants.

Unfractionated BMMNCs also contain mesenchymalstem cells, which can differentiate into cardiomyocytesin animal models.69 The efficacy of mesenchymal stemcells, which are hypoimmunogenic and release antifi-brotic matrix metalloproteinases, has been observedin animal HF models.79 Enrichment of mesenchymalstem cells with stromal antigens leads to improved cel-lular regeneration and grafting. Lately, the impact onmyocardial recovery of injection of allogeneic mesen-chymal stem cells during implantation of left ventricu-lar assistance devices (LVADs) was tested in 30 patientswith advanced HF.80 Adipose tissue-derived stem cellscan also differentiate into cardiomyocytes. Liposuctionto obtain these cells is less invasive than bone mar-row aspiration. In animal HF and myocardial infarctionmodels, they appear to be better than BMMNCs.

The efficacy of transplanting autologous cardiac stemcells together with fibroblastic growth factors in pa-

tients with ischemic cardiomyopathy and severe HF isbeing investigated in the ALCADIA trial (AutoLogoushuman CArdiac-Derived stem cell to treat IschemiccArdiomyopathy; NCT00981006). Another developmentinvolving cardiac stem cells is cardiospheres, a mixtureof cardiac stem cells, mesenchymal stem cells, andendothelial cells that grow in self-adherent clusters.81

Allogeneic cardiosphere–derived cells in patients postmyocardial infarction with left ventricular dysfunctionare under investigation in the ALLSTAR trial (ALLogeneicheart STem cells to Achieve myocardial Regeneration;NCT01458405), a placebo-controlled safety and effica-cy trial.69

The best cell type, processing method, and administra-tion route, dose, and timing remain to be determined,but currently mesenchymal stem cells and cardiacstem cells are leading the race as the best cell candi-dates. Other avenues being explored with cell therapyinclude genetically enhancing the regenerative capac-ity using allogeneic cells and the transfer of geneticmaterial into transplanted cells.69

Technology in heart failure

Left ventricular assistance devicesAs with other medical conditions, technological ad-vances look set to revolutionize the realm of HF throughpositive, new developments in LVADs, implant-basedmultiparameter telemonitoring, and chronic vagalstimulation.69 LVADs have come a long way since theywere first used to provide short-term assistance topatients in cardiogenic shock secondary to acute my-ocardial infarction, cardiotomy, or acute myocarditis.Improvements have been occurring regularly eversince, ie, miniaturization, portability, better reliability,change from pulsatile to continuous flow, and longerbattery life. Totally implanted wireless LVADs couldbe next. This led to the use of LVADs in the mediumterm as a bridge to cardiac transplantation and then,following the REMATCH study (Randomized Evalua-tion of Mechanical Assistance for the Treatment ofCongestive Heart failure),82 to their long-term use asdestination therapy in critically ill patients with ad-vanced HF ineligible for transplantation.

The other common indications for long-term LVA areas an extended bridge to cardiac transplantation (inend-stage HF patients) and bridge to decision (in crit-ically ill patients). In the US, the number of patientsusing LVADs over the long term is converging with thenumber of cardiac transplantations.69

18



19

Three out of four advanced HF patients treated with anLVAD will still be alive after 2 years.83 It is, however,worth noting that LVADs are not risk-free; biventriculardevices for right ventricular failure are associated withincreased mortality rates and bleeding risk is elevatedbecause of the requirement for constant anticoagula-tion. Other difficulties associated with LVAD use in-clude infection, stroke, and thrombosis.

Treatment with LVA can lead to reverse remodeling—typified by a reduction in cardiac chamber size andmyocyte hypertrophy regression—and reductions inpreload and afterload.84,85 In some cases, LVAD canserve as a bridge to myocardial recovery,86 when a deteriorating heart stabilizes and then recuperates al-lowing it to circulate blood normally again. A regime ofintensive pharmacological therapy can aid the processof myocardial recovery with LVAD.87 Device removal(explantation) and recovery is most likely to occur ina patient <50 years old, with no more than one HFevent in 1 year caused by idiopathic dilated cardiomy-opathy or myocarditis rather than ischemic cardiomy-opathy. It has, however, been speculated that the ad-dition of revascularization to pharmacotherapy andLVAD could lead to myocardial recovery in patientswith ischemic cardiomyopathy in nonadvanced HFwithout irreversible myocardial damage.88 Adjunctivecell-based therapy may also have a role to play here.The prospect of myocardial recovery with LVA maysignal the beginning of a change in our perception ofadvanced HF as irreversible.69

Implant-based multiparameter telemonitoringImplant-based multiparameter telemonitoring is apromising new technology to improve outcomes inHFREF. In a recent randomized clinical trial of telemon-itoring in 664 HFREF patients with a recently implant-ed ICD or CRT-D,89 the primary composite outcome(clinical score combining all-cause death, overnightHF hospital admission, change in NYHA class, andchange in patient global self-assessment) worsened lessin the telemonitoring group than the control group af-ter 1 year (18.9% vs 27.2%; OR, 0.63; 95% CI, 0.43-0.90;P=0.013). With appropriate data-management proto-cols in place, telemonitoring provides a potential meansof further reducing outcomes in HFREF patients im-planted with an ICD or CRT-D. As not all previousstudy results have indicated this, consistent reportingof the benefits of remote monitoring is required be-fore this technology becomes more widely accepted.61

Chronic vagal stimulationDirect vagal nerve stimulation could be used to en-hance parasympathetic tone in HF, but it is still tooearly to conclusively say how useful this technique willbe in HF. Quality of life measures were significantlyimproved by vagal nerve stimulation after 6 months vscontrol in the NECTAR-HF trial (NEural Cardiac Ther-Apy foR Heart Failure),90 but the primary end point ofchange in left ventricular end systolic diameter wasnot (–0.04±0.25 cm vs –0.08±0.32 cm for stimulationvs control). More information is expected from forth-coming studies in the next few years.61

CONCLUSION

HF is a disease of our times: as populations in devel-oped nations age, chronic HF and HFPEF in particularwill become more prevalent, putting further strain oncurrent healthcare systems in terms of increased mor-bidity, mortality, and costs. Nevertheless, thanks to ad-vances in HF therapy and management, the prognosisof patients with HF is better than it once was. Our un-derstanding of HF has never been so good, but as al-ways there is room for improvement. A better under-standing of the pathophysiology of HFPEF and of waysof recognizing HFPEF phenotypes will be particularlyuseful for finding ways other than antihypertensivetherapy to manage and treat HFPEF.

Progress has also been made in the areas of HFREFand acute HF. Heart rate has been identified as a prog-nostic factor in HFREF, and ivabradine has provided a new way of reducing HFREF outcomes further. Theangiotensin receptor–neprilysin inhibitor valsartan/sacubitril also promises to further improve outcomesin HFREF.

A lot of research is going into the impact of comor-bidities on HF and into new ways of treating these.Research is also looking into novel ways of treatingHF, such as by targeting cardiac metabolism or calciumcycling. A modern-day technological revolution hasallowed us to envisage replacing cardiomyocytes usinggene therapy, miRNA, and cell therapy. This revolutionis not only biological and genetic, but electronic too.Advances in LVAD technology have allowed us to begin dreaming of myocardial recovery as a realistictreatment objective in advanced HF. The future of HFtreatment and management is full of possibilities, andinnovation is the watchword.



(See references on next page)

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Gene therapy for heart failure: the end of the beginning?A. C. Morley-Smith, C. Hayward,

S. E. Harding, A. R. Lyon

What is the role of telemonitoring in heart failure?M. R. Cowie

Expert Answers to Three Key Questions

What is the role of the heart failure nurse?J. P. Riley

1

2

3


eart failure continues toincrease in prevalence andnow affects millions of peo-ple throughout the world.

Despite enormous advances, thoseaffected remain at an increased riskof a reduced quality of life. Patientshave repeated hospital admissionsand many die prematurely. The de-veloping evidence base for medica-tions and implantable devices hascontributed to an improvement inoutcomes; however, these techno-logical advances carry an increasedrisk of adverse events and increasethe “burden” of self-care. In addi-tion, there is a growing populationof elderly and frail patients withcomorbid conditions.

This all adds to the complexity ofpatient management. In many coun-tries, this has led people to recon-sider both the way in which heartfailure services are organized andthe delivery of structured outpatientmonitoring and follow-up. Theboundaries of traditional and pro-fessional health care roles are chang-ing and heart failure nurses now pro-vide a range of health care services.

Nurses’ roles and responsibilitiesdiffer throughout Europe. This vari-ation largely relates to the legisla-tive framework within which healthcare professionals work. However,it is likely that local “customs andpractices” have also defined theroles of members of the heart fail-ure team. This paper acknowledgesthese wide variations and role di-versities. Yet, it also acknowledgesthat the role of the nurse within theheart failure team can transformthe patient’s experience through afocus that goes beyond the biomed-ical approach and considers thepsychological and social influenceson illness and outcome. Startingwith a discussion of the traditionalrole for the nurse in the manage-ment of chronic heart failure disease,this paper discusses some of thenewer areas where the heart failurenurse is establishing a role, eg, mon-itoring during an acute inpatientepisode, preventing heart failure,and managing care at the end oflife (Table I). The paper concludesby describing the education andsupport necessary to strengthenthis role development.

H

27Copyright © 2016, AICH - Servier Research Group. All rights reserved www.dialogues-cvm.org


The specialized role of the heartfailure nurse rose to prominenceduring the 1990s. Studies reportedbenefits in outcomes in patients receiving follow-up care by a multi-disciplinary care team and in whichnurses were key players. Since then,the nurse’s contribution through-out the journey of the heart failurepatient has become widely recog-nized. In many countries, heartfailure nurses are now establishingtheir role in optimizing outcomesduring admission for acute heartfailure, routine follow-up and mon-itoring, and at the end of life.Recent interest in service develop-ment for the prevention of heartfailure opens up newer avenues fornurses. This paper considers thecontribution of the nurse to an effective heart failure service anddiscusses the value of a “task shar-ing” approach to care.

Keywords: acute heart failure; diseasemanagement; heart failure; nurse-led care;patient education Address for correspondence:Jillian Riley, National Heart & LungInstitute, Imperial College, DovehouseStreet, London SW3 6NP, UK(e-mail: [email protected])Dialogues Cardiovasc Med. 2016;21:27-34

What is the role of the heart failure nurse?Jillian P. Riley, PhD, RN, NFESC

National Heart & Lung Institute - Imperial College - London - UK

Alleviate distressing symptoms (physical and emotional)

Optimize evidence-based heart failure management (medication and self-care support)

Monitor and recognize effectiveness of treatment

Triage to safe environment for care

Provide patients and their family with information, education, and support

Ensure prompt communication between the patient/family and the health care professional

Provide end-of-life care

Table I. Roles and responsibilities of heart failure nurses.

HEART FAILURE DISEASE MANAGEMENT

PROGRAMS

Organization of care

Emphasis for the majority of workin the management of chronic dis-ease has been on the organizationof care to ensure a “seamless serv-ice” between hospital and homeand help the patient live with theirillness. Early studies on approachesto the management of heart failureled the way for this reorganizationof care, allowing nurses to quicklyestablish a position within heartfailure management programs tomonitor for clinical deterioration,optimize medication, and provideeducation and support for self-care.These early studies demonstratedthe effectiveness of heart failuremanagement programs, and theseresults have been confirmed througha meta-analysis that reported a re-duction in the risk of hospital read-mission for heart failure (risk ratio[RR], 0.74; 95% CI, 0.63-0.87), all-cause hospital admission (RR, 0.81;95% CI, 0.71-0.92), and mortality(RR, 0.75; 95% CI, 0.59-0.96) in pa-tients who received structured fol-low-up by a specialized heart fail-ure team.1 Within these programs,nurses primarily managed patientcare through regular follow-up vis-its in either a heart failure clinic orat the patient’s home.

Various follow-up models now ex-ist. These include face-to-face andremote approaches. Local need andexpertise will influence the way inwhich individual services are organ-ized. However, patients are likely tobenefit from different approachesat varying time points in their dis-ease trajectory. For example, homevisits may be particularly usefulsoon after hospital discharge for theelderly or for those with functionallimitations that make traveling to

the hospital or clinic problematic.Home visits may be time consum-ing for health care professionals,especially regarding travel time;therefore, this may limit the num-ber of patients who are able to receive this level of care. Remotemonitoring and follow-up usingtelephone contact or a specializedtelemonitoring program may pro-vide a suitable alternative.

A Cochrane meta-analysis of ran-domized studies of remote monitor-ing in patients at a high risk of re-hospitalization reports a reductionin the risk of heart failure–relatedhospital admission with both tele-phone follow-up and telemonitor-ing (telephone [RR, 0.77; 95% CI,0.68-0.87; P<0.0001] and telemoni-toring [RR, 0.79; 95% CI, 0.67-0.94;P=0.008]). A significant reductionin all-cause mortality was observedwith telemonitoring (RR, 0.66; 95%CI, 0.54- 0.81; P<0.0001), whereasthere was a nonsignificant reductionusing telephone follow-up support(RR, 0.88; 95% CI, 0.76-1.01; P=0.08).2

These findings have been challengedby two recent and large studies.The first study was conducted in a stable, lower-risk patient group,where telemonitoring data were re-viewed and responded to by physi-

cians in a telemonitoring call cen-ter,3 and the second study was atelephone-based interactive system,where almost 50% of the sampledid not use the equipment for theentire study.4 Remote monitoringhas a useful role in widening accessto care, which may be particularlyvaluable to patients living in remoteareas. The substantial increase inpatients with heart failure that ispredicted for the next decade showsthat the development of sustainableservices for follow-up is needed;something that may be aided byremote monitoring. In many remotemonitoring services, nurses play acentral role in regularly reviewingthe data, triaging patients for earlyfollow-up through a home visit oroutpatient review, answering pa-tient or family queries, and helpingthe patient develop self-care skills.5

Although patients are likely to ben-efit from contact with a heart fail-ure team soon after discharge fromthe hospital (preferably within 10 days), the follow-up frequencyshould be tailored to an individ-ual’s needs. The physician can usethis appointment to assess the pa-tient and discuss current and futuretreatment options and prognosiswith the patient. The heart failurenurse can reinforce information onheart failure management, answerpatient and family questions, iden-tify and manage early anxieties,and help the patient develop self-care skills. However, outlining professional responsibilities in thisway is artificial and an effectiveheart failure team will ideally work together to ensure that all goals ofthe first outpatient review are ad-dressed.

The level of care that is offered inmultiprofessional disease manage-ment programs is now recognized ininternational guidelines.6 Extend-ing this, and acknowledging the

28


What is the role of the heart failure nurse? - Riley

SELECTED ABBREVIATIONSAND ACRONYMS

COMET Carvedilol Or Meto-prolol European Trial

NIL-CHF Nurse-led Interventionfor Less Chronic Heart Failure [study]

PAL-HF PALliative care in Heart Failure [study]

PREFER Palliative advanced home caRE and heartFailurE caRe [study]

STOP-HF Screening TO Prevent Heart Failure [study]

clear value of a heart failure nursewithin the team, the Heart FailureAssociation of the European Socie-ty of Cardiology has suggested thateach acute hospital have 1 heartfailure nurse for every 100 000 peo-ple.7 Disease management programsare now established in many Euro-pean countries. A recent survey of33 countries of the European Soci-ety of Cardiology reports that heartfailure clinics are present in 25 coun-tries (75%).8 Encouragingly, thisrepresents an increase from an ear-lier survey.

However, there are variations inthe structure of these clinics andthe heart failure nurse is involvedin only 18 of the 25 countries withheart failure clinics (72%). Thesedata are limited by their method ofdata collection, but suggest thatmany patients may still not be ableto access high-quality heart failurecare provided by a multidiscipli-nary team.

MONITORING

Monitoring is a key component ofheart failure management programs.International guidelines have yet toprovide recommendations on keymonitoring parameters, somethingthat may be related to the limitedevidence on the topic. Despite this,it appears intuitive to regularly mon-itor heart failure symptoms, fluidvolume status, hemodynamic val-ues, laboratory blood tests, and self-care understanding (Table II). Localguidelines may provide some clarity(eg, in England, monitoring is rec-ommended at intervals of 6 and 12months for stable patients).9 Morefrequent monitoring will be neces-sary during periods of therapy opti-mization, immediately followinghospital admission for worseningheart failure, or during periods ofdeteriorating symptoms.10 The spe-cialist heart failure nurse’s focus is

on the routine monitoring of stablepatients, checking for side effectsof medication during periods of op-timization, and reviewing barriersto self-care.

Medication

The evidence for heart failure med-ication is strong. Many of thesedrugs are started at low doses andthen steadily increased, which re-quires careful patient monitoringfor both drug and adverse effects.Patients do not necessarily achievethe target dose quickly and somenever do.11 A multidisciplinary teamapproach may help. For many years,nurses have worked within clinicalprotocols to optimize medication.Such protocols outline good prac-tice advice for the management ofcommon heart failure medications,guide the nurse on when to meas-

ure blood chemistry, and outlinethe changes in blood chemistry andvital signs that necessitate referralto a physician and those values thatare considered safe for uptitration.6

Within the UK, the nurse’s contri-bution to optimal medication hasbeen extended further. In 2006,changes in the law enabled inde-pendent nonmedical prescribing.12

Following a period of additionaleducation and mentoring, nursescan independently prescribe med-ication, and therefore, play a moreautonomous role within the heartfailure management team. This pro-cess has gained acceptance amongprofessionals and patients and hasbeen positively evaluated for pro-viding safe and timely care.13 A doc-umented evaluation of nurse pre-scribing has confirmed that nursesappropriately prescribe medica-tions.14 Patients were satisfied withnurse prescribing and reported nodifference between nurse prescribersand physicians in the quality ofcare, the information they received,or support for self-care.15 Althoughthe results from a more robustevaluation are still awaited, suchstudies point to the safety and qual-ity of care that can be provided bywidening the “pool” of health careprofessionals, with the responsibili-ty of safely prescribing medications.

Self-care support

If indicators of worsening heartfailure are recognized and managedearly, it may be possible to preventsome hospital admissions. Self-carerequires patients to monitor theircondition, recognize significantchanges, and take appropriate ac-tions. Breathlessness commonlytriggers patients to seek profession-al help. However, delays in present-ing to a health care professionalcan be lengthy with patients onlyseeking professional help when their

29



Clinical assessment

Review of medication

Laboratory tests

Self-care ability

Devices

Signs and symptoms

Functional capacity

Fluid statusCardiac rhythmCognitive statusNutritional status

DoseSide effectsMedication recall

Urea and electrolytes

CreatinineHemoglobin

KnowledgeBarriers to

self-care Anxiety and

depressionCognitive function

Patient understanding

SymptomsAdverse events

Table II. Key monitoring undertaken byheart failure nurses during follow-up.

symptoms become intolerable.16

Various reasons for such delayshave been described with studiesreporting difficulty accessing healthcare, limited self-care information,and uncertainty over when to seekprofessional help.17,18

Other important aspects of self-carebehavior include lifestyle behav-iors and adherence to medication,yet adherence is an acknowledgedproblem. Again, there are probablyseveral explanations, including so-cial and economic reasons thatleave prescriptions unfilled. Patientsmay have limited knowledge or maysimply forget, and some patients

will deliberately decide not to taketheir medication due to their con-cerns about both the drug and sideeffects.19 Wide variation in patients’adherence with lifestyle advice andself-care behaviors is not surpris-ing. For example, in 2007, the Euro-Heart Failure Survey reported thatpatients recalled only 46% of theself-care advice that they had re-ceived.20 In a substudy of the COMETtrial (Carvedilol Or Metoprolol Eu-ropean Trial), Ekman et al reportedthat adherence with medicationwas associated with patient beliefsabout their medication.21 This allpoints to the complexity of educa-tion for self-care and supporting self-

care behavioral changes (Table III).Successful education depends onthe extent to which the patient es-tablishes rapport with and trust inthe advice. For the professional,time is needed to establish individ-ual needs, assess the patient’s per-spectives and beliefs, and provideappropriately tailored information.

This is time consuming and it israrely possible to achieve within thetime constraints of a routine physi-cian outpatient clinic. Within heartfailure management programs, theheart failure nurse has embracedthe role of providing patient educa-tion and supporting the develop-

30



Education topic

Definition, etiology, and trajectory

Symptom monitoring and self-care

Medication

Diet and alcohol

Smoking and recreational drugs

Exercise

Immunization

Sleep and breathing

Psychosocial aspects

Nursing actions

• Provide oral and written information tailored to individual education grade,health literacy, and culture/language

• Use pictorial health diaries when necessary• Provide information at regular time intervals

• Provide information to support self-care➢ In the case of increasing dyspnea or edema or a sudden unexpected

weight gain of >2 kg in 3 days, increase the diuretic dose and/or alert the patient’s health care team

• Provide written information on dosing, effects, and side effects• Encourage regular recording of weight and blood pressure• Provide an individualized medication “passport”

• Individualize information on fluid intake to be consistent with body weight, climate, etc

• Individually tailor alcohol advice to the etiology of heart failure, eg, abstinence for alcoholic cardiomyopathy

• Offer cognitive behavioral theory (if trained) and psychological support • Refer for specialist advice for smoking cessation, drug withdrawal, and

replacement therapy

• Encourage exercise within physical limitations• Provide advice on methods of exercise, such as a specific heart failure

exercise program

• Communicate information on local guidance and immunization practice • Discuss timing of diuretics, environment for sleep, etc

• In the presence of sleep disordered breathing, encourage weight reduction/control and use of mask support therapy, if appropriate

• Communicate information on disease, treatment options, and self-care• Refer to specialist for psychological support, when necessary

Table III. Key issues in self-care support and specific nursing actions.

ment of self-care skills. Many nursesnow run clinics that focus on pa-tient education. Group educationsessions and patient support groupsmay also be beneficial. Technologycan provide supportive self-care resources. For example, some tele-monitoring systems provide infor-mation videos and reminders. In-ternet-based information sites alsoexist, eg, heartfailure matters.org.22

However, the greatest benefit willprobably be seen when the advicefrom technological resources is in-tegrated into routine clinical visitsand telephone reviews and rein-forced at regular intervals. We havereported that such an approach canincrease the patient’s ability toprovide self-care.5

Self-care support extends beyondproviding information to identify-ing and addressing barriers to self-care, such as anxiety, depression,cognitive impairment, and low lev-els of education and health literacy.

ACUTE HEART FAILURE

The focus for the role of the heartfailure nurse has been on outpa-tient follow-up. Yet, many patientsare admitted with acute heart fail-ure as either the first manifestationof heart failure or an acute decom-pensation of chronic heart failure.During the acute phase, the imme-diate focus is on alleviating distress-ing symptoms (both physical andemotional). However, once stabi-lized, the patient should be triagedto an appropriate environment forcontinued monitoring of the pa-tient’s mental status, respiratoryrate, fluid balance, and hemodynam-ic stability. The heart failure nursethen coordinates care, providesheart failure education, and ensuresreferral to the heart failure team forpostdischarge follow-up.23

Outcomes are improved when careis provided by a specialized heartfailure team and by ward nurses fa-miliar with the management of heartfailure. A recent UK audit reportedlower in-hospital mortality whenpatient care was managed in spe-cialist cardiology wards (7.8%) vsgeneral medical wards (13.2%). Thisreduction in the risk of death ex-tends into the follow-up period, sug-gesting a longer-term benefit fromensuring that patients start an ap-propriate heart failure pathway asearly as possible. Mortality was low-er for patients referred for follow-

up by heart failure liaison services(34.7%) compared with those whowere not (39.4%) (Figure 1).24 Whilethis is the ideal acute heart failureservice, it is not always possible. In certain organizations, some pa-tients may be cared for in nonspe-cialist environments. In such situa-

tions, a specialist heart failure nursecan provide an outreach service.Using medical admission records,they can identify patients with sus-pected heart failure, act as a pointof contact for specialist advice, andensure appropriate discharge plan-ning and follow-up.

PREVENTION OF HEART FAILURE

The individual etiology of heart fail-ure varies; however, certain popula-tions have a high incidence of heartfailure (eg, following myocardial

infarction or in patients with hyper-tension). While the nurse has es-tablished a clear role in the primaryand secondary prevention of coro-nary heart disease, the heart failurepathway after a myocardial infarc-tion has received less attention andmany patients receive little or no

31



Referred to heart failure liaison services

Not referred to heart failure liaison services

100

90

80

70

60

50

40

30

20

10

0

0 200 800 1000 1200600400

Days after discharge

% S

urv

iva

l

Figure 1. Postdischarge survival rates for patients referred to heart failure nurse liai-son follow-up on hospital discharge.

From reference 24: Cleland et al. http://www.hqip.org.uk/assets/NCAPOP-Library/NCAPOP-2012-13/Heart-Failure-2011-12-Audit-Report-pub-2012.pdf. © 2012, UCL, Nicor National Heart Failure Audit.

follow-up after the immediate re-covery period and rehabilitationprogram. The onset of heart failuremay be delayed by appropriatelymanaging the risk factors. The STOP-HF study (Screening TO PreventHeart Failure) recruited 1374 pa-tients from primary care in Ireland. Patients with cardiovascular riskfactors and a brain natriuretic pep-tide level >50 pg/mL received amultidimensional intervention thatincluded referral for a specialist car-diology review, optimal risk factormanagement, and coaching by aspecialist nurse. There was a meanfollow-up of 4.2 years. The STOP-HFstudy reported a statistically signif-icant difference in the number of pa-tients with left ventricular dysfunc-tion (with or without heart failuresymptoms) when compared withpatients who received standardcare (P=0.003).25 Using a similarapproach, the Australian NIL-CHFstudy (Nurse-led Intervention forLess Chronic Heart Failure) recruit-ed 611 patients hospitalized withcardiovascular disease who were at a high risk of developing heartfailure. After a mean follow-up of4.3 years, the study investigatorsreported no difference in their pri-mary end point of admission withheart failure or all-cause mortality(P=0.76), but suggested that therewas a potential benefit in reducinghospitalizations and the length ofthe hospital stay26; however, the fullreport of the NIL-CHF study is await-ed. Together, the STOP-HF and NIL-HF studies may be useful to directfuture services.

The nurses’ role in heart failure pre-vention clinics has emphasized theindividual patient’s risk status andhas encouraged adherence to med-ication and healthy lifestyle behav-iors. This could be extended tomonitoring for potential side effectsof medications, optimizing doses,and commencing appropriate med-

ication. Critics of these studies maypoint to difficulties replicating thesecomplex study interventions inroutine practice. However, similarlycomplex nurse-led interventionswere used in the EuroAction trialsand effectively implemented for thesecondary prevention of cardiovas-cular disease.27 Questions remainabout patients’ willingness to beinvolved in regular follow-up in theabsence of overt disease, in whatmay be perceived as the “medical-ization” of daily life. Should largerstudies of chronic heart failure pre-vention programs extend these ear-ly findings and demonstrate clearevidence of benefit, such challengeswill need to be addressed.

Other “at risk” populations are simi-larly being targeted for preventionand early detection of heart failure.The field of cardio-oncology is onesuch example. Survivorship fromcancer is increasing and many pa-tients now live for many years aftertreatment with potentially cardio-toxic chemotherapeutic agents andthey remain at an increased risk ofdeveloping heart failure. Regularechocardiography may enable ear-lier detection of heart failure andappropriate treatment. This sub-group of heart failure patients mayhave different information and sup-port needs and may benefit fromspecific psychosocial support. Therole of the nurse in meeting patient’sneeds in this area is currently un-derresearched.

END-OF-LIFE CARE

The progressive nature and highmortality of heart failure necessi-tates a role for optimizing care to-ward the end of life. The aim ofpalliative care is to provide holisticcare that embraces the manage-ment of symptoms and offers psy-chological and spiritual support.Predicting prognosis in heart failure

is not always easy, as the patient’spathway is rarely linear. Rather it en-compasses periods of health punc-tuated by periods of poorer physi-cal functioning. Identifying when tomove to an end-of-life pathway isnot easy. Consequently, such diffi-cult, yet important, topics may beleft unsaid.

Ideally, all professionals in the heartfailure team should provide pallia-tive care and seek advice and sup-port from specialist palliative careservices when necessary. Heart fail-ure specialist nurses are well placedto address patient concerns andmake appropriate referrals to bothhealth and social care services. Theevidence to support the local im-plementation of palliative care serv-ices, particularly the role of thenurse, is limited. Various examplesof palliative care services in heartfailure have been described. Manyuse a shared care approach betweencardiologist and specialist pallia-tive care physicians. Within thesemodels, the heart failure nurse is akey worker that liaises between pri-mary, secondary, and hospice care.Using data collected from two inte-grated heart failure and palliativecare services in the UK, Johnson et al suggest that end-of-life careplanning, referral to specialist pal-liative care services, and enablingpatients to die in their preferredplace was mostly achieved by theactions of the heart failure nursewho discussed patients’ concernsand was central to the coordinationof their care.28

More recently, results from thePREFER study (Palliative advancedhome caRE and heart FailurE caRe),which was conducted in Sweden,have been reported.29 A total of 72patients were randomized to usualcare or care provided by palliativecare and chronic heart failure dis-ease management experts (both

32



physicians and nurses). Patientswhose care was managed by spe-cialists in palliative care and heartfailure reported an improvement inquality of life (P=0.05), better con-trol of nausea (P=0.02), and re-duced hospitalizations (P=0.009).The nurses’ role in this study wasto provide patient support duringhome visits and phone calls. Symp-tom relief was aided by administer-ing intravenous diuretics at the pa-tient’s home. For some patients,contact with the nurse was highand occurred several times duringthe day. Other studies, which mayprovide clarity on the best way tooptimize palliative care in heartfailure, are still recruiting (eg, thePAL-HF study [PALliative care inHeart Failure]30). Further studies willbe necessary to drive change in thisimportant area of care. Optimisti-cally, this all points to a growingrecognition of the importance ofpalliative care and for a clear roleof the heart failure nurse to coordi-nate services.

EDUCATION FOR ROLE EXPANSION

Such roles must be underpinnedwith appropriate education. Nursesrequire sufficient education to sup-port safe practices. Patients deserveto be cared for by knowledgeableprofessionals in whom they canplace their trust. Nurse educationvaries between countries, but toprovide some standardization, theEuropean heart failure nurse’s cur-riculum has been updated. Howev-er, access to specific education andtraining for heart failure nurses isvariable. For nurse education, it isthe responsibility of country-spe-cific registrations to regulate for safecare, yet it is the specialist profes-sional organizations that can helpdevelop roles and expand profes-sional horizons to improve thestandards of care.

CONCLUSION

Significant progress has been madeto improve the outcomes for pa-tients living with heart failure andpatients can now expect to live forseveral years. Despite this, there isstill much that can be done. Newertherapies that promise reductionsin symptoms and improvements inhealth-related quality of life are inthe pipeline. In addition, much canstill be done to streamline the careprovided to ensure that patients donot “fall in the gap” between hospi-tal and home and between activefollow-up and end of life. All patientsshould also expect to receive thesame high standard of care regard-less of age or sex. Similar challengesare faced by all health care organi-zations—to provide high-qualitycare despite the increasing numberof people with heart failure, the in-creasing complexity of the disease,decreasing professional resources,and increasing patient expectationsfor care. Imaginative solutions willbe required. Optimizing the contri-bution of all members of the heartfailure team, including the heartfailure nurse, will go some way to-ward this goal.

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4. Chaudhry SI, Mattera JA, Curtis JP,et al.

Telemonitoring in patients with heart failure.

N Engl J Med. 2010;363:2301-2309.

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Does telemonitoring in heart failure em-power patients for self-care? A qualitativestudy.

J Clin Nurs. 2013;22:2444-2455.

6. McMurray JJ, Adamopoulos S,Anker SD, et al; ESC Committee forPractice Guidelines.

ESC guidelines for the diagnosis and treatment of acute heart failure 2012.

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7. McDonagh TA, Blue L, Clark AL,et al.

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Eur J Heart Fail. 2011;13:235-241.

8. Seferovic PM, Stoerk S, FilippatosG, et al.

Organization of heart failure managementin European Society of Cardiology membercountries: survey of the Heart Failure Associ-ation of the European Society of Cardiologyin collaboration with the Heart FailureNational Societies/Working Groups.

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9. National Institute of ClinicalExcellence.

Management of chronic heart failure inprimary and secondary care.

https://www.nice.org.uk/guidance/cg108/resources/guidance-chronic-heart-failure-pdf. Published August 2010. AccessedAugust 25, 2015.

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35


eart failure disease man-agement programs arewell established and theirrole in supporting self-care

and improving outcomes is recog-nized in international guidelines.1,2

Access to such programs is limited,and even in wealthy countries, suchas the UK, only 56% of patients areoffered specialist follow-up onhospital discharge.3

Heart failure typically affects theelderly, and their limited mobilityand lack of social support may makefrequent attendance at the hospital,

clinic, or doctor’s office difficult. Insome countries, home visits by adoctor or nurse specialist are pos-sible, but are costly in travel timefor the health care professional.

Therefore, traditional health careapproaches often struggle to meetthe demands of evidence-basedcare for heart failure. This problemis set to increase as the populationages at an unprecedented rate. Thepercentage of European citizenswho are 65 and over is expected toincrease from 17% to 30% between2010 and 2060.4


H

What is the role of telemonitoring in heart failure?Martin R. Cowie, MD, MSc, FRCP, FRCP (Ed), FESC

Imperial College London (Royal Brompton Hospital) - London - UK

Keywords: e-health; heart failure; remotemonitoring; telemonitoringAddress for correspondence:Professor Martin R. Cowie, National Heartand Lung Institute, Imperial CollegeLondon, Dovehouse Street, London SW36LY, UK (e-mail: [email protected])Dialogues Cardiovasc Med. 2016;21:35-44

Heart failure disease managementprograms are well established andtheir role in supporting self-careand improving outcomes is recog-nized in international guidelines.However, access to such programsis limited. Telemonitoring, themonitoring of patients using information technology to collecthealth-related information andtransmit this data to a health careprofessional, who is remote fromthat patient, offers the opportunityfor the patient and health careprofessional to adopt a proactiveapproach to the early detection ofclinical deterioration, optimizationof medication, and education forself-care. However, the evidencethat it improves outcomes over andabove the best usual practice isthin, meaning that any benefit willcome at an additional expenseand organizational disruption.Convenience and acceptability arehigh for the patients, but adoptionremains slow due to a frequent lackof reimbursement.


CRT cardiac resynchronization therapy


STUDY ACRONYMS

CHAMPION CardioMEMS Heart sensor Allows Monitoring of Pressure to Improve Outcomes in NYHA class III heart failure patients [study]

COMPASS-HF Chronicle Offers Management to Patients with Advanced Signs and Symptoms of Heart Failure [study]

CONNECT Clinical evaluation Of remote NotificatioN to rEduCe Time to clinical decision [study]

DOT-HF Diagnostic Outcome Trial in Heart Failure

HOME-HF HOME Heart Failure [study]

IN-TIME INfluence of home moniToring on mortality and morbidity in heart failure patients with IMpaired lEft ventricular function [study]

REM-HF REmote Monitoring: an evaluation of implantable devices for the management of the Heart Failure patients [study]

TEN-HMS Trans-European Network–Home-care Management System[study]

TIM-HF II Telemedical Interventional Management in Heart Failure II[study]

WHARF Weight monitoring in HeARt Failure [study]

In response to the ever increasingdemand and the challenge of fund-ing, policy makers have promotedthe use of “e-health” (ie, the use ofinformation and communicationtechnologies to support health andhealth-related activities) as a meansto improve outcomes and ensurethe sustainability of health careprovisions.5 The belief is that thiswill widen access to high-qualitycare and support care closer tohome—technology is seen as atool that can help take the exper-tise to the patient, rather than thepatient to the expertise.

In theory, technological innovationshould improve interprofessionalcooperation, information sharing,decision support, and flexibility inthe health care system. However,the impact of such innovation isreduced by legal, ethical, and dataprotection concerns. Health careprofessionals may be resistant tosuch innovations, particularly if thetechnologies are considered “solu-tions seeking a problem” and wherethe evidence for the impact on qual-ity of care is seen as less than ro-bust. Ensuring proper integration ofnew technologies into the healthcare system is often difficult, re-quiring process redesign or “dis-ruption.”6 Regulatory bodies andreimbursement authorities find itdifficult to react quickly, or consis-tently, to this rapidly changing area,thus creating further barriers toimplementation.

WHAT IS TELEMONITORING?

Telemonitoring can be defined asthe monitoring of patients usinginformation technology to collecthealth-related information andtransmit it to a remotely locatedhealth care professional. Telephonesupport could be considered thesimplest form of telemonitoring,

but more typically, telemonitoringis taken to mean the use of equip-ment (eg, a sphygmomanometer orweighing scale) at the patient’shome to collect data, which is thentransmitted over the telephone orvia the internet to a health careprofessional. Data from devices im-planted for therapeutic reasons,such as a pacemaker or defibrillator,can also be remotely monitored.Implantable devices that are solelyused for monitoring purposes haverecently been developed and thesedevices will be discussed in this article.

RATIONALE FOR TELEMONITORING

Patients with chronic heart failureare prone to frequent exacerbations,with worsening symptoms that re-duce their quality of life and sub-stantially increase their use of healthcare resources. Despite many ad-vances in therapy, the rehospitaliza-tion rate remains high—typicallyaround 25% within 30 days.7 Man-agement is not straightforward andrequires both specialized knowl-edge to optimize care and frequentmonitoring to ensure stability.1,2

Education of the patient regardingthe nature of the chronic condition,the need for therapy, the symp-toms that may indicate possibledecompensation, and methods forself-care are viewed as central to agood heart failure managementprogram.1,2,8

Retrospective studies suggest that a patient typically notices a changein their symptoms several days be-fore seeking help.9 Physiologicalvariables may start to change manydays before a patient notices anychange in symptoms. The premisefor telemonitoring is that frequentmonitoring by a health care profes-sional may enable earlier interven-tion to treat deterioration.

Intervention may take several forms,including reminders about lifestyleand diet, advice to alter medica-tion (such as diuretics), recall forearly clinical review, a home visit,or urgent hospitalization.

Abnormal telemonitoring data trig-gers contact with the patient bytelephone and provides importantfeedback that may help the patientreport their feelings of breathless-ness or fatigue, vital signs, and anyrecent changes in lifestyle or drugcompliance. In this way, their under-standing of heart failure increases,as does their confidence to identifyappropriate actions to take to avertor manage symptoms.10

WHAT CAN BE MONITORED?

Traditionally, patients are taught tomonitor weight and symptoms orsigns of fluid overload.1 These mea-surements can easily be made re-motely, along with blood pressureand heart rate. Questions commonlyasked during patient assessmentcan be included in specific tele-monitoring systems. For example,the patient can answer using a “yes/no” response button to questions,such as “did you sleep with extrapillows last night” or “do you feelmore breathless than yesterday?”

In studies that have reported theactions taken by health care pro-fessionals as a result of telemoni-toring data have shown that themost frequent action relates to vol-ume overload presenting as dys-pnea or weight gain.11,12 It seemsappropriate to consider monitoringweight and key disease-relatedsymptoms as the minimum data setfor a telemonitoring service.

For implanted electrical devices,such as pacemakers or defibrillators,it is possible to monitor the tech-

36


What is the role of telemonitoring in heart failure? - Cowie

nical features of the device andepisodes of arrhythmia (such asatrial fibrillation or ventricular tachy-cardia/fibrillation), the therapeuticactions of the cardioverter-defibril-lator (such as antitachycardia pac-ing or a direct current shock), anda range of physiological variables,often termed “heart failure diagnos-tics.”13 Such “diagnostics” includeintrathoracic impedance, which canbe measured between the right ven-tricular lead and the generator of apacing device. Accumulating intra-thoracic fluid decreases impedance,which identifies trends that wouldsuggest the development of pul-monary edema. Other physiologicalmeasurements that can be remotelymonitored with such devices includeheart rate variability, nocturnalheart rate, and patient activity.14,15

Data from implanted devices canalso be linked to data from stand-alone devices, such as a sphygmo-manometer or weighing scales, andthis data can provide an even broad-er assessment of the patient’s car-

diovascular status (Figure 1). It ispossible to identify patients at amuch higher risk of decompensa-tion by applying an algorithm tothe trends observed for a numberof remotely monitored variables incardiac resynchronization therapy(CRT) or implantable cardioverterdefibrillator systems.16,17 “High”-risk individuals that have a 10-foldincreased risk of decompensationin the next month compared with“low”-risk individuals can be iden-tified, although the absolute riskremains low (≈7%). Therefore, it isimportant that the health care pro-fessional responsible for monitor-ing the data does not overreact, asthis could lead to increased clinicalactivity (such as clinical review orhospitalization) without necessarilyimproving outcomes. Just such aneffect was observed in the DOT-HFstudy (Diagnostic Outcome Trial inHeart Failure),18 a randomized studywhere clinicians and patients wereissued with an “alert” in response tochanges in only one physiological

parameter—intrathoracic imped-ance.19 There was no change in mor-tality in this study, but there was a79% increase in the risk of beinghospitalized with suspected decom-pensation (P=0.02).

DATA TRANSMISSION

The privacy and security of person-al data are of concern to patients,health care professionals, and healthcare regulators. It is important thatthe monitoring data be encryptedbefore being transferred throughthe home telephone line, mobilephone, or internet. Access to anytelemonitoring “station” shouldalso be secure, with access restrict-ed to people with a legitimate in-terest in the data and the patient’smanagement. Web-based applica-tions can easily be password pro-tected, but concerns regarding thestorage of data on servers in coun-tries with less stringent data pro-tection rules than in the EuropeanUnion can cause problems.

37



Figure 1. Telemon-itoring of a heartfailure patient us-ing a combinationof stand-aloneequipment and datafrom an implantedcardiac device.

Data are transmittedfrom the implanteddevice and/or stand-alone devices to thecommunicator in thepatient’s home. Thisthen transmits thedata via the internetto a server, which canbe accessed by themonitoring health careprofessional. Upon re-viewing the trends inthe data, the patientmay be telephoned for additional informa-tion and a decision ismade about whetherany action is required.

38

TRIAGE OF REMOTELYCOLLECTED DATA

Remotely transmitted data are typ-ically compared against preset“limits,” which are often tailored tothe patient’s physiology. Customar-ily, the initial response to data thatpossibly represents clinical deterio-ration, such as an increase in weightor symptoms, is a telephone assess-ment and/or advice from a trainedheart failure professional, often aspecialist nurse. Early review or aplanned hospital admission is nec-essary only when the issues cannotbe resolved remotely through tele-phone advice on medication or life-style. In some countries, the initialtriage of data occurs at a call center,with the patient’s usual health careprovider contacted only if required.

In the HOME-HF study (HOMEHeart Failure), a randomized trialof home telemonitoring in WestLondon, UK, only 64% of the tele-monitored patients had data-trig-gered contact that required actionin the 6-month period after dis-charge from the hospital. This wasan average of one phone call to apatient each month during the first3 months of monitoring. After tele-phone contact, only 19% of patientsrequired early clinical review insecondary care.20 Similarly, in theIN-TIME study (INfluence of homemoniToring on mortality and mor-bidity in heart failure patients withIMpaired lEft ventricular function)on remote monitoring of implanteddevices, which remotely followed-up 333 patients over 12 months,the telemonitoring center sent in-formation on 280 patients to theindividual centers, with 238 patientsbeing contacted at least once. Inmore than 60% of the cases, thiswas only because there had been agap in daily transmission of datafor more than 3 days.21 For 75% ofpatients, there were ≤3 telephone

contacts per year. Timeliness of re-sponse to remotely collected datais important for both technical andlegal reasons. A standard operatingprocedure should be set up before aservice is introduced; patients needto be aware of how often their datawill be viewed and what to do whenfeeling unwell. In some systems,the patients can contact their healthcare professional or a call center atany time of the day or night, but inmost services, such contact is lim-ited to working hours, and accessto other health care services shouldcontinue as usual. Delays in re-sponding to changes in monitoreddata defeat the purpose of remotemonitoring, and health care staffinvolved in telemonitoring need tobe empowered to make decisionsand receive guidance as to when tocontact the cardiologist, implantingphysician, etc.

WHAT IS THE CLINICAL BENEFIT OFTELEMONITORING?

Despite increasing interest in tele-monitoring in heart failure and agrowing number of service providers,there is no clear guidance in inter-national heart failure guidelines asto whether telemonitoring is worth-while, and if so, for which patientsand at what time point it is valu-able.1,2 Therefore, further researchis recommended. Early studies oftelemonitoring were observational,with before and after comparisonspotentially inflating the estimatesof clinical effectiveness. More re-cently, several randomized trialshave been conducted in a varietyof health care settings.

NONIMPLANTED SYSTEMS

One of the first, large randomizedtrials to assess the regular use oftelemonitoring rather than telephone

monitoring was the WHARF study(Weight monitoring in HeARt Fail-ure), which enrolled 280 patientshospitalized with New York HeartAssociation (NYHA) class III or IVand an ejection fraction less than35%.22 Patients were randomly as-signed to receive usual care or usu-al care plus daily telemonitoring ofweight and symptoms. Patientswere followed-up for a maximum of180 days. The study reported no dif-ference in the primary end point ofall-cause rehospitalization during 6months of monitoring (65 [47%] inthe telemonitoring group vs 67 [47%]in the usual care group; P=0.28)and no difference in the time to re-hospitalization or death (P=0.16).They did, however, report a 56%(P<0.003) reduction in the mortali-ty rate in the telemonitoring group.

The TEN-HMS study (Trans-Euro-pean Network–Home-care Manage-ment System) randomized 426 pa-tients (mean age 67 years) withNYHA class II to IV and left ventric-ular systolic dysfunction (left ven-tricular ejection fraction <40%) tohome telemonitoring, nurse tele-phone support, or usual care.23 Thismulticenter study recruited patientsfrom 16 centers and 3 Europeancountries. There were no statisticallysignificant effects on heart failure–related hospitalization or averagelength of stay for such admissions.Although it was not a primary out-come, there was a statistically sig-nificant reduction in mortality inthe telemonitoring group comparedwith the usual care group at 1 year(P=0.03). A greater number of pa-tients in the telemonitored groupwere ultimately on optimal drugtherapy vs the usual care group.

The HOME-HF study, a randomizedtrial of home telemonitoring in atypical elderly heart failure popula-tion (mean age, 71; 45% were >75years), which included those with



39

either preserved or impaired leftventricular systolic function, com-pared 6 months of daily telemoni-toring with specialist heart failurecare in 182 patients discharged from3 district hospitals in West London,UK.20 There was no difference inthe primary outcome of all-causehospitalization, but a significantdecrease in the proportion of emer-gency hospitalizations for heartfailure (usual care [81%] vs telemon-itoring [36%]; P=0.01). There wasalso a reduction in the number ofvisits to the emergency room andsecondary care clinical visits withtelemonitoring.

A recent meta-analysis of random-ized trials, which included 6317 patients, suggested that telemoni-toring was associated with a non-significant 24% reduction in mortal-ity for office hour–based programs(95% credible interval, 51% reductionto 18% increase) and a nonsignifi-cant 51% reduction in mortality forprograms that provided medicalsupport 24 hours per day, 7 days perweek (95% credible interval, 80% re-duction to 18% increase).24 Exclud-ing the HOME-HF study (with only180 patients) from the meta-analy-sis, where support to the usual caregroup may have been better than“usual” care, made these estimatesstatistically significant, showing thatthe estimates are perhaps ratherunstable.

Most of the recently publishedsmall, randomized trials have beenconducted on patients who havehad a recent episode of decompen-sation. Koehler et al studied a groupof 710 German patients receivingoptimal medical therapy with stable,ambulatory heart failure with NYHAclass II or III and an ejection frac-tion <35%.25 Patients were random-ized to usual care or daily telemoni-toring, where data on weight, bloodpressure, and a three-lead ECG

were transmitted. The authors re-ported reasonable compliance withremote monitoring, with 70% of pa-tients in the remote monitoringarm transmitting data daily. Therewere no statistically significant dif-ferences in the rates of all-causemortality (hazard ratio [HR], 0.95;95% CI, 0.67-1.17; P=0.87), cardio-vascular death (HR, 0.86; 95% CI,0.56-1.31; P=0.49), or hospitalizationbetween the two groups. Patients inthe remote monitoring arm showeda significant improvement in physi-cal functioning, which was mea-sured using the short form 36 (SF-36)questionnaire (P<0.05). In this study,>90% of the patients were takingangiotensin-converting enzyme in-hibitors and b-blockers at baselineand had heart failure for >6 years onaverage, perhaps limiting the scopefor the addition of telemonitoring.

An additional larger study is cur-rently underway in Germany that is targeting higher-risk patients(TIM-HF II study [Telemedical Inter-ventional Management in HeartFailure II]; NCT01878630).26

IMPLANTED SYSTEMS

Observational data from a large USregistry27 suggest that patients whoare remotely monitored have alower risk of mortality or hospital-ization than patients who are notremotely monitored, although selec-tion bias is highly likely in terms of both patients choosing to be re-motely monitored and physicianswilling to offer this service. Remotetransmissions occurred weekly onaverage, with additional clinicalvisits occurring twice per year onaverage.

In the CONNECT study (Clinicalevaluation Of remote NotificatioNto rEduCe Time to clinical decision),automatic clinician alerts wereprogrammed for serious clinical

“events,” such as two implantablecardioverter defibrillator shocks,ventricular rate >120 beats/minutewhen in atrial fibrillation, or atrialfibrillation episodes lasting morethan 12 hours per day.28 There wasevidence for a reduced length ofstay for cardiovascular hospitaliza-tions, and the average time fromclinical event to clinical decisionwas reduced from 22 days in theusual care arm to 4.6 days in theremotely monitored arm (P<0.001).

In the DOT-HF study, heart failurehospitalization increased by 79%after programing an “alert” in re-sponse to a preset change in trans-thoracic impedance.19

In the IN-TIME study, 664 patientswere randomized (1:1) to automaticdaily implant-based multiparamet-ric telemonitoring in addition tousual care or usual care alone at36 centers in Australia, Europe, andIsrael.21 At 12 months, 19% of pa-tients in the telemonitoring armhad a worsened composite scorecompared with 27% in the usualcare arm (P=0.013). Although mor-tality was not the primary end point,10 patients died in the telemoni-toring arm compared with 27 in theusual care arm (P=0.004). Most ofthe actions were related to check-ing on compliance with the monitor-ing, reduction in CRT efficacy (CRTpacing <80%), or identification ofatrial arrhythmias.

Within 12 months, the REM-HFstudy (REmote Monitoring: an eval-uation of implantable devices forthe management of Heart Failurepatients), one of the world’s largestrandomized trials of remote moni-toring of implanted devices, willreport the results after monitoring1650 patients who were random-ized to either weekly remote datadownloads or usual care at 9 Eng-lish hospitals, with a minimum fol-



40

low-up of 2 years.29 This shouldprovide robust data on both theclinical effectiveness and cost-effec-tiveness of this approach.

Currently, the strongest evidencefor improved outcomes in remotelymonitored patients using an im-

planted device comes from systemsthat can monitor pulmonary arterypressure. The COMPASS-HF study(Chronicle Offers Management toPatients with Advanced Signs andSymptoms of Heart Failure), a ran-domized controlled study of theaddition of data from an implanted

hemodynamic monitor to the usu-al clinical review, reported a non-significant 21% reduction in heartfailure hospitalizations or urgentcare visits requiring intravenous ther-apy in 134 patients with advancedheart failure in the active arm com-pared with 140 patients randomized



Figure 2. The implantable pulmonary artery pressure monitoring system used in the CHAMPION trial.

Panel A. Implantable device. Panel B. Selective pulmonary angiogram showing the device’s position. Panel C. The patient is instructed to take a dailyreading from home using the equipment. Panel D. The health care professional reviews the trends in the pulmonary artery pressure. Panel E. Trends inpulmonary artery pressure.Abbreviations: CHAMPION, CardioMEMS Heart sensor Allows Monitoring of Pressure to Improve Outcomes in NYHA class III heart failure patients.From reference 31: Abraham et al. Lancet. 2011;377:658-666. © 2011, Elsevier Ltd.

41

to the control arm.30 Pulmonary artery pressure was indirectly esti-mated by applying an algorithm to the measured right ventricularpressure.

Directly measuring pulmonary ar-tery pressure is even more useful.Recent data from the CHAMPIONstudy (CardioMEMS Heart sensorAllows Monitoring of Pressure toImprove Outcomes in NYHA class IIIheart failure patients), which useddata collected from an implantedwireless pulmonary artery pressuremonitoring device in heart failurepatients with reduced or preservedejection fraction, show a 30% re-duction in heart failure hospitaliza-tions over 6 months (P<0.0001) inpatients with NYHA class III.31 Inthis study, patients transmitted theirpulmonary artery pressure daily andphysicians targeted an acceptablerange of pressure, with increaseduse of diuretic and oral nitrates(and other medications) at the dis-cretion of the monitoring physi-cians in the remotely monitored arm(Figure 2).

WHAT IS THE COST OF TELEMONITORING?

Despite the inclusion of cost sav-ings as a political rationale for tele-care, there are few reports on thecost of telemonitoring. When stud-ies report the cost of telemonitor-ing, it varies considerably accordingto the health care setting and thecomponents of both “usual” careand telemonitoring. Our experiencewith telemonitoring in the Home-HF study in West London, UK sug-gests a mean incremental cost ofGBP £1600 (US $2500) per patientfor telemonitoring over 6 months,although there were no statisticallysignificant differences in the overallcosts between the telemonitoringarm and the usual care arm of thestudy.20

In a decision-analysis model of cost-effectiveness for patients recentlydischarged from the hospital aftera heart failure exacerbation, anoth-er UK analysis, based on a networkmeta-analysis, reported an incre-mental cost-effectiveness of GBP£11 873 (US $18 550) per quality-adjusted life year, representing areasonable value for the money,but increased expenditures wouldbe needed to reap the benefits.32

Important questions remain aboutthe optimal model of monitoringand the patients most likely to ben-efit. The cost and organizationalchanges required to run such a serv-ice appear to be substantial andmay not be good value for money.To have a higher value for the mon-ey, the home monitoring equipmentshould be inexpensive and an indi-vidual service should monitor alarger number of patients; however,there are likely to be limits on howmany patients a single health careprofessional can follow at any pointin time.

A recent survey of cardiologists inthe European Union involved withthe European Heart Rhythm Asso-ciation Electrophysiology ResearchNetwork identified a lack of reim-bursement (80% of 43 centers) as amajor barrier to the introduction of remote monitoring services forpatients with implanted devices inEurope. Additional workload wasalso identified as a significant bar-rier, although most cardiologistsconsidered remote monitoring aclinically useful practice, with sig-nificant benefits for patients andhealth care organizations.33

WHAT DO PATIENTS THINK

OF TELEMONITORING?

Patients with heart failure indicat-ed that a major issue in their carewas the need for better access to

specialist advice, including an iden-tified contact who is familiar withtheir medical condition.34,35 Thiswish can be partially addressedthrough telemonitoring, which di-rectly and indirectly increases con-tact with the health care profession-al and leaves the patient and theirfamily less isolated. When help issought, the health care profession-al has easy access to up-to-dateclinical information upon which tobase their advice. In addition, thepatient gains confidence that if thereis a medical problem, the healthcare professional is likely to contactthem, rather than worrying aboutwhether or not to contact the healthcare professional.

Despite concerns about the feasi-bility of home-based technology tomonitor chronic conditions, particu-larly in the elderly, patients gener-ally find the equipment easy to use,with some studies reporting >80%usage.

PRACTICALITIES OF TELEMONITORING

International guidelines for heartfailure care suggest early (within 2 weeks) face-to-face follow-up after hospitalization, education tofacilitate self-care, and ongoing sup-port from a multiprofessional teamthat is responsive to the patient’sneeds.1,2 The highest risk periodfor rehospitalization is in the firstfew weeks after discharge from thehospital. If telemonitoring is to be conducted for such patients, itshould be installed as soon as pos-sible following hospital dischargeand the patient should be instruct-ed on its use.

The optimal time for telemonitoringis unclear. The follow-up in tele-monitoring studies has ranged from90 days to >12 months. In our ex-perience, the greatest amount of



telemonitoring data outside presetlimits occurs during the first 90 daysof monitoring, which is reduced by≈50% over the subsequent months.

However, it is particularly duringthese latter months that telemoni-toring helps patients understandmore about their heart failure andthe actions required for self-care. Inpractice, most telemonitoring serv-ices enroll patients for at least 6months following discharge, with anevaluation of its usefulness conduct-ed at 30-day intervals thereafter.

International guidelines for the useof telemonitoring in heart failurehave not yet been developed. In theirabsence, it is likely that the heartfailure nurse will remain central tothe success of this new approachto care by triaging and respondingto the data and maintaining con-tact with the lead clinician for heartfailure. In some countries, the nurseis also able to prescribe medica-tions, although policies vary be-tween countries. Telemonitoringrelies on the confidence and abilityof the health care professional tointerpret and use the information.

There is likely to be a steep learn-ing curve associated with handlingincreased amounts of informationregarding physiological parameterswithout visual cues from face-to-face contact.

ORGANIZATION OF SERVICES

Heart failure disease managementservices and studies of telemoni-toring, while designed to providefollow-up after hospital discharge,have primarily been led by second-ary care. Such models potentiallystrengthen the relationship betweenthe patient and the secondary care–based specialist, perhaps at the expense of the primary care team.

Patients with heart failure are gen-erally elderly with multiple comor-bid conditions, and simultaneously,they are likely to be under the careof a number of health care profes-sionals and can become confusedwhen they receive care from such abroad range of practitioners.

The successful introduction of tele-monitoring is likely to depend on afunctional multi-disciplinary team.Ensuring close collaboration be-tween all agencies involved whenaction is appropriate is likely to bemore important than whether theinitial triage of data is undertaken inprimary or secondary care or evenoutsourced to a call center.

CONCLUSIONS

With an increasingly elderly popula-tion living with heart failure, theneed for high-quality disease man-agement programs to “reach out”to patients in their normal livingenvironment is set to dramaticallyincrease. Telemonitoring offers theopportunity to provide a modernapproach to the monitoring of suchpatients. It enables the patient andprofessional to adopt a proactiveapproach for recognizing problemsand resolving issues together andit reduces unnecessary travel to thehospital or cardiology clinic. Tele-monitoring ensures that patientshave close contact with someonewho knows their current health sta-tus, provides easy access to spe-cialist help, and aids in schedulinghospital admissions when needed.

The benefits extend beyond theearly detection of clinical deterio-ration to optimizing medicationand facilitating education for self-care. However, the evidence that itimproves outcomes over and abovethe best usual practice is thin, andthe available data suggest that, although it may improve outcomes,

this will come at additional expens-es and organizational disruption.Convenience and acceptability arehigh for the patients, but imple-mentation remains slow due to alack of reimbursement. The addedvalue of remotely monitoring alarge number of physiological pa-rameters in patients with an im-planted device remains unclear andfurther research is required.

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Impact of remote telemedical managementon mortality and hospitalizations in ambu-latory patients with chronic heart failure:the telemedical interventional monitoringin heart failure study.

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Telemedical Interventional Management inHeart Failure II (TIM-HF II).

https://clinicaltrials.gov/ct2/show/NCT01878630. Accessed August 27, 2015.

27. Saxon LA, Hayes DL, Gilliam FR,et al.

Long-term outcome after ICD and CRT implantation and influence of remote devicefollow-up: the ALTITUDE survival study.

Circulation. 2010;122:2359-2367.

28. Crossley GH, Boyle A, Vitense H,Chang Y; CONNECT Investigators.

The CONNECT (Clinical evaluation of re-mote notification to reduce time to clinicaldecision) trial: the value of wireless remotemonitoring with automatic clinician alerts.

J Am Coll Cardiol. 2011;57:1181-1189.

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29. Morgan JM, Dimitrov BD, Gill J,et al.

Rationale and study design of the REM-HFstudy: remote management of heart failureusing implanted devices and formalized follow-up procedures.

Eur J Heart Fail. 2014;16:1039-1045.

30. Bourge RC, Abraham WT,Adamson PB, et al; COMPASS-HFStudy Group.

Randomized controlled trial of an implant-able continuous hemodynamic monitor inpatients with advanced heart failure: theCOMPASS-HF Study.

J Am Coll Cardiol. 2008;51:1073-1079.

31. Abraham WT, Adamson PB,Bourge RC, et al; CHAMPION TrialStudy Group.

Wireless pulmonary artery haemodynamicmonitoring in chronic heart failure: a ran-domised controlled trial.

Lancet. 2011;377:658-666.

32. Thokala P, Baalbaki H, Brennan A,et al.

Telemonitoring after discharge from hospitalwith heart failure: cost-effectiveness model-ling of alternative service designs.

BMJ Open. 2013;3:e003250.

33. Mairesse GH, Braunschweig F,Klersy K, Cowie MR, Leyva F.

Implementation and reimbursement of remote monitoring for cardiac implantableelectronic devices in Europe: a survey fromthe health economics committee of theEuropean Heart Rhythm Association.

Europace. 2015;17:814-818.

34. Boyd KJ, Murray SA, Kendall M,Worth A, Benton FT, Clausen H.

Living with advanced heart failure: a pros-pective, community based study of patientsand their carers.

Eur J Heart Fail. 2004;6:585-591.

35. Rogers AE, Addington-Hall JM,Abery AJ, et al.

Knowledge and communication difficultiesfor patients with chronic heart failure:qualitative study.

BMJ. 2000;321:605-607.

45

he worldwide burden of heartfailure (HF) is large and in-creasing, driving an ongoingsearch for new disease modi-

fying therapies. Cardiac gene thera-py is a promising technique to tacklethis unmet need. The classic formof gene therapy involves deliveringtherapeutic nucleic acid to the celltype of interest to correct loss offunction of the gene of interest.

Studies to date have focused on theconvergence of molecular pathwayscontrolling excitation-contractioncoupling, and specifically, on thecardiac sarco(endo)plasmic reticu-lum Ca2+ ATPase type 2a (SERCA2a)enzyme as the final common path-way. A long program of laboratoryresearch generated a translationalcardiac gene therapy program usinga recombinant adeno-associatedvirus type 1 (rAAV1) to transducecardiomyocytes with a copy of thehuman SERCA2a gene. This culmi-nated in the CUPID-2 study (CalciumUpregulation by Percutaneous ad-ministration of gene therapy In car-diac Disease). The results from thisstudy were much anticipated, butwhen they arrived, they were great-ly disappointing.1 While there wereno safety issues with infusion of thevirus at the dose studied, the trialfailed to identify any clinical bene-fit from treatment with AAV1.SER-CA2a in patients with chronic HF.1

Far from being the end of the story,this setback marks the end of achapter in a story that will contin-ue to develop. The CUPID programhas blazed a trail, challenged thepublic’s and physicians’ perceptionsabout the practicability and safetyof gene therapy, tested hypothesesabout vector design and mode ofdelivery, and laid the foundation forfuture work.2 This review introducescardiomyocyte calcium homeosta-sis as a target for gene therapy, re-views results from clinical trials todate, considers the reasons for thefailure of the CUPID-2 trial to showefficacy, and on this basis, looksahead to the future of gene therapyin HF.

CALCIUM AS A THERAPEUTIC TARGET

The HF syndrome is a progressivedysregulation of cardiovascular func-tion that is usually initiated by aspecific insult facilitated by an indi-vidual’s inherited susceptibilities,and perpetuated by maladaptiveneurohormonal responses to thefailing homeostasis, particularly bythe sympathetic nervous systemand the renin-angiotensin system.This dysregulation occurs at all lev-els from systems physiology, organand tissue maladaptive remodeling,cellular dysfunction, and ultimate-ly, to dysregulation of cardiac gene

Gene therapy for heart failure:the end of the beginning?Andrew C. Morley-Smith, MB BChir, MRCP1,2; Carl Hayward, MB BChir, MRCP1,2; Sian E. Harding, PhD2; Alexander R. Lyon, MD PhD, FRCP1,2

1NIHR Cardiovascular Biomedical Research Unit - Royal Brompton & Harefield NHS Foundation Trust - Sydney Street - London - SW3 6NP - UK2National Heart and Lung Institute - Imperial College London - Imperial Centre for Translational and Experimental Medicine - Du Cane Road - London - W12 0NN - UK

T



Keywords: adeno-associated virus; CUPID; gene therapy; heart failure; SERCA Address for correspondence:Alexander R. Lyon, NIHR CardiovascularBiomedical Research Unit, Royal Brompton& Harefield NHS Foundation Trust, Sydney Street, London, SW3 6NP, UK(e-mail: [email protected])


New therapies are required to improve myocardial function inpatients with severe heart failure.Within the failing cardiomyocyte,a fundamental abnormality andpotential therapeutic target is dysfunctional cellular calciumhomeostasis and excitation-contrac-tion coupling. Viral vector–medi-ated delivery and transduction of cardiomyocytes with a cardiacsarco(endo)plasmic reticulumCa2+ ATPase type 2a (SERCA2a)transgene can recover electrophysi-ological properties and contractilefunction in animal models and inex vivo human cardiomyocytes.However, a recent phase 2b studyfailed to show clinical benefit inheart failure patients. This articlereflects on the experience to dateand looks ahead to what is next in gene therapy for heart failure.

expression. Extensive cell biologystudies over the last 30 years haveidentified a number of proteinsthat appear central to this process.In the search for new HF therapeu-tics to combat the growing HF epi-demic,3 gene therapy could targetthese alterations to gene expres-sion and return the proteome to itshealthy composition, helping to re-gain a normal physiological milieu.However, the challenge is to deter-mine which gene to select and howto deliver it to the diseased humanheart in a manner that increasesthe levels of functional target pro-tein to modify the underlying dis-ease effectively.

Calcium is central to excitation-con-traction coupling, cellular electro-physiology, signaling, and even geneexpression itself. At the cellular lev-el, the final common pathway of allHF syndromes involves a malfunc-tion in SERCA2a calcium handling,and in particular, a reduction in theexpression and activity of cardiacSERCA2a (the SERCA2a isoform ispredominant in the cardiomyocytesarcoplasmic reticulum [SR]).4 Inhealthy cardiomyocytes, depolariza-tion of the cardiomyocyte triggerscardiac systole by opening voltage-gated (L-type) calcium channelsand calcium influx into the cytosol.This, in turn, triggers an opening of

ryanodine receptors (RyR) in theSR, and a much larger calcium fluxfrom the SR into the cytosol, whichinitiates cardiomyocyte contraction.5

The speed and magnitude of thecalcium flux determines the rate andforce of contraction. Restoration ofcytosolic calcium to baseline levelsoccurs in cardiac diastole througha combination of active transportfrom the cytosol back to the SR andinto the extracellular space, bothagainst calcium concentration gra-dients. The former occurs by theaction of SERCA2a in the SR mem-brane and the latter occurs via aNa+/Ca2+ exchanger (NCX) in thecell membrane.

SR calcium reuptake is under tightphysiological control to facilitateadjustments to inotropy, chrono-tropy, and relaxation kinetics, par-ticularly via changes to the phos-phorylation status of the proteinphospholamban, which associateswith SERCA2a and modulates itsfunction.6 SR calcium reuptake isalso regulated by posttranscriptionalregulation of component gene ex-pression (eg, by noncoding RNAs,such as microRNA-257), posttrans-lational modifications to SERCA2a(eg, by small ubiquitin-like modifier[SUMO] proteins8), protein-proteininteractions (eg, with S100A1, whichregulates the activity of SERCA2aand RyR9), and redox regulation.However, in the failing cardiomyo-cyte, a combination of factors re-duce SERCA2a activity and impaircytosolic calcium clearance. Thisleads to the following: (i) increasedend-diastolic cytosolic calcium thatcauses impaired cardiomyocyte re-laxation, and in particular, slowerrates of relaxation and stiffness;(ii) depletion of SR calcium stores,causing reduced systolic RyR calci-um flux and systolic impairment;and (iii) compensatory mechanisms,such as RyR leakage and upregula-tion of NCX, leading to electrical

46


Gene therapy for heart failure - Morley-Smith and others


AAVI adeno-associated virus type 1

BNP bioengineered nanoparticles

HF heart failure

LVAD left ventricular assist device

LVEF left ventricular ejection fraction

NAb neutralizing anti–AAV antibody

NCX Na+/Ca2+ exchanger

NT-proBNP N-terminal pro–brain natriuretic peptide


rAAV recombinant AAV

RyR ryanodine receptor

SCID-X1 severe combined immunodeficiency

SERCA2a sarco(endo)plasmic reticulum Ca2+ ATPase type 2a

SR sarcoplasmic reticulum

SUMO small ubiquitin-like modifier

wtAAV wild type AAV

STUDY ACRONYMS

AC6 Adenylyl Cyclase type 6 gene transfer for chronic HF [trial]

AGENT-HF AAV1-CMV-Serca2a GENe Therapy trial in Heart Failure

CUPID Calcium Upregulation by Percutaneous administration of gene therapy In cardiac Disease [trial]

SDF-1 Stromal cell-Derived Factor gene transfer for HF [trial]

SERCA-LVAD investigation of the safety and feasibility of AAV1-SERCA2a gene transfer in patients with chronic heart failure and a Left Ventricular Assist Device

47

instability and a greater propensityfor ventricular arrhythmias. Thiscombination is evident in isolatedcardiomyocytes where contractionoccurs with lower amplitude andslower onset (Figure 1).10

Restoring activity of SERCA2a mightbe one strategy to augment func-tion in the failing cardiomyocyte.This could be achieved by directlyincreasing SERCA2a expression, byenhancing SERCA2a activity, by in-creasing the expression of factorsthat enhance its activity (eg, theSUMO proteins), or by removingfactors that inhibit its function (eg,unphosphorylated phospholamban).Translational gene therapy programsin HF have, to date, focused on approaches to directly increaseSERCA2a expression.

CLINCAL TRIALS WITHAAV1.SERCA2A

The laboratory data supportingstrategies to directly increase SER-CA2a expression have been exten-sively reviewed elsewhere.5,11 Briefly,

studies in isolated human cardiomy-ocytes and animal models using viral vector transduction with theSERCA2a transgene show normal-ization of calcium fluxes, correctionof cell contractile properties, andimprovements in overall cardiacfunction with a reduction in left ven-tricular (LV) volumes (Figure 1).10,12,13

Furthermore, in contrast with otherpositive inotropes that are typicallyproarrhythmic, preclinical studiesfrom our lab and others demonstratethat SERCA2a gene therapy im-proves myocyte energetics and re-duces the propensity for ventriculararrhythmias.14 Multiple mechanismsmay explain the observed antiar-rhythmic effects (Figure 2, page 48).5

Vector choice

To achieve target protein (eg, SER-CA2a) expression at levels sufficientto influence myocardial biology andorgan function, the transgene mustreach the myocardium, bind to andenter individual cardiomyocytes,be transported into the cell nucle-us, and be recognized by the host

transcriptional complexes. Virusesare a natural example of these bio-logical steps being achieved in anefficient manner. Viral vectors re-main the most commonly usedvector above nonviral alternatives,such as microparticles that have tobe engineered to enter cells andcooperate with translation, or nakedplasmid DNA that, although non-pathogenic and mildly immuno-genic, is largely destroyed by lyticenzymes before reaching the cellnucleus and results in a lower effi-ciency.15 Several viruses carry a pre-evolved predilection for specificcell types, and as a result, can fa-cilitate tissue targeting despite astraightforward systemic administra-tion. AAVs, adenovirus, lentiviruses,and retroviruses have all been stud-ied as candidate vectors.

Disadvantages of viruses are promi-nently related to their immuno-genicity. Recognition of viral anti-gens potentially stimulates bothantibody- and cell-mediated re-sponses, which clinically presentsin a wide spectrum of responsesfrom asymptomatic seroconversionto a severe systemic inflammatoryresponse. In an early dose-escala-tion study using an adenovirus vec-tor for ornithine transcarbamylasedeficiency, one subject receiving thehighest dose developed a severeinflammatory response, which ledto multiorgan failure and death.16

This reflects the immunogenic ef-fects of adenovirus as a commonpathogen. Moreover, while virusescan have tropism for specific organsor cells and can be physically deliv-ered to specific body compartments,off-target transfection of other tis-sues is common and has the po-tential to provoke inadvertent, off-target side effects. Aside from thedeleterious systemic effects of anacute immune response, the genesisof anticapsid antibodies and specif-ic memory T cells may prevent the



Figure 1. Abnormal contraction profiles and calcium transients are corrected afterSERCA2a gene transfer.

Human cardiomyocytes from failing (left, right) and nonfailing (center) hearts were obtained andstudied in isolation. Failing cardiomyocytes show reduced velocity and amplitude of cell shorteningcompared with nonfailing cardiomyocytes, which was associated with a prolonged calcium transient.Isolated cells were treated with an experimental adenovirus containing the SERCA2a transgene, and24-hours postinfection the cells showed a normalization of contractile properties and calcium transientduration. Fura-2 ratio is a measure of intracellular calcium. Abbreviations: SERCA2a, sarco(endo)plasmic reticulum Ca2+ ATPase type 2a.From reference 10: del Monte et al. Circulation. 1999;100:2308-2311. © 1999, American HeartAssociation, Inc.

Myocyte from afailing heart

Fura-2 ratio

(360/380)

Cell shortening

(%)

1 sec

0

6

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Myocyte from anonfailing heart

Myocyte overexpressingSERCA2a from a failing heart

48

therapeutic virus from transducingthe target cell, thus limiting its effects both in subjects who havepreviously received the recombinantvirus and in subjects who have pre-viously encountered a wild typevirus displaying similar capsid anti-gens.17 This has important implica-tions for retreatment, if required,in individuals and for potential ben-efit in populations with high ratesof existing immunity. In general,adenoviruses have shown greaterimmunogenicity than other candi-date vectors, in particular, comparedwith the nonpathogenic AAV.

Another concern with viral vectorsis the potential for insertional mu-tagenesis resulting from recombina-tion of the transgene with the hostgenome, which risks initiating can-cer.18 Again clinical trials yield di-

rect experience. Trials of a retroviralgene transfer for severe combinedimmunodeficiency (SCID-X1) showedinitial promise, but these trials werestopped after the emergence of aclonal T-cell population in 2 patientsat 3 years posttransfection, occur-ring due to transgene integrationnear an oncogenic promoter re-gion.19 This is a major concern forintegrating vectors, including retro-viruses and some lentiviruses.15

Despite these specific limitations,viruses are currently the best vectorfor administration of gene therapy.Historically, the adenovirus hasbeen favored and is still efficient asa laboratory tool, but more recently,AAVs have come to the fore. AAVsare small (25 nm, 4.7 kb), nonen-veloped viruses from the Parvovirusfamily.15 A total of 12 human sero-

types have been identified (AAV1to AAV12). The specific characteris-tics that make AAVs preferable incardiac gene therapy are: 1. Low pathogenicity. AAV doesnot cause a recognized disease inhumans and requires coinfectionwith an adenovirus or herpesvirusto replicate; 2. AAV elicits only a mild and pre-dominantly antibody-mediated im-mune response; 3. There is a predilection of AAVserotypes 1, 6, 8, and 9 to transducecardiac and skeletal muscle, thustargeting the transduction to thetissue of interest; 4. Wild type AAV (wtAAV) can inte-grate into the host genome, butrAAV persists in the nucleus as astable episomal concatemer,20 withvery low rates of integration, whichgreatly reduces the risk of insertion-



Figure 2. SERCA2a gene therapy as an antiarrhythmic positive inotrope.

The declining heart function propagates a series of electrophysiological abnormalities that cause a greater propensity to ventricular arrhythmia. These abnormalities can be modulated by SERCA2a gene transfer. Abbreviations: APD, action potential duration; DAD, delayed after depolarization; EAD, early after depolarization; I/R, ischemia/reperfusion; HF, heartfailure; LV, left ventricle; MI, myocardial infarction; RyR2, cardiac ryanodine receptor; SERCA2a, sarco(endo)plasmic reticulum Ca2+ ATPase type 2a; SR,sarcoplasmic reticulum; VF, ventricular fibrillation; VT, ventricular tachycardia.From reference 5: Sikkel et al. Br J Pharmacol. 2014;171:38-54. © 2014, The British Pharmacological Society.

al mutagenesis.21 No rAAV-inducedtumors have been identified in human studies to date,22 although a recent paper described circum-stances under which integration ofAAV vectors in mice could result inhepatocarcinomas23; 5. AAV’s durability within cardiomy-ocytes. Once present as an episome,the transgene remains present forthe lifetime of that cell, if they donot divide or they are not deacti-vated by cell-cycle machinery. Thisdurability has been seen in animalmodels and in clinical trials usingan AAV vector in hemophilia pa-tients, and it is likely to be relatedto the low level of cardiomyocyteturnover and cell-mediated immu-nity to AAV infection24; and6. rAAV vectors have already showna reassuring safety profile in exist-ing clinical trials for cystic fibrosis25

and hemophilia B.26

For these reasons, AAV was chosenfor the SERCA2a gene therapy clin-ical trials and for the forthcoming I-1c and S100A1 gene therapy trials.The rAAV designed for SERCA2agene delivery in clinical studiescombines the wild type capsid se-quence from AAV1 with the invertedterminal repeat sequences fromAAV2. The human SERCA2a gene(as copy DNA) with a cytomegalo-virus promoter is substituted inplace of the wtAAV’s two open read-ing frame elements (the rep andcap genes). The lack of the wtAAV’srep and cap genes yields the recom-binant virus replication deficient,and the AAV capsid proteins are theonly potentially immunogenic anti-gens expressed. The AAV1.SERCA2aproduct was manufactured by Cel-ladon as MYDICAR™.

The initial phase 1/2a studies in hu-mans were undertaken with indus-try leadership from the CelladonCorporation in the two stages of theCUPID-1 trial.22,27-29 This was fol-

lowed by an industry phase 2b study(CUPID-2) assessing efficacy in alarger cohort,30 with two further ac-ademically led studies (SERCA-LVAD[investigation of the safety and fea-sibility of AAV1-SERCA2a genetransfer in patients with chronicheart failure and a Left VentricularAssist Device] and AGENT-HF[AAV1-CMV-Serca2a GENe Therapytrial in Heart Failure]) runningalongside. The mode of delivery ofthe AAV1.SERCA2a product in allof these studies was a single intra-coronary infusion procedure, whichwas planned according to individualcoronary anatomy to achieve maxi-mal delivery to the LV myocardium.

CUPID-1 trial

This study tested the first applica-tion of gene therapy as an HF ther-apeutic, with a primary aim to testsafety as a first-in-man study.31 TheCUPID-1 trial was a two-stage, mul-ticenter trial in the US that coveredthe phase 1 and 2a stages of devel-opment. All patients in CUPID-1had advanced HF with persistentNew York Heart Association (NYHA)class III symptoms despite optimizedmedical therapy, LV ejection fraction(LVEF) <30%, and maximal oxygenconsumption <16 mL/kg/min. A pre-existing implantable cardioverterdefibrillator (ICD) was mandated forprotection against the possibility ofinduced arrhythmia and for monitor-ing arrhythmia burden. Initially, pa-tients could enroll with absent (titer<1:2) or low (titer 1:2) levels of neu-tralizing anti–AAV antibody (NAb).

Stage 1 was an open-label, single-arm, dose-escalation study in 4 cohorts (very low-, low-, mid-, andhigh-dose cohorts; each n=3) andthe primary aim was to establishsafety. The different dosing regimenscorrespond to the number of rAAVviral particles infused, with verylow-, low-, mid-, and high-dose

regimens infusing 1.4x1011, 6x1011,3x1012, or 1x1013 DNase-resistantparticles, respectively. Allocation tothe high-dose group did not occuruntil the Data Monitoring Commit-tee reviewed safety data from thevery low-, low-, and mid-dose co-horts, and these data are presentedin the first report from Jaski et al.29

This interim analysis was reassur-ing (there were a variety of expectedadverse events, including 1 deathadjudicated as expected and notrelated to the study drug) and, fol-lowing review by the Data Monitor-ing Committee, authorization wasgiven to progress to the high-dosecohort of stage 1 and commencerecruitment for stage 2.29

Stage 2 was a randomized, con-trolled, double-blind study to eval-uate the low-, mid-, and high-dosecohorts, which were compared witha blinded, placebo-controlled groupreceiving a sham infusion. The LVEFcriterion was relaxed to <35% andthe maximal oxygen consumptionto <20 mL/kg/min. Crucially, the in-vestigators adjusted the inclusioncriteria regarding NAb status, suchthat henceforth only patients withabsent NAb levels (titer <1:2) couldbe enrolled. This was on the basisthat, in stage 1, the clinical statusof 2 patients quickly deterioratedand LV assist device (LVAD) implan-tation and cardiac transplantationwere required. The subsequent examination of excised myocardialtissue using quantitative polymerasechain reaction assays showed anabsence of the SERCA2a transgene,suggesting neutralization of therAAV vector by preexisting NAbsprior to successful transduction.29

The key result was a dramatic screen-ing dropout caused by the pres-ence of NAbs. Of the 509 patientsscreened, 265 patients (52%) wereexcluded due to NAbs. After otherexclusions, 39 patients were en-rolled in stage 2 (Figure 3, page 50).

49



The key finding was confirming safe-ty in these small patient numbers,as patients in all arms of the studysuffered expected adverse eventsrelated to HF, without complicationsattributable to the gene therapyproduct or its administration. Theoccurrence of HF adverse eventswas lower with an increasing doseof the study drug, suggesting a pos-sible dose-related efficacy. Whilethis study was relatively small andthe prespecified primary end pointwas incidence and severity of ad-

verse events,28 potential efficacywas further evaluated in the reportof this data at the 12-month fol-low-up.27

The investigators studied multipleend points. First, they studied thechange in 7 markers of HF clinicalefficacy at 6 months by individualand by group, and they assessedclinical outcomes using the Kaplan-Meier approach. The efficacy mark-ers were grouped into 4 domains ofefficacy: symptomatic (NYHA class

and HF questionnaire), functional(6-minute walking distance andmaximal oxygen consumption oncardiopulmonary exercise testing),biomarkers (natriuretic peptides),and structural (echo markers of re-modeling). For the group analyses,a comparison of mean data wasused, while a scoring system basedon clinically meaningful changeswas used for the individual analyses,highlighting concordant or discor-dant changes of the multiple vari-ables. These parameters formed

50



Excluded (n=298)• NAb titer too high (n=265)• Inclusion/exclusion criteria (n=16)• Excluded for medical condition (n=4)• Declined participation (n=4)• Inadequate quality echo (n=3)• Other (n=3)

Allocated to andtreated with

AAV1/SERCA2alow dose

6x1011 DRP(n=8)


AAV1/SERCA2amid dose

3x1012 DRP(n=8)


AAV1/SERCA2ahigh dose1x1013 DRP

(n=9)


placebo (n=14)

Excluded (n=24)• Inclusion/exclusion criteria (n=20)• Declined participation (n=2)• Noncompliant (n=1)• Other (n=1)

Prescreened for AAV NAb(n=509)

Assessed further foreligibility (n=63)

Randomized (n=39)

Analyzed (n=8) Analyzed (n=8) Analyzed (n=9) Analyzed (n=14)

Figure 3. Screening and enrollment in the CUPID-1 trial.

For stage 2 of this trial, the accepted titer for NAbs was modified such that any patients with a titer ≥1:2 were excluded. Of the 509 patients screened,52% were ineligible using this criterion. Abbreviations: AAV, adeno-associated virus; CUPID, Calcium Upregulation by Percutaneous administration of gene therapy In cardiac Disease; DRP,DNase-resistant particles; NAb, neutralizing anti–AAV antibodies; SERCA2a, sarco(endo)plasmic reticulum Ca2+ ATPase type 2a.From reference 27: Jessup et al. Circulation. 2011;124:304-313. © 2011, American Heart Association, Inc.

the primary efficacy end point suc-cess criteria, which required any ofthe following: (i) improvement inat least 2 of the 4 efficacy domainsin the group analysis with a P<0.2,with a numeric superiority of activevs placebo in all domains; (ii) im-proved score in the individual effi-cacy analysis with a P<0.2; or (iii)improved time to event in theKaplan-Meier analysis. Second, theystudied the occurrence of recurrentclinical events as a marker of clini-cal outcome, using a joint frailtymodel to account for factors oftenconfounding standard outcometests. The joint frailty model allowsthe analysis to account for the num-ber of clinical events (eg, numberof HF hospitalizations rather thanthe time to first hospitalization),varying severity of clinical events(eg, cardiovascular death vs HF hos-pitalization), and the effect of ter-minal events on the risk of furtherclinical events (ie, early death pre-vents further hospitalizations).

Using these criteria, the primary ef-ficacy outcome was met. Patientsreceiving high-dose therapy showedstabilization of their HF comparedwith patients receiving placebo whoshowed progressive HF deteriora-tion. In the individual-level analysis,there was a significant improvementin the individual efficacy score inhigh-dose vs placebo groups (whichalone was sufficient to meet the pri-mary outcome criteria). In the group-level analysis, there was an improve-ment in active vs placebo groups in3 out of 4 domains (though not exclusively in the high-dose group).The outcome end point was met witha significant reduction in the dura-tion of cardiovascular hospitaliza-tions in placebo vs high-dose groups.

CUPID-1 confirmed the safety ofAAV1.SERCA2a delivery in patientswith advanced HF at 12 months,which has been reiterated at 36

months in this small initial cohort.22

This report also provided further evi-dence of a persistent efficacy benefitin high-dose vs placebo groups,22

with the joint frailty model methodshowing an 82% reduction in recur-rent cardiovascular events adjustedfor individual frailties (ie, suscepti-bility to recurrent events) and cor-related with terminal events (hazardratio [HR], 0.18; P=0.048; Figure 4).A total of 13 of the 39 patients haddied after 3 years of follow-up, nonerelated to the gene product or itsadministration, and there was a nu-merically, but not statistically, greaterchance of survival in patients treatedwith high-dose therapy vs placebo.22

Potential limitations of CUPID-1relate to the inferences about effi-cacy that can be drawn from thedata, and these have received closeattention since the neutral CUPID-2trial report. It is important to em-phasize that the CUPID-1 investiga-tors clearly acknowledged that the

trial was small and designed onlyto demonstrate safety, and the re-port correctly discusses efficacy withclear statements about the limita-tions of available data.27 Beyondthis, commentators have questionedthe matching of baseline HF severitybetween the experimental groups.The report does not perform statis-tical comparisons of baseline char-acteristics, but numerically, patientsin the placebo group have higherN-terminal pro–brain natriureticpeptide levels (NT–proBNP), lowerLVEF, lower peak VO2, and greaterincidence of preexisting additionalcardiovascular conditions in com-parison with the AAV1.SERCA2agroups (Table 2 in the main body ofthe Jessup et al report and Table 10in its supplementary data27). Thisimbalance is particularly apparentin the high-dose group. In addition,recruitment to the high-dose grouponly commenced after 15 patientshad already been recruited to place-bo, low-dose, and mid-dose groups.

51



Placebo

AAV1.SERCA2a; HR, 0.18; P=0.048

2.0

1.8

1.6

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1.2

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0.00 2 8 10 3264 12 18 201614 22 28 30 322624

Month

Cu

mu

lati

ve r

ate

of

no

nte

rmin

al

eve

nts

Figure 4. Cumulative clinical events at 3 years after administration ofAAV1.SERCA2a.

CUPID-1 examined the clinical outcome using a joint frailty model that reports time to recurrentclinical events adjusted for correlated terminal events, and at 3 years, there was a significant reductionin events in patients who received high-dose AAV1.SERCA2a compared with placebo. Abbreviations: AAV, adeno-associated virus; CUPID, Calcium Upregulation by Percutaneous ad-ministration of gene therapy In cardiac Disease; HR, hazard ratio; SERCA2a, sarco(endo)plasmicreticulum Ca2+ ATPase type 2a.From reference 22: Zsebo et al. Circ Res. 2014;114:101-108. © 2014, American Heart Association, Inc.

This delay was appropriate and pre-specified due to the dose escala-tion in stage 1, such that completesafety data for the high-dose cohortwas awaited when stage 2 recruit-ment started. Together, these factorsimply that any apparent clinicalbenefit, specifically the dose rela-tionship (ie, added benefit of thehigh dose vs low dose or mid dose),may also be partly explained bybaseline imbalances, proceduralexperience, and study progressionrather than a treatment effect.

The methodology has come undersome scrutiny. Proponents of thestated primary efficacy outcomewould argue that its three strands(group, individual, and clinical out-come) and its emphasis on concor-dance of efficacy outcomes providegreater specificity and allow thestatistical testing to accept the lessrigorous P<0.2 level used as the testfor significance, and would arguethat the joint frailty model carriesimportant advantages over Kaplan-Meier outcome analyses as out-lined above. However, detractorsmight make the following comments:(i) in the symptom and functionalcriteria, it is the least robust meas-ure that provides the significant re-sult (for symptoms, the subjectiveassessment of NYHA class is signif-icant, but an objective HF question-naire shows no difference; in thefunctional testing, the submaximal6-minute walking test shows signif-icant change, but maximal oxygenuptake as the gold standard meas-ure shows no difference); (ii) in thegroup-level analysis, the domainsuccess criteria generalize to activevs placebo and actually rely on thelow-dose group as much as the high-dose group to meet the primaryend point, where the authors’ con-clusions emphasize a dose-relatedrelationship and improved efficacyin the high-dose group; and (iii)there is justification for using P<0.2

for the individual efficacy scoreswhere there are multiple sorting cri-teria and statistical controls, butthis is less clear for the group-levelanalysis, where the statistical poweris weaker simply due to the smallnumber of patients.

In summary, CUPID-1 certainly pro-vided evidence for feasibility andsafety of using AAV1.SERCA2a inpatients with advanced HF, whichjustified progression to larger clini-cal studies to examine the product’sclinical efficacy in more detail.

CUPID-2 trial

Drawing on the experience from theCUPID-1 trial, the investigators setout to demonstrate clinical efficacyof AAV1.SERVCA2a in patients withadvanced HF.30 CUPID-2 was a phase2b, double-blind, randomized, place-bo-controlled trial that allocatedpatients 1:1 to receive placebo orhigh-dose AAV1.SERCA2a (1x1013

DNase-resistant particles).32 All pa-tients with NAb titers ≥1:2 were in-eligible (which, similar to CUPID-1,excluded 59% [921/1558] of patientsinitially screened). The trial used ajoint frailty model for the primaryoutcome to properly account forthe burden of recurrent HF events,similar to CUPID-1, and there werestrict HF severity criteria (LVEF <35%,hospitalization for HF within theprevious 6 months, and high brainnatriuretic peptide levels within theprevious 30 days) to ensure a highrate of clinical events. Recruitmentconcluded in June 2014 after en-rolling 250 patients in 54 centers.Our institution was the lead UK cen-ter and the largest European recruit-ing site.

The results from the CUPID-2 trialare now available; however, theydo not support the hypothesis that AAV1.SERCA2a is efficaciousin patients with advanced HF on

optimized medical and device ther-apy.1,33 In the final modified inten-tion-to-treat population, 121 pa-tients received treatment withAAV1.SERCA2a and 122 patientsreceived placebo (total n=243). Forthe primary outcome, there were232 recurrent events recorded—128 in the placebo group and 104in the treatment group—equatingto a nonsignificant 7% risk reduc-tion for recurrent HF events in thepresence of HF terminal events inpatients treated with AAV1.SERCA2avs placebo (HR, 0.93; 95% CI, 0.53-1.65; P=0.81). Similarly, there wasno treatment effect evident for thepowered secondary end points (all-cause death, need for a mechanicalcirculatory support device, or hearttransplant) or exploratory endpoints (improvement in NYHAfunctional class, 6-minute walkingdistance, and quality of life [as-sessed by a questionnaire]). In theprespecified subgroup analyses,there were no subgroups where theresults differed. Specifically, therewas no sustained benefit seen inthe nonischemic HF subgroup, patients who might have a bettersubstrate for effective gene therapy.Importantly, no safety concernswere reported. Almost all partici-pants were Caucasian males, butthat aside, randomization achieveda good balance of baseline parame-ters between placebo and treatmentgroups, and an excellent propor-tion of participants were receivingthe guidelines’ recommended HFtherapies.

Other clinical trials using AAV1.SERCA2a

Three further studies were in pro-gress in April 2015 when the initialfindings from CUPID-2 were an-nounced. However, at the time thatthis manuscript was prepared, twoof these were suspended and oneclosed due to the neutral outcome

52



of the CUPID-2 trial. None of thethree studies had completed re-cruitment, so any data yielded willbe incomplete, but nonetheless,they may provide further substanceto the debate around CUPID-2.

SERCA-LVAD trial

The SERCA-LVAD trial (NCT00534703)was an investigator-led trial based atour institution and funded by theBritish Heart Foundation.34 At thetime of writing this article, the trialhad been suspended. This studyaimed to test safety and efficacy inpatients with long-term LVADs for chronic HF. Recruitment com-menced in June 2014 and the firstpatient received the investigationalmedicinal product at Harefield Hos-pital on July 23, 2014. This was thefirst LVAD patient in the world toreceive gene therapy for HF. Thedesign was a two-center, double-blind, randomized, controlled trialthat enrolled 24 stable patients withchronic HF treated with an LVADand allocated these patients 2:1 toreceive AAV1.SERCA2a or placebo.There were 4 goals of the study: (i)assess the safety and feasibility inLVAD patients (primary outcome);(ii) systematically assess the mag-nitude of SERCA2a gene expressionin transfected patients using tissuefrom an elective percutaneous LVbiopsy taken 6-months posttrans-fection; (iii) directly address thehypothesis that the presence of cir-culating NAbs blocks viral transduc-tion, considering that all NAb posi-tive patients were excluded fromthe CUPID-1 and CUPID-2 studies—here randomization was stratified toinclude both NAb positive and NAbnegative patients in equal propor-tions in the active and placebo arms;and (iv) test the exploratory hypoth-esis that the effects of SERCA2agene therapy might be magnified inthe presence of optimal LV loadingconditions facilitated by the LVAD.

AGENT-HF trial

The AGENT-HF trial (NCT01966887)was an investigator-led trial based inFrance, with the aim of further elu-cidating the reverse ventricular re-modeling effects of AAV1.SERCA2ain ambulatory patients with HF.35

The study had a double-blind, ran-domized, placebo-controlled designand had planned to recruit 44 ad-vanced HF patients without Nabsand use the same product and meth-od of administration as previousstudies. The primary outcome wasLV end-systolic volume assessed bycomputed tomography, and second-ary outcomes included various bio-markers and structural/functionaltests. These detailed assessmentsconducted at a single institutionwould greatly assist interpretationof the CUPID-2 outcome data.

High-dose trial

A further phase 1/2 study (study ofhigh-dose genetically targeted en-zyme replacement therapy [MYDI-CAR] for advanced HF; NCT02346422)was initiated by the Celladon Cor-poration in January 2015 to assessa higher dose administration ofAAV1.SERCA2a.36 The study wasplanned in two phases similar toCUPID-1, with an initial, open-labelphase followed by a phase of ran-domized, double-blind allocation.The “high dose” in the CUPID-1 andCUPID-2 studies was 1x1013 DNase-resistant particles; however, in thisstudy, DNase-resistant particlesand dosing were planned to be 2.5-fold greater. The rationale wasbased on the observed dose-re-sponse in CUPID-1, such that thetreatment effect could be multipliedby increasing the dose. This wouldhave been important if CUPID-2 hadshown either equivocal or clear effi-cacy. However, due to the neutraloutcome from CUPID-2, this studyhas been closed.

WHY DID CUPID-2 FAIL TO SHOW EFFICACY?

These results undoubtedly representa significant setback for the field,but reflect just the first chapter of along story in developing gene ther-apy for HF. The key to going forwardis to understand why the CUPID-2trial yielded neutral results and howthis understanding can be appliedto future studies. The key factors toconsider include: (i) the efficiencyof SERCA2a transgene transductioninto cardiomyocytes, particularlyconsidering the choice of AAV1 asthe delivery vector, the dose used,and the mode of administration;and (ii) the choice of the SERCA2atransgene as a target.2

Transduction efficiency:vector choice, dose, andmode of administration

One explanation for the lack of effi-cacy could be that an insufficientquantity of the SERCA2a transgeneis reaching an insufficient numberof cardiomyocytes to appreciablyalter functioning of the whole heart.Early indications suggest that therewas an inadequate transduction of cardiomyocytes by the SERCA2atransgene due either to an inade-quate number of viral particlesreaching the cardiomyocytes or apoor transduction of the transgeneby the viral vector. The physiologicaleffects observed in animal modelsand isolated cells were associatedwith a several-fold greater increasein the copies of the SERCA2a genethan has been observed in tissuerecovered from patients transfectedin both CUPID studies.37 This im-plies that the rAAV1 vector was inefficient for delivering the trans-gene, that an inadequate dose ofAAV1.SERCA2a was used, that themode of administration was subop-timal, or that it was a combinationof all three.

53



The rAAV1 was adopted as a vectorfor strong reasons that were out-lined earlier, with the main disad-vantage being the high occurrenceof NAbs in the population.17 Cer-tainly, data from the CUPID studieshave confirmed its safety, and inparticular, its low immunogenicity,which is reflected by the absenceof inflammatory sequelae seen withother vectors, such as the adeno-virus.1,16,27 However, it remainspossible that the AAV1’s ability totransduce human cardiomyocytes isreduced in vivo. Further serotypesof AAV have been discovered or en-gineered since the CUPID programwas initiated, and in particular, theAAV9 serotype may show greater ef-ficiency in transduction and greatertropism for cardiac muscle, allow-ing larger doses to be used moreefficienctly.38 A new generation ofso-called bioengineered nanoparti-cles (BNPs) may come to fruition,allowing further cardiac specificityand conferring other advantages,such as an enlarged genome sizeand a nontypical antigenic profilefor AAVs (helping to avoid cross-reactive NAbs).39 The dose used inCUPID-2 was the highest of thedoses tested in CUPID-1 (1x1013

DNase-resistant particles),30 and isequivalent to or exceeding the doseused in other AAV studies,26 but inthe absence of safety concerns withthis dose, there could be rationaleto increase the dose (indeed therewas a study planned to test 2.5x1013

DNase-resistant particles, which hasnow been closed; NCT02346422).36

The mode of vector delivery shouldalso be reviewed. CUPID and asso-ciated studies all used a single an-terograde intracoronary infusion,but there are different modes ofdelivery with their advantages anddisadvantages.15 With a rAAV, thepossible other routes could include:(i) peripheral intravenous infusion,which is beneficial for the patient

and relies on the rAAV’s cell tropismto select cardiomyocytes, but suf-fers from the dilutional effect of thelarge circulating volume; (ii) retro-grade infusion via the coronary sinus, which may allow controlleddwell times and prolonged expo-sure—this has been tested withgood results in a large animal mod-el40; (iii) closed-loop recirculation,with the vector infused into thecoronary artery and then drawn fromthe coronary sinus back to the coro-nary artery catheter via a cardiopul-monary bypass system for oxygena-tion, thereby increasing exposuretime41; (iv) direct intramyocardialinjection (such as was used in therecent STOP-HF trial [Stromal cell-derived factor-1 plasmid TreatmentfOr Patients with Heart Failure]42,43),which can yield sustained trans-gene expression, but may only bein a limited cell number aroundthe injection site; or (v) injectioninto the pericardial space.

Transduction efficacy by differentroutes was examined in animalstudies, and while the anterogradecoronary route initially showedmodest results, subsequent studieswith modifications (eg, greater virusconcentrations, adjustments tocatheter delivery systems, increasedvirus exposure time) yielded im-provements and detailed toxicityand dosing assessments.28 Furtherefforts have included anterogradeinfusion with venous occlusion, is-chemic preconditioning to increasevascular permeability, and concur-rent glyceryltrinitrate infusion toprevent coronary vasospasm andachieve coronary vasodilation,44

though only the latter was adoptedin the CUPID and associated studies.

Is SERCA2a the correct target?

The SERCA2a enzyme is the finalcommon pathway of a complex

molecular network and its activityis subject to control by other fac-tors.6-9 While data from animalstudies and ex vivo human cardio-myocytes support direct transduc-tion of the human SERCA2a geneinto cardiomyocytes as a therapeu-tic approach,10-13 if the cellular milieu is already downregulatingSERCA2a activity, the exogenousSERCA2a may be subject to thesame processes. This could explainthe lack of observed effect.

One such SERCA2a modulator isphospholamban, which complexeswith SERCA2a and inhibits its ac-tivity, most potently when in itsdephosphorylated form. In turn, thephosphorylation state of phospho-lamban is determined by the bal-ance of kinase activity (particularlyprotein kinase A, whose activity isupregulated via b-adrenergic activity)and phosphatase activity (particu-larly protein phosphatase-1 [PPI-1],whose activity is downregulated by the modulator molecule inhib-itor 1c [I-1c]). In HF, the SERCA2a-phospholamban ratio is reducedwith a relatively higher preponder-ance of dephosphorylated phos-pholamban, I-1c activity is de-creased, and b-receptor signalingis desensitized. Conversely, signsof therapeutic benefit have beenseen by blocking phospholambanwith RNA interference in a rat HFmodel,45 increasing I-1c activity using AAV9- or BNP-mediated I-1cgene delivery in a pig HF model,39

delivering of the G protein-inhibitorypeptide b-adrenergic receptor ki-nase C-terminus (bARKct) via AAV6in a pig HF model,46 and overex-pressing adenyl cyclase-6 in amouse HF model.47

Some of these approaches are al-ready in clinical program develop-ment (discussed below). Notably,development of direct phospho-lamban inhibitors for clinical use

54



55



Table I. Completed, ongoing, and planned gene therapy trials in human heart failure.Abbreviations: AAV, adeno-associated virus; AC6, adenylyl cyclase type 6; AdV, adenovirus; AGENT-HF, AAV1-CMV-Serca2a GENe Therapy trial inHeart Failure; BNP, biological nanoparticles; CUPID, Calcium Upregulation by Percutaneous administration of gene therapy In cardiac Disease; HF,heart failure; LVAD, left ventricular assist device; NAb, neutralizing anti–AAV antibodies; RCT, randomized controlled trial; SDF-1, stromal cell-derivedfactor 1; SERCA2a, sarco(endo)plasmic reticulum Ca2+ ATPase type 2a; SERCA-LVAD, investigation of the safety and feasibility of AAV1-SERCA2a genetransfer in patients with chronic heart failure and a Left Ventricular Assist Device; STOP-HF, Stromal cell-derived factor-1 plasmid Treatment fOr Patientswith Heart Failure; VP, viral particles.

Trial

CUPID-1

First-in-man SDF-1 trial

AC6 gene transfer for chronic HF

CUPID-2

STOP-HF

AGENT-AF

SERCA-LVAD

Higher dose AAV1. SERCA2a

First-in-man inhibitor 1-c trial

First-in-man S100A1 trial

Transgene

SERCA2a

SDF-1

AC6

SERCA2a

SDF-1

SERCA2a

SERCA2a

SERCA2a

I1-c

S100A1

Vector

AAV1

Plasmidform

AdV5

AAV1

Plasmidform

AAV1

AAV1

AAV1

AAV2i8 (BNP)

AAV9

Mode of delivery

Single antero-grade intra-coronary infusion

Endomyocard-ial injectionto infarctborder zone



Endomyocard-ial injectionto infarctborder zone





Retrograde infusion via coronary sinus

Dose delivered (VPunless stated)

Very low, low, mid, or high dose (1.4x1011, 6x1011, 3x1012, or 1x1013)

Low, mid, or high dose (5 mg, 15 mg,or 30 mg)

3.2x109 to 1x1012 in 5 dose groups

1x1013

15 mg or 30 mg

1x1013

1x1013

2.5x1013

Very low, low, mid, or high dose (3x1012,1x1013, 3x1013, or 1x1014)

Not yet specified

Phase

1/2a

1

1/2a

2b

2

2b

2a

1/2a

1/2a

1

Trial design

Phase 1: open-label, dose-escalation (n=12);

Phase 2: double-blind RCT using high dose (n=39)

Dose-escalation study (n=17)

Initial dose-escalation phase, then RCT 3:1 (n=56)

Double-blind RCT (n=250)

Double-blind RCT (n=196)

Double-blind RCT (planned n=44)

Double-blind RCT (planned n=24)

Phase 1: open-label;

Phase 2: double-blind RCT (planned n=36)

Phase 1: open-label (plannedn=12);

Phase 2: double-blind RCT (planned n=45)

Not yet specified

Comments

First human HF gene therapy study

Only ischemicHF patients included.

Detailed imagingassessment forfunctional improvement

First use of genetherapy in LVADpatients; first delivery to patients with AAV1.NAb+

BNP to overcome NAb and improve cardiactropism

Highest planneddose is 100-foldhigher than CUPID trials

Retrograde infu-sion may in-crease uptake

Current status

CompletedConfirmed safety, suggestion of efficacy

CompletedConfirmed safety, suggestion of efficacy

ReportingResults expected 2015/2016

CompletedFailed to show efficacy

CompletedFailed to show efficacy

Suspended after CUPID-2results

Suspended after CUPID-2results

Closed after CUPID-2 results

Planning stageTarget phase 1to start first quarter 2016

Planning stageExpected startdate 2016

Ref.

22,27,29,31

44

49

1,30-32

42,43,50

35

34

36

has been slowed after observing asevere HF phenotype in humanswith a sporadic loss-of-functionmutation in phospholamban.48

Separately, the molecules SUMO-1and S100A1 (a small calcium-bind-ing protein) have roles regulatingSERCA2a activity. Sumoylation bySUMO-1 at specific and conservedsites causes posttranscriptionalmodification of the SERCA2a en-zyme to increase its activity andstability. Levels of sumoylatedSERCA2a are reduced in HF, andSUMO-1 gene delivery using AAV9restores function in a pressure over-load model in mice.8 S100A1 isdownregulated in HF and regulatesSERCA2a activity and RyR activityin the SR membrane. S100A1 genetransfer using an AAV6 vector hasshown signs of efficacy in small andlarge animal models.40

All of these factors (and many oth-ers) could have impinged on thesuccess of direct SERCA2a genetransfer in the CUPID-2 study, andequally, could form targets for indi-rect modulation of SERCA2a activity.However, none can be taken com-pletely separate from the next: theyform a complex network of interac-tions, which will all be vulnerableto reciprocal regulation that couldblunt clinical efficacy. However, forthe time being, SERCA2a remainsa very attractive option for clinicalgene therapy for HF.

WHAT IS NEXT IN THECLINICAL PIPELINE?

While the community continues toreflect on results from CUPID-2,there are already a variety of furthergene therapy paradigms ready forclinical evaluation (Table I, page55).1,22,27,29,30-36,42,43,49,50 The I-1c andS100A1 trials should commenceshortly, and the investigators ofthese trials should be congratulated

for their program development andpersistence in light of the CUPID-2trial results.

A few general challenges should bekept in mind. First, it will be impor-tant to ensure clarity of scientificeffect with new trials: already thenext trials planned are changingseveral variables at once (eg, theS100A1 trial will use a different vec-tor, different transgene, and differ-ent delivery route compared with theAC6 trial [Adenylyl Cyclase type 6gene transfer for chronic HF],49

SDF-1 trial [Stromal cell-DerivedFactor gene transfer for HF],50 andCUPID trials). While the novel ap-proaches may be valuable, the riskis that understanding and integrat-ing the outcome data with other tri-als could become more challenging.

Second, the challenge of preexist-ing NAbs remains. In the case ofAAV1, this seems to occur in around60% of patients, and is particularlyproblematic due to cross-reactivityof antibodies to AAVs of varyingserotypes. Currently, the paradigmis to exclude these patients fromtrials, which could significantly im-pede widespread clinical uptake.Various approaches to combat NAbsare being studied, such as plasma-pheresis and bioengineering theAAV capsid to alter its antigenic regions as with the BNP AAV2i8proposed for the I-1c study,17,51

and these ideas warrant further in-vestigation. Finally, the importanceof investor funding for these inno-vative programs should not be underestimated, and we would en-courage all investors to have pa-tience and continue to support thedevelopment of effective clinicalgene therapy programs. While wehave come a long way already onthe journey from the laboratory tothe first clinical trials, we have onlycompleted the first chapter of theclinical development of gene thera-

py for HF, which we hope one daywill deliver important benefits tothe health of our patients.

CONCLUSION

Gene therapy for HF illustrates the scientific transitional journeythrough scientific hypothesis, labo-ratory experimentation, and transla-tion to clinical trials. Much progresshas been made, though many un-answered questions and unmetchallenges remain. What is certainis that SERCA2a gene transfer hasa logical and coherent body of lab-oratory evidence in its support, andthe onus is now on the clinical re-search community to understandand overcome the current limita-tions.2 There are plenty of questionsto be addressed regarding SERCA2agene transfer, but in many ways, thestory is only just beginning.

Acknowledgments. Andrew C. Morley-Smith

is a British Heart Foundation Clinical Research

Training Fellow (FS/13/34/30173) and Alexander

R. Lyon is a British Heart Foundation Intermediate

Clinical Research Fellow (FS/11/67/28954).

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41. Mariani JA, Smolic A, Preovolos A,Byrne MJ, Power JM, Kaye DM.

Augmentation of left ventricular mechanics byrecirculation-mediated AAV2/1-SERCA2agene delivery in experimental heart failure.

Eur J Heart Fail. 2011;13:247-253.

42. Chung ES, Miller L, Patel AN, et al.

Changes in ventricular remodelling andclinical status during the year following asingle administration of stromal cell-derivedfactor-1 non-viral gene therapy in chronicischaemic heart failure patients: the STOP-HF randomized Phase II trial.

Eur Heart J. 2015;36:2228-2238.

43. clinicaltrial.gov.

Study to Evaluate the safety and efficacy ofjvs-100 administered to adults with ischemicheart failure (STOP-HF).


44. Karakikes I, Hadri L, Rapti K, et al.

Concomitant intravenous nitroglycerin withintracoronary delivery of AAV1.SERCA2aenhances gene transfer in porcine hearts.

Mol Ther. 2012;20:565-571.

45. Suckau L, Fechner H, Chemaly E,et al.

Long-term cardiac-targeted RNA interfer-ence for the treatment of heart failure restorescardiac function and reduces pathologicalhypertrophy.

Circulation. 2009;119:1241-1252.

46. Raake PW, Vinge LE, Gao E, et al.

G protein-coupled receptor kinase 2 ablationin cardiac myocytes before or after myocar-dial infarction prevents heart failure.

Circ Res. 2008;103:413-422.

47. Roth DM, Bayat H, Drumm JD, et al.

Adenylyl cyclase increases survival in car-diomyopathy.

Circulation. 2002;105:1989-1994.

48. Haghighi K, Kolokathis F, Pater L,et al.

Human phospholamban null results in lethaldilated cardiomyopathy revealing a criticaldifference between mouse and human.

J Clin Invest. 2003;111:869-876.


Adenylyl cyclase type 6 gene transfer forchronic HF.


50. Asokan A, Conway JC, Phillips JL,et al.

Reengineering a receptor footprint of adeno-associated virus enables selective and systemicgene transfer to muscle.

Nat Biotechnol. 2010;28:79-82.

51. Penn MS, Mendelsohn FO,Schaer GL, et al.

An open-label dose escalation study to eval-uate the safety of administration of nonvi-ral stromal cell-derived factor-1 plasmid totreat symptomatic ischemic heart failure.

Circ Res. 2013;112:816-825.

58




59

his brief review will describe thecurrent therapeutic status ofangiotensin receptor antagonists,placing them in the context of

the evolving understanding of therenin-angiotensin system. A descrip-

tion of the renin-angiotensin systemwas described in a previous article in2001.1 Since then, the physiologicalimportance of the autocrine andparacrine actions of angiotensin andits metabolites has fundamentally

changed the nature of the renin-an-giotensin system from being that ofjust an enzyme cascade generatingcirculating angiotensin II to one thatincludes a renin-based system foundin many tissues and organs.

In order to describe the different an-giotensin antagonists, it is necessaryto summarize the metabolic pathwaysthat produce different angiotensins(Figure 1).2 Angiotensins are generat-ed from angiotensinogen, the 14 aminoacid parent peptide. Angiotensinogenis present in both plasma and tissuesand it is synthesized in the liver. An-giotensin I, a 10 amino acid peptide,is generated by either the circulatingaspartate-protease enzyme renin orcathepsins in the tissue (lysosomeserine proteases). There are three en-zyme isoforms, including the d-iso-

form that is present in the cardiovas-cular system and the γ-isoform that isfound in neutrophils. Tonin, an addi-tional tissue serine protease, formsangiotensin II, an 8 amino acid pep-tide, from tissue angiotensinogen. The

various angiotensin peptide subtypes(II-V) are generated by a family ofpeptidases termed angiotensinases.These physiologically active peptidesbind to different angiotensin recep-tors whose activity results in a widerange of physiological responses (Fig-ure 1), although some of the claimedresponses are still speculative.

Clearly, the cascade of angiotensinsubtype peptides generated by therenin-angiotensin series of enzymesprovides a complex network of physi-ological effects. These will not be fur-

T

Trails of DiscoveryAngiotensin receptor antagonists

J. Desmond Fitzgerald, BSc, FRCP, FFPMMateria Medica - Mere Croft - Nr Knutsford - UK

Keywords: angiotensin receptor antagonist;angiotensin II receptor; G protein-coupled receptorAddress for correspondence:Dr J. Desmond Fitzgerald, Materia Medica, Mere Croft, Chester Road, Mere, Nr Knutsford,Cheshire WA16 6LG, UK(e-mail: [email protected])



Figure 1.Angiotensin peptide formation.

Abbreviations: Ang,angiotensin; APA,aminopeptidase A;APN, aminopeptidase N;AT4R, angiotensin type 4 receptor; MasR,Mas receptor; NEP,neutral endopeptidase(neprilysin); POP,prolyl endopeptidase;(P) RR, proreninreceptor; TOP, thimetoligopeptidase.From reference 2:Gironacci et al. ClinSci (Lond). 2013;125:57-65. © 2013,Biochemical Society.

ther discussed, but the nature of theangiotensin subreceptors and specificantagonists will now be described.

Angiotensin II type 1 receptor (Figure2)3 activation by angiotensin II causesa range of intracellular responses dueto the activation of receptor-specificG proteins. It is now clear that the an-giotensin receptor can be activated bymechanical, nonpeptide, and peptidesignal mediators. The G proteins thatinteract with angiotensin I include G1,Gq/II, G12, and G13.4 Activation of thesesubreceptor types results in a rangeof intracellular downstream effects,including calcium release, diacyl glyc-

erol signaling, etc.5 Given the rangeof tissue responses to angiotensin(Figure 1), the rationale for seekingspecific inhibitors of their receptorsfor therapeutic purposes is clear.

INITIAL DISCOVERIES

In the mid–1950s, Peart first identifiedangiotensin and called it “hyperten-sion,” though subsequently this waschanged to angiotensin II.6 Gross, work-ing in Ciba, showed that angiotensin IIstimulated aldosterone release fromthe adrenal cortex.7 The identificationof nonpeptide angiotensin II antago-nists enabled clinical scientists to ex-

plore the actions of angiotensin II inmany experimental and clinical situa-tions. The first angiotensin II antago-nist to be discovered was saralasin in1971.8 Saralasin was a close analogueof angiotensin II, where the asparagine,isoleucine, and phenylalanine at po-sitions 1, 5, and 8 were replaced witha sarcosine, valine, and isoleucine(Sar1, Val3, Ala8). Other analogueswith substitutions in the 8th positionof angiotensin II were also synthesized.

The initial research leading to the discovery of saralasin was performed in the Norwich-Eaton pharmaceuticalcompany (US) by Pals et al.8 Their ini-


Angiotensin receptor antagonists - Fitzgerald

60

Figure 2. Human angiotensin II receptor type 1 model.

The α-helical regions are denoted by a twist in the structure and the green arrows denote the direction of the helix. Cysteine disulfide bonds are indicatedby blue lines with an orange-shaded S. Abbreviations: Ang, angiotensin; ARB, angiotensin receptor blocker.From reference 3: Nistala et al. Am J Physiol Renal Physiol. 2013;304:F1105-F1113. © 2013, The American Physiological Society.

tial research strategy was to identifycompounds that would block differentelements of the renin-angiotensin sys-tem by inhibiting three potential reac-tions: (i) renin release; (ii) the conver-sion of angiotensin I to angiotensin IIby carboxypeptidases; or (iii) the vas-cular contractile actions of angioten-sin II. In retrospect, these were ambi-tious aspirations. Subsequently, thisgroup focused on angiotensin II an-tagonists, partly because the synthe-sis of these peptides, based on theknown structure of angiotensin II, waseasier than the other biological targets.Furthermore, there was a well-charac-terized in vitro rabbit aortic vascularmuscle system that contracted to angiotensin II; therefore, the systemcould be used to detect antagonistsof angiotensin II vasoconstrictor ac-tions.9 They discovered that the Sar1,Val3, Ala8 analogue of angiotensin IIblocked the contractile actions in therabbit model. This reaction was po-tent (pA2=8.61) and selective becauseit did not block responses to nora-drenaline or histamine. This peptideanalogue, now called saralasin, whichironically had been their first synthe-sized compound, was taken into clini-cal trials after regulatory approval.

In clinical studies, responses to sar-alasin correlated with renin levels inpatients when infused for 30 min withsaralasin (10 µg/kg). Patients with lowrenin levels who were infused with sar-alasin showed a large pressor response,which was attributed to the partialagonist properties of saralasin actingon unoccupied angiotensin II recep-tors. However, in patients with highrenin levels, saralasin caused a largedepressor response, which was attrib-uted to the blockade of angiotensin IIreceptors.10

While saralasin could be used as a di-agnostic test for assessing an individ-ual patient’s renin status, it could notbe used as an antihypertensive agentbecause it was not orally active and,

more importantly, it was only a partialagonist and not a full antagonist.11

One of the somewhat complex proper-ties of many G protein-coupled recep-tors is that of inverse agonism, oftendetected more easily in mutated G pro-tein-coupled receptors. This somewhatcounterintuitive phenomenon of ei-ther antagonism or agonism, depend-ing on the experimental conditions, isdiscussed at length by Miura S et al.11

ORALLY ACTIVE ANTAGONISTS

The increasing concerns of clinicalcardiologists about the potentiallyharmful effects of excess activation ofthe renin-angiotensin system, such asacute myocardial infarction and stroke,made antagonism of the endogenouseffects of angiotensin II an attractivedrug target.



61

Figure 3. Structural modifications to the S-8307 and S-8308 compounds to developlosartan and eprosartan. From reference 12: Aulakh et al. Life Sci. 2007;81:615-639. © 2007, Elsevier Inc.

In the early 1980s, scientists in theTakeda Laboratories (Japan) patentedtwo compounds (S-8307 and S-8308)claiming a mild antihypertensive ef-fect that was attributed to binding atthe angiotensin II receptor. As far asis known, these were serendipitousobservations that were noted in theDuPont Merck pharmaceutical com-pany (US) by a drug discovery groupled by “Hank” Timmerman who joinedthe company from the Department ofPharmacology, University of Leiden(Holland).

While the Takeda compounds provid-ed a valuable clue as to the structuralrequirements for angiotensin II recep-tor antagonism, a program of structuraland functional studies was carriedout in the DuPont Company using theTakeda compounds as basic models.This led to the discovery of the angio-tensin II receptor blocker losartan,which was potent, selective, and orallyactive. Losartan was a selective antag-onist of the angiotensin II G protein-coupled receptor.

Medicinal chemists used nuclear mag-netic resonance techniques to obtaindetails of the structures of S-8307 andS-8308. A range of different chemicalsubstitutions was applied to thesebasic structures to improve the speci-ficity and oral activity, which led to thediscovery of losartan in 1986 (Figure 3,page 61).12

Losartan was originally known by thenumber DuP 753. DuP 753 was care-fully evaluated in a range of pharma-cological tests that are summarized in Table I.13 In essence, DuP 753 wasa potent, orally active, specific angio-tensin II antagonist with a long dura-tion of action.14 This latter propertywas subsequently, and serendipitously,attributed to the formation of EXP3174,a 5-carboxylic substituted analogueand active metabolite of DuP 753.15

DuP 753, which was subsequentlycalled losartan, was patented in 1988,

and, in 1991, its profile was publishedafter the first studies on its effects inhuman volunteers and patients werepublished.

SECOND GENERATION ANGIOTENSIN II ANTAGONISTS

The considerable interest in develop-ing improved angiotensin receptorblockers was due to their improvedselectivity of action on the renin-an-giotensin system compared with theirpredecessors—angiotensin-convert-ing enzyme (ACE) inhibitors. It be-came clear that ACE inhibitors wereunable to inhibit the generation ofangiotensin peptides when they areformed in tissues by other enzymes,such as chymases.16 Furthermore, ACEinhibitors block the enzymes respon-sible for metabolizing bradykinin, sothey enhance the endogenous levelsof the angiotensin peptide.

Angiotensin II acts on angiotensintype 1 receptors not only in vascularsmooth muscle, but also in the adre-nal glomerulosa, sympathetic nervoussystem, brain, and heart. Angiotensin IIstimulation of the heart can lead tocardiac hypertrophy and cardiac remod-eling associated with an increase in

tissue collagen. The potential of ex-cess angiotensin II tissue activationto cause different cardiovascular dis-eases has promoted greater interest inantagonizing the widespread actionsof angiotensin II rather than the lessereffects of ACE inhibition on angioten-sin II levels. In addition, ACE inhibi-tion of kininase II leads to an increasein endogenous bradykinin, which mayresult in cough and angioedema.17

In 1990, the DuPont research teampublished three papers demonstratingthat losartan was a specific, orally active angiotensin II antagonist thatlowered blood pressure in experimen-tal hypertension.18,19 Such a publica-tion presumably triggered much inter-est among the cardiovascular groupsof competing pharmaceutical compa-nies. As a result, numerous analoguesbased on the initial biphenyltetrazolenucleus were synthesized.20 Losartanwas marketed in 1994, and within 4

years, 13 other angiotensin II antago-nists entered clinical trials and the firstcompetitive compound to be market-ed was Ciba-Geigy’s valsartan in 1996.

There are now 12 angiotensin recep-tor blockers either in late clinical de-velopment or marketed. Most of the

62



Tests

Binding to rat adrenal cortex microsomes

Specificity

Response to angiotensin II

Blood pressure in renal hypertensive rats

Heart rate or blood pressure in human volunteers

Outcomes3H-angiotensin II Ki =16-30 n/M

No effect on contractile responses to acetyl choline, noradrenaline, renin, angiotensin-converting enzyme, bradykinin, histamine, or serotonin

Blocked vascular contractile responses

Adrenal release of aldosterone: no agonist effects (unlike saralasin)

Reduced elevated blood pressure (ED50parenteral 0.78mg/kg: 0.3mg/kg per os)

Efficacy equivalent to angiotensin-convertingenzyme inhibitors

No effect11,12

Table I. Summary of the in vitro and in vivo pharmacological properties of Losartan.

compounds are structurally analogousto losartan, where 4 of them have thesame biphenyl substitution attachedto the acidic tetrasole contained inlosartan. The affinity of these com-pounds for the angiotensin type 1 receptor, as measured by radioligand-binding techniques, varies between 7 to 9 pKi, with losartan being the low-est and irbesartan the highest. Whenthe compounds are compared for an-tagonism of angiotensin II receptor–mediated contractility of vascularsmooth muscle (rabbit aorta), the pA2ranges from 7 to 10 for the 9 majorcompounds (Table II). While the phar-macological profiles of the above an-giotensin receptor blockers all showpotent antagonism of the actions ofangiotensin II–mediated responses,the individual compounds differ interms of in vitro and in vivo effects.All of the compounds lack effects onother G protein-mediated receptors.However, some of the angiotensin re-ceptor blockers bind to peroxisome-proliferator-activated receptors (PPARs)(Figure 4).21 For example, irbesartanand telmisartan induce transcriptionalactivation of PPAR-γ, but eprosartanlacks this action. Losartan, telmisar-tan, and irbesartan have an effect onthe PPAR-γ nuclear receptor with apotency equivalent to pioglitazone,which is an antidiabetic agent from the

thiazolidinedione group.22 It remainsto be established by appropriate clin-ical studies whether angiotensin re-ceptor blockers with PPAR-γ propertieslead to improved clinical outcomescompared with non–PPAR-γ angioten-sin receptor blockers.

In high concentrations, some angioten-sin receptor blockers can modify thefunction of potassium channels. While

such effects could lead to QT prolon-gation, this has never been observedfor any of the angiotensin receptorblockers in clinical studies.

CLINICAL EFFICACY

Angiotensin receptor blockers are usedextensively in the management of es-sential hypertension.23 They comparefavorably with other classes of antihy-pertensive therapy. Many patientswith diabetes also have hypertension.Some studies in diabetic patients sug-gest that modulating the actions of therenin-angiotensin system has a reno-protective effect.24

A critical clinical aspect is the effectthat modulation of the renin-angio-tensin system has on long-term out-comes, including acute myocardial in-farction, stroke, and overall mortality,both in diabetic and nondiabetic pa-tients. A recent extensive meta-analysiscomparing the effects of ACE inhibitorsvs angiotensin receptor blockers onall-cause mortality, cardiovasculardeaths, and cardiovascular events in

63



Table II. Comparison of the pharmacokinetic profiles of second-generation angiotensin IIreceptor blockers.

Figure 4. Angiotensin receptor blockers with a partial PPAR-γ agonistic effect may en-hance PPAR-γ stimulation to inhibit AT1 receptor activity and activate the AT2 receptor.

Abbreviations: ARB, angiotensin receptor blocker; AT1, angiotensin II type 1 receptor; AT2, angio-tensin II type 2 receptor; ERK, extracellular-signal-regulated kinase; NFKB, nuclear factor-κB;PPAR-γ, peroxisome-proliferator-activated receptor γ.From reference 21: Horiuchi et al. Clin Sci (Lond). 2012;123:193-203. © 2012, Biochemical Society.

Oral dose Prodrug Half-life (hr) Inverse agonist

Losartan 25-100 mg bid + 2.5 ?

EXP3174 – Metabolite 6-9 +

Eprosartan 400-800 mg bid -- 5-9 → N/A

Irbesartan 150-300 mg od -- 11-15 N/A

Olmesartan 20-40 mg od + 10-15 +(Medoxomil)

Telmesartan 40-80 od -- 24 +

Valsartan 80-320 mg od -- 9 +

Candesartan 4-12 mg bid + 9 ?(Cilexetil)

All analogues are more than 90% bound to plasma proteins

diabetic patients concluded that an-giotensin receptor blocker treatmenthad no beneficial effect on these car-diovascular outcomes compared withplacebo, while ACE inhibitors signifi-cantly reduced the incidence of theseevents.25 In summary, angiotensin receptor blockers had no significanteffect on mortality, acute myocardialinfarction, or heart failure hospitaliza-tion, whereas ACE inhibitors reducedall three of these parameters. Thissuggests that a highly specific block-ade of the angiotensin II receptor doesnot have the expected benefit com-pared with ACE inhibitors.26 Angioten-sin receptor blockers did, however, reduce the incidence of stroke in pa-tients with essential hypertension.

The reason for these contrasting effectson outcomes between ACE inhibitorsand angiotensin receptor blockers isnot known, despite the widespreadphysiological role played by angioten-sin II. Perhaps the non–angiotensin IIoff-target properties of ACE inhibitorsplay a role in the differing clinicaloutcomes.

REFERENCES

1. Fitzgerald JD.

Trails of Discovery. A close call: the discov-ery of ACE inhibitors.

Dialog Cardiovasc Med. 2001;6:38-42.

2. Gironacci MM, Longo CarbajosaNA, Goldstein J, Cerrato BD.

Neuromodulatory role of angiotensin-(1-7)in the central nervous system.

Clin Sci (Lond). 2013;125:57-65.

3. Nistala R, Andresen BT, PulakatL, et al.

Angiotensin type 1 receptor resistance toblockade in the opossum proximal tubulecell due to variations in the binding pocket.

Am J Physiol Renal Physiol.2013;304:F1105-F1113.

4. Karnik SS, Gogonea C, Patil S,Saad Y, Takezako T.

Activation of G-protein-coupled receptors: a common molecular mechanism.

Trends Endocrinol Metab. 2003;14:431-437.

5. Higuchi S, Ohtsu H, Suzuki H,Shirai H, Franck GD, Eguchi S.

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Clin Sci (Lond). 2007;112:417-428.

6. Peart WS.

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8. Pals DT, Masucci FD, Denning GSJr, Sipos F, Fessler DC.

Role of the pressor action of angiotensin IIin experimental hypertension.

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9. Furchgott RF, Bhadrakom S.

Reactions of strips of rabbit aorta toepinephrine, isopropylarterenol, sodium nitrite and other drugs.

J Pharmacol Exp Ther. 1953;108:129-143.

10. Wallace JM, Case DB, Laragh JH,Keim HJ, Drayer JI, Sealey JE.

Immediate pressor response to saralasin in man: a test of angiotensin II receptor vacancy.

Circ Res. 1979;44:38-44.

11. Miura S, Fujino M, Hanzawa H,et al.

Molecular mechanism underlying inverseagonist of angiotensin II type I receptor.

J Biol Chem. 2006;281:19288-19295.

12. Aulakh GK, Sodhi RK, Singh M.

An update on non-peptide angiotensin receptor antagonists and related RAASmodulators.

Life Sci. 2007;81:615-639.

13. Wong PC, Price WA, Chiu AT, et al.

Nonpeptide angiotensin II receptor antago-nists: VIII. Characterization of functionalantagonism displayed by DuP753, an orallyactive antihypertensive agent.

J Pharmacol Exp Ther. 1990;252:719-725.

14. Christen Y, Waeber B,Nussberger J, et al.

Oral administration of DuP 753, a specificangiotensin II receptor antagonist, to nor-mal male volunteers. Inhibition of pressorresponse to exogenous angiontensin I and II.

Circulation. 1991;83:1333-1342.

15. Hagino T, Abe K, Tsunoda K,Yoshimhea K.

Chronic effects of MK954, a non-peptideangiotensin II receptor antagonist, on 24hour ambulatory blood pressure, renin-an-giotensin-aldosterone system and renalfunction in essential hypertension.

J Hypertens. 1992;10(suppl 4):224.

16. Urata H, Nishimura H, Gantan D.

Chymase-dependent angiotensin II formingsystem in humans.

Am J Hypertens. 1996;9:277-284.

17. Lacouciére Y, Brunner H, Irwin R,et al; Losartan Cough Study Group.

Effects of modulators on the renin-an-giotensin-aldosterone system on cough.

J Hypertens. 1994;12:1387-1393.

18. Wong PC, Price WA Jr, Chiu AT, et al.

In vivo pharmacology of DuP 753.

Am J Hypertens. 1991;4:288S-298S.

19. Wong PC, Heart SD, Dunsier JV,Timmermans PB.

Nonpeptide angiotensin II receptor antago-nists. Studies with DuP 753 and EXP3174in dogs.

Eur J Pharmacol. 1991;202:323-330.

20. Miura S, Karnik SS, Saku K.

Angiotensin II type I receptor blockers: classeffects versus molecular effects.

J Renin Angiotensin Aldosterone Syst.2011;12:1-7.

21. Horiuchi M, Iwanami J, Mogi M.

Regulation of angiotensin II receptors beyondthe classical pathway.

Clin Sci (Lond). 2012;123:193-203.

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22. Benson SC, Pershadingh HA, Ho CI, et al.

Identification of telmisartan as a uniqueangiotensin II receptor antagonist with selective PPARg-modulating activity.

Hypertension. 2004;43:993-1002.

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Angiotensin receptor antagonists as a treat-ment for hypertension.

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Advanced heart failure treated with continuous-flow left ventricular assist device

M. S. Slaughter and others. N Engl J Med. 2009

67Copyright © 2016, AICH - Servier Research Group. All rights reserved


1 6

2

Efficacy of β blockers in patients with heart failureplus atrial fibrillation: an individual-patient data

meta-analysis D. Kotecha. Lancet. 2014

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Summaries of Ten Seminal PapersAli Vazir, MB, BS, PhD, FRCP, FESC

National Heart and Lung Institute - Imperial College London - Institute of Cardiovascular Medicine and Science Royal Brompton Hospital - UK (e-mail: [email protected])


4Wireless pulmonary artery haemodynamic monitoring in chronic heart failure: a randomised controlled trial

W. T. Abraham and others. Lancet. 2011

9Adaptive servo-ventilation for

central sleep apnea in systolic heart failureM. R. Cowie and others. N Engl J Med. 2015

Coronary-artery bypass surgery in patients with ischemic cardiomyopathyE. J. Velazquez. N Engl J Med. 2016

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The effect of coenzyme Q10 on morbidity and mortality in chronic heart failure: results from Q-SYMBIO: a randomized double-blind trial

S. A. Mortensen. JACC Heart Fail. 2014

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5

Ivabradine and outcomes in chronic heart failure(SHIFT): a randomised placebo-controlled study

K. Swedberg and others. Lancet. 2010

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Selection of seminal papers by Ali Vazir, MB, BS, PhD, FRCP, FESCNational Heart and Lung Institute - Imperial College London - Institute ofCardiovascular Medicine and Science - Royal Brompton Hospital - UK

www.dialogues-cvm.org

Spironolactone for heart failure with preserved ejection fraction

B. Pitt and others. N Engl J Med. 2014


Telemonitoring or structured telephone supportprogrammes for patients with chronic heart failure:

systematic review and meta-analysis R. A. Clark and others. BMJ. 2007

Angiotensin–neprilysin inhibition versus enalapril in heart failure

J. J. McMurray and others. N Engl J Med. 2014

Highlights of the years by Sherri Smith, PhDPublications office

68


Summaries of Ten Seminal Papers - Vazir

n this study, the authors aimed to determine whetherremote monitoring (ie, structured telephone supportor telemonitoring) without regular clinic or homevisits improves outcomes for patients with chronicheart failure. They looked at 15 electronic databases,

hand searched previous studies, and made contact withauthors and experts. Data was extracted by two investiga-tors, who independently screened the results. They re-viewed published randomized controlled trials comparingremote monitoring programs with usual care in patientswith chronic heart failure managed within the community.They discovered 14 randomized controlled trials (4264 patients) on remote monitoring meeting the inclusion criteria, of which, 4 evaluated telemonitoring, 9 evaluatedstructured telephone support, and 1 evaluated both.

They found that remote monitoring programs reduced therates of hospital admissions for chronic heart failure by21% (95% CI, 11%-31%) and all-cause mortality by 20% (95%CI, 8%-31%). Of the 6 trials evaluating health-related qualityof life, 3 reported significant benefits with remote moni-toring, and, of the 4 studies examining health care costswith structured telephone support, 3 reported reducedcost and 1 reported no effect. The authors concluded thatprograms for chronic heart failure that include remotemonitoring have a favorable effect on clinical outcomes in community-based patients with chronic heart failure.

In 2015, some of the authors of this publication performeda Cochrane systematic review, incorporating the latest trialsof structured telephone support and noninvasive hometelemonitoring. They included 41 studies, and, of these, 25studies evaluated structured telephone support (9332 par-ticipants), 18 evaluated telemonitoring (3860 participants),and 2 included studies that compared both structuredtelephone support and telemonitoring with usual care.

In the Cochrane review, they found that noninvasive tele-monitoring reduced all-cause mortality (risk ratio [RR],0.80; 95% CI, 0.68-0.94; n, 3740; studies, 17; I2=24%; grade:moderate-quality evidence) and heart failure–related hos-pitalizations (RR, 0.71; 95% CI, 0.60-0.83; n, 2148; studies,

8; I2=20%; grade: moderate-quality evidence). Furthermore,structured telephone support also reduced all-cause mor-tality (RR, 0.87; 95% CI, 0.77-0.98; n, 9222; studies, 22; I2=0%; grade: moderate-quality evidence) and heart failure–related hospitalizations (RR, 0.85; 95% CI, 0.77-0.93; n, 7030;studies, 16; I2=27%; grade: moderate-quality evidence).These interventions also demonstrated improvements inhealth-related quality of life, heart failure knowledge, andself-care behaviors.

Therefore, there is compelling support for the use of struc-tured telephone support and noninvasive home telemoni-toring, as they reduced the risk of all-cause mortality andheart failure–related hospitalizations, and they improvedhealth-related quality of life, heart failure knowledge, andself-care behaviors. Studies also demonstrated that partici-pants were satisfied with the majority of these interventions.

I

Telemonitoring or structured telephone support programmes for patients with chronic heart failure: systematic review andmeta-analysis

R. A. Clark, S. C. Inglis, F. A. McAlister, J. G. Cleland, S. Stewart

BMJ. 2007;334:942

The President of Ukraine, Viktor Yushchenko, dissolves the Ukrainian Parliament;

Gliese 581 c, a potentially Earth-like extrasolarplanet habitable for life, is discovered in the constellation Libra; and Yolanda King, an American activist and daughter of civil

rights leader Reverend Dr Martin Luther King, Jr, dies at age 51

2007

69



ardiac transplantation is the only definitivetherapy for patients with advanced and med-ically refractory heart failure. However, cardiactransplantation is a suboptimal option in viewof the large number of potential patients with

advanced heart failure, the lack of donors, and the comor-bidities that make most patients ineligible for cardiac trans-plantation. The concept of using a left ventricular assistdevice (LVAD) as a permanent solution for end-stage heartfailure was tested in the landmark REMATCH randomizedtrial (Randomized Evaluation of Mechanical Assistance forthe Treatment of Congestive Heart failure) over a decadeago. In REMATCH, pulsatile-flow LVAD dramatically reducedmortality by 48% in 129 patients who had severe heartfailure and who were not eligible for transplantation. In2002, the FDA subsequently approved LVAD for destinationtherapy in the US. The 1-year and 2-year survival rates forpulsatile-flow LVAD were still suboptimal when comparedwith medical therapy for patients with advanced heart fail-ure that were unsuitable for cardiac transplantation (52%vs 25% of the medically treated patients at year 1 and 23%vs 8% at year 2).

The aim of this study was to assess the efficacy and dura-bility of newer and smaller LVADs with continuous-flowcompared with pulsatile-flow LVADs. Enrolled patients withadvanced heart failure who were ineligible for transplanta-tion were randomized, in a 2:1 ratio, to undergo implanta-tion of a continuous-flow device (134 patients) or the es-tablished and approved pulsatile-flow device (66 patients).The primary composite end point at 2 years was a survivalfree from a disabling stroke and reoperation to repair orreplace the device. Secondary end points included survival,frequency of adverse events, quality of life, and functionalcapacity.

Preoperative characteristics were similar in the two treat-ment groups, with a median age of 64 years (range, 26-81),a mean left ventricular ejection fraction of 17%, and nearly80% of patients were receiving intravenous inotropic agents.The primary composite end point was achieved in morepatients with continuous-flow devices than with pulsatile-

flow devices (62 of 134 [46%] vs 7 of 66 [11%]; P<0.001;hazard ratio, 0.38; 95% CI, 0.27-0.54; P<0.001), and pa-tients with continuous-flow devices had superior actuarialsurvival rates at 2 years (58% vs 24%, P=0.008). Adverseevents and device replacements were less frequent in pa-tients with the continuous-flow device. The quality of lifeand functional capacity improved significantly in bothgroups. A limitation of the study was a lack of blinding,which may have influenced the reporting of adverse eventsand generally favored the continuous-flow pump.

The authors of the study concluded that treatment with acontinuous-flow LVAD in patients with advanced heart fail-ure significantly improved the probability of survival freefrom stroke and device failure at 2 years compared with apulsatile-flow LVAD. Both devices significantly improvedthe quality of life and functional capacity. This study is animportant step in LVAD technology and destination therapy,with a doubling in survival with newer continuous-flowpumps vs pulsatile-flow pumps (1 year increased to 2 yearswith continuous flow) and quadrupling survival when com-pared with inotropic therapy alone (6 months vs 2 years).

C

Advanced heart failure treated with continuous-flow left ventricular assist device

M. S. Slaughter, J. G. Rogers, C. A. Milano, S. D. Russell, J. V. Conte, D. Feldman, B. Sun, A. J. Tatooles, R. M. Delgado 3rd, et al; HeartMate II Investigators

N Engl J Med. 2009;361:2241-2251

Congolese rebel leader Laurent Nkunda is captured by Rwandan forces after crossing

over the border into Rwanda;Iceland’s Prime Minister Geir Haarde immediately resigns after the government and banking-system collapse; and

the President of Madagascar, Marc Ravalomanana,is overthrown in a coup d’état

2009

aised resting heart rate is a known risk factorfor adverse outcomes in patients with heartfailure and reduced ejection fraction (HFREF).This study aimed to assess the effect of heart-rate reduction by the If inhibitor ivabradine on

outcomes in HFREF. Other than reducing heart rate, ivabra-dine has no other apparent direct cardiovascular effects.

The main eligibility criteria for the study included patientswith symptomatic HFREF (New York Heart Association[NYHA] class II-IV, left ventricular ejection fraction [LVEF]≤35%), who were in sinus rhythm with a heart rate ≥70 beatsper min, a history of hospitalization for heart failure with-in the previous year, and on stable background treatment,including a b-blocker if tolerated. Patients were randomlyassigned to either ivabradine or placebo in a double-blindfashion. The dose of ivabradine was titrated to a maximumof 7.5 mg twice daily. Patients and investigators weremasked to treatment allocation. The primary end point wasthe composite of cardiovascular death or hospital admis-sion for worsening heart failure. Analysis was by intentionto treat.

In this study, 6558 patients were randomly assigned totreatment groups (3268 ivabradine, 3290 placebo). Of the6558 patients, 84% were on diuretics, 22% on digoxin, 79%on an ACE inhibitor, 14% on an ARB, 90% on a b-blocker(26% were on a full-dose b-blocker), and 60% on an MRA.Data were available for analysis for 3241 patients in theivabradine group and 3264 patients allocated to placebo.Patients were followed up for a median of 23 months.

The primary end point occurred in 793 (24%) patients inthe ivabradine group and 937 (29%) in the placebo group(hazard ratio [HR], 0.82; 95% CI, 0.75-0.90; P<0.0001). The effects were driven mainly by hospital admissions forworsening heart failure (672 [21%] placebo vs 514 [16%]ivabradine; HR, 0.74, 95% CI, 0.66-0.83; P<0.0001) and deathsdue to heart failure (151 [5%] vs 113 [3%]; HR, 0.74; 95%CI, 0.58-0.94; P=0.014). There were no significant reduc-tions in all-cause or cardiovascular mortality. There was aconsistent treatment effect in multiple prespecified sub-

groups, but a diminishing benefit of ivabradine in patientswith lower baseline heart rates (<77 beats per min). Sub-sequent reports suggested improvements in quality of lifeand LV systolic function.

Ivabradine was tolerated well, with fewer serious adverseevents in the ivabradine group (3388 events) than in theplacebo group (3847; P=0.025). However, 150 (5%) in theivabradine group had symptomatic bradycardia comparedwith 32 (1%) in the placebo group (P<0.0001). Visual sideeffects (phosphenes) were reported by 89 (3%) patients on ivabradine and 17 (1%) on placebo (P<0.0001). In thisstudy, only 3% of patients had implantable defibrillatorsand 1% had cardiac resynchronization therapy. This studysupported the importance of reducing heart rate withivabradine by showing an improvement in clinical out-comes in HFREF patients in sinus rhythm and confirmedthe important role of heart rate in the pathophysiology ofthis disorder.

Following the results of the SHIFT trial (Systolic Heart failuretreatment with the If inhibitor ivabradine Trial), the 2012ESC guidelines on the management of heart failure recom-mended the use of ivabradine for patients with HFREF insinus rhythm and a heart rate >75 bpm on maximally tol-erated doses of disease-modifying drugs for heart failure.Ivabradine could also be considered in patients with a con-traindication to a b-blocker or with a b-blocker intolerance.

70



Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study

K. Swedberg, M. Komajda, M. Böhm, J. S. Borer, I. Ford, A. Dubost-Brama, G. Lerebours, L. Tavazzi; SHIFT Investigators

Lancet. 2010;376:875-885

R

Theodore DeReese Pendergrass, an Americansinger–songwriter and composer, dies at age 59;British scientists report that they have made artificial arteries using a flexible polymer;

and a 6.2 magnitude earthquake strikes Spain, the first large earthquake in the Iberian region

in half a century

2010

71



atients are usually admitted to the hospital forheart failure (HF) because of worsening signsand symptoms of congestion. Previous investi-gations have shown that increases in intracardiacand pulmonary artery pressures are the cause

of this clinical congestion and are apparent several daysto weeks before the onset of worsening signs, symptoms,and hospital admission, suggesting that early interventiontargeting these pressures might reduce the risk of admis-sion to the hospital. In a previous clinical trial, increasesin intracardiac pressures often arose independently ofweight changes, such that monitoring weight alone wasinadequate to identify congestion in time to avert the eventsassociated with HF. This observation might account for whytelemonitoring systems that rely on patient-reported assess-ment of general health, symptoms of HF, and daily weightchange have not reduced readmission or mortality rates.

In the CHAMPION trial (CardioMEMS Heart sensor AllowsMonitoring of Pressure to Improve Outcomes in NYHAclass III heart failure patients), the hypothesis tested wasthat management of HF by using pulmonary artery pres-sures would greatly reduce the rate of HF-related hospital-izations. Patients with New York Heart Association (NYHA)class III HF, irrespective of the left ventricular ejectionfraction, and a previous hospital admission for HF wereenrolled in 64 centers in the US. A total of 550 patientsunderwent implantation of a wireless pulmonary arteryhemodynamic monitor. These patients were then random-ized to either management with a wireless implantablehemodynamic monitoring (W-IHM) system (ie, treatmentgroup) or to a control group where information from thewireless device was not used. Patients were followed up forat least 6 months. Only patients were masked to their assign-ment group. In the treatment group, clinicians used dailymeasurements of pulmonary artery pressures in additionto standard care vs standard care alone in the control group.The primary efficacy end point was the rate of HF–relatedhospitalizations at 6 months. The safety end points as-sessed at 6 months were freedom from device-related or sys-tem-related complications (DSRC) and freedom from pres-sure-sensor failures. All analyses were by intention to treat.

In 6 months, 84 HF–related hospitalizations were reportedin the treatment group (n=270) compared with 120 in thecontrol group (n=280; rate, 0.32 vs 0.44; hazard ratio [HR],0.72; 95% CI, 0.60-0.85; P=0.0002). During the entire fol-low-up (mean, 15 months; SD, 7), the treatment group hada 37% reduction in HF–related hospitalizations comparedwith the control group (158 vs 254; HR, 0.63; 95% CI, 0.52-0.77; P<0.0001). A total of 8 patients had DSRC; overallfreedom from DSRC was 98.6% (97.3-99.4) compared witha prespecified performance criterion of 80% (P<0.0001);and overall freedom from pressure-sensor failures was 100%(99.3-100.0).

The results of the CHAMPION study are consistent with,and extend, previous findings by definitively showing a sig-nificant and large reduction in hospitalization for patientswith NYHA class III HF who were managed with a W-IHMsystem. The addition of information about pulmonary ar-tery pressure to clinical signs and symptoms allows forimproved HF management. Further technological advanceswill come with the increasing clinical use of these devices,which is likely to be the beginning of this revolution inpatient monitoring that could reduce hospitalizations, becost-effective, and may improve the patients’ experience.

P

Wireless pulmonary artery haemodynamic monitoring in chronic heart failure: a randomised controlled trial

W. T. Abraham, P. B. Adamson, R. C. Bourge, M. F. Aaron, M. R. Costanzo, L. W. Stevenson, W. Strickland, S. Neelagaru, N. Raval, S. Krueger, et al; CHAMPION Trial Study Group

Lancet. 2011;377:658-666

Former Bosnian Serb Army commander RatkoMladic, wanted for genocide, war crimes, andcrimes against humanity, is arrested in Serbia;Tropical Storm Washi causes 1268 flash flood

fatalities in the Philippines; andthe Kepler space telescope discovers a solar system

of six planets orbiting the star Kepler-11

2011

72



ineralocorticoid receptor antagonists im-prove the prognosis for patients with heartfailure (HF) and a reduced left ventricularejection fraction. In this randomized, dou-ble-blind, placebo-controlled trial, the

TOPCAT investigators (Treatment Of Preserved Cardiacfunction heart failure with an Aldosterone antagonisT) eval-uated the effects of spironolactone in patients with HFand a preserved left ventricular ejection fraction (HFPEF).

The main eligibility criteria for the study were patients >50years old, with the presence of HF symptoms (New YorkHeart Association class II-IV), LVEF ≥45%, and either a re-cent admission to the hospital within the last 12 monthswith HF being the major component of treatment or ele-vated brain natriuretic peptide (≥100 pg/mL) or elevatedN-terminal pro–brain natriuretic peptide (level ≥360 pg/mL)within the last 60 days. Trial randomization was stratifiedaccording to whether patients were enrolled based onhospitalization or brain natriuretic peptide levels.

A total of 3445 patients were assigned to receive eitherspironolactone (15 to 45 mg daily) or placebo. The primaryoutcome was a composite of death from cardiovascularcauses, aborted cardiac arrest, or hospitalization for themanagement of HF. Patients were followed up for a meanof 3.3 years, the primary outcome occurred in 320 of 1722patients in the spironolactone group (18.6%) and 351 of1723 patients in the placebo group (20.4%) (hazard ratio[HR], 0.89; 95% CI, 0.77-1.04; P=0.14). Of the componentsof the primary outcome, only hospitalization for HF had asignificantly lower incidence in the spironolactone groupthan in the placebo group (206 patients [12.0%] vs 245 pa-tients [14.2%]; HR, 0.83; 95% CI, 0.69-0.99; P=0.04). Neithertotal deaths nor hospitalizations for any reason were significantly reduced by spironolactone. Treatment withspironolactone was associated with increased serum crea-tinine levels and a doubling of the rate of hyperkalemia(18.7% vs 9.1% in the placebo group).

The overall findings of the study were that, in patients withHFPEF, treatment with spironolactone did not significantly

reduce the incidence of the primary composite outcome.However, there was a nominally significant reduction inthe secondary outcome of hospitalization for HF withspironolactone. Further reports from TOPCAT have shownthat there were significant treatment differences based onhow patients were recruited into the study. Spironolactoneseemed to benefit patients enrolled in the natriuretic pep-tide stratum, but not those in the hospitalization stratum.Furthermore, the majority of these patients enrolled basedon the hospitalization criterion (mainly from Russia andGeorgia) had low event rates, which were similar to trialsof hypertension as opposed to trials of HFPEF, and so pa-tients were at a low risk for events. These reports showedthat patients recruited from the Americas, who were en-rolled mainly via the natriuretic peptide stratum, had sig-nificant improvements in the primary outcome.

Learning from TOPCAT, future trials of HFPEF are recom-mended to include a more precise definition of what ismeant by hospitalization for HF and details of the admis-sion could also be verified. Furthermore, TOPCAT empha-sized the important role that the natriuretic peptide playsin the inclusion criterion of HF trials, particularly those onHFPEF, as they are powerful indicators of adverse events.Already, the Canadian Cardiac Society has endorsed spirono-lactone as a consideration for patients with HFPEF andelevated natriuretic peptides.

M

Spironolactone for heart failure with preserved ejection fraction

B. Pitt, M. A. Pfeffer, S. F. Assmann, R. Boineau, I. S. Anand, B. Claggett, N. Clausell, A. S. Desai, R. Diaz, J. L. Fleg, et al; TOPCAT Investigators

N Engl J Med. 2014;370:1383-1392

Belgium becomes the first country in the world to legalise euthanasia for terminally ill patients of any age; the Ukrainian parliament votes

to remove President Viktor Yanukovych from office,replacing him with Oleksandr Turchynov; and

Nicolás Maduro, the President of Venezuela, seversdiplomatic and political ties with Panama

2014

73



his publication introduces a new class of drugreferred to as angiotensin receptor–neprilysininhibitors (ARNI). LCZ696 is a combination ofthe angiotensin receptor blocker valsartan andthe neprilysin inhibitor sacubitril. Neprilysin

inhibition blocks the degradation of neuroendopepidases,leading to an accumulation of endogenous neuropetidesthat have vasodilator and likely antioxidant properties. Italso leads to the accumulation of other peptides, such asbradykinin, adrenomedullin, substance P, and calcitoningene–related peptide (other powerful vasodilators).

The PARADIGM-HF investigators (Prospective comparisonof Angiotensin Receptor–neprilysin inhibitor with an An-giotensin-converting enzyme inhibitor to Determine Impacton Global mortality and Morbidity in Heart Failure trial)aimed to assess the effectiveness of LCZ696 vs an estab-lished treatment with the angiotensin-converting enzyme(ACE) inhibitor, enalalpril. The primary outcome was acomposite of death from cardiovascular causes or hospi-talization for heart failure (HF), but the trial was designedto detect a difference in the rates of death from cardiovas-cular causes.

Randomization followed a run-in period where patients hadto tolerate either LCZ696 200 mg twice daily or enalapril10 mg twice daily. Approximately 10 521 patients enteredthe run-in period. Of these patients, 2079 did not fulfillthe criteria for randomization. A total of 8442 patients withNew York Heart Association class II, III, or IV HF and anejection fraction ≤40% were randomized in a double-blindmanner to receive guideline-recommended therapy pluseither LCZ696 200 mg twice daily or enalapril 10 mg twicedaily.

The trial was stopped early, according to prespecified rules,after a median 27-month follow-up, because the boundaryfor an overwhelming benefit with LCZ696 was crossed.Patients treated with LCZ696 had 20% fewer events of car-diovascular death and hospitalization for HF comparedwith those taking enalapril (914 vs 1117; hazard ratio [HR]in the LCZ696 group, 0.80; 95% CI, 0.73-0.87; P<0.001).

A total of 558 (13.3%) and 693 (16.5%) patients, respectively,died from cardiovascular causes (HR, 0.80; 95% CI, 0.71-0.89; P<0.001). As compared with enalapril, LCZ696 alsoreduced the risk of hospitalization for HF by 21% (P<0.001)and decreased the symptoms and physical limitations ofHF (P=0.001). The LCZ696 group had higher proportionsof patients with hypotension and nonserious angioedema,but lower proportions with renal impairment, hyperkalemia,and cough than the enalapril group.

A criticism of the study is that enalapril at a dose of 10 mgtwice daily, where the maximum dose is 20 mg twice daily,was compared with LCZ696 at dose of 200 mg twice daily.The rationale for using this ACE inhibitor and this dosewere the fact that enalapril is the only ACE inhibitor shownto reduce mortality in chronic HFREF and the average doseachieved in PARADIGM-HF was greater than that used ineither the CONSENSUS (COooperative North ScandinavianENalapril SUrvival Study) or SOLVD (Studies Of Left Ven-tricular Dysfunction) studies.

In summary, this new class of drug is likely to replace theuse of ACE inhibitors as the cornerstone of therapy forHFREF due to its overwhelming results. However, its en-dorsement to date has been slow by the clinical community,probably due to a combination of issues related to costand slow uptake by guideline committees and prescribers.

T

Angiotensin–neprilysin inhibition versus enalapril in heart failure

J. J. McMurray, M. Packer, A. S. Desai, J. Gong, M. P. Lefkowitz, A. R. Rizkala, J. L. Rouleau, V. C. Shi, S. D. Solomon, K. Swedberg, M. R. Zile; PARADIGM-HF Investigators and Committees

N Engl J Med. 2014;371:993-1004

An estimated 276 girls and women are abductedand held hostage from a school in Nigeria;

Burkina Faso President Blaise Compaoré resignsafter widespread protests in response to the attempt to abolish presidential term limits; andMiklós Jancsó, a Hungarian film director

and screenwriter, dies at age 92

2014

eart failure (HF) is an energy-depleted stateassociated with low myocardial adenosinetriphosphate (ATP) production, mitochondriadysfunction, abnormal calcium handling,increased reactive oxygen species genera-

tion, and endothelial dysfunction. Coenzyme Q10 (CoQ10)has a critical role in ATP production, is a potent anti-inflam-matory agent, and it may improve endothelial function.Lower CoQ10 levels are seen in patients with advancedHF symptoms and with lower ejection fractions. In severalsmall studies, CoQ10 was shown to have little or no bene-fit with respect to improving outcomes. However, the largeprospective, randomized, double-blind, placebo-controlled,multicenter trial Q-SYMBIO (coenzyme Q10 as adjunctivetreatment for chronic HF focusing on changes in SYMptoms,BIomarker status, and long-term Outcome) has shownpromise for CoQ10 as a potential therapeutic option for HF.

In Q-SYMBIO, 420 patients with heart failure and reducedsystolic function with New York Heart Association classIII-IV were randomized to standard therapy and eitherCoQ10 (n=202) given as 100 mg thrice daily or placebo(n=218). The primary short-term end points at 16 weekswere changes in NYHA functional classification, 6-minwalk test, and levels of N-terminal pro–B-type natriureticpeptide. The primary long-term end point at 2 years wasthe composite of major adverse cardiovascular events asdetermined by a time to first event analysis.

This trial showed that there were no significant changes inthe short-term end points; however, the primary long-termend point was reached by 15% (30 events) of patients inthe CoQ10 group vs 26% (57 events) in the placebo group(hazard ratio [HR], 0.50; 95% CI, 0.32-0.80; P=0.003). Fur-thermore, the CoQ10 group had lower cardiovascular mor-tality (9% vs 16%; P=0.026), all-cause mortality (10% vs18%; P=0.018), and incidence of hospital stays for HF(P=0.033). A significant improvement in the NYHA classwas observed in the CoQ10 group after 2 years (P=0.028).

The results of this trial have renewed interest in the useof CoQ10 for HF. A limitation of the study included the

extended time period that was required to fulfill recruit-ment (>8 years) in more than 17 centers and 9 countries.The reasoning for the extended time required to completestudy enrollment is attributed to the combination of thenonpatentable feature of CoQ10 and a low budget for thestudy that had to compete with drug company–sponsoredstudies.

In summary, Q-SYMBIO showed that treating chronic HFpatients with CoQ10 was safe and it improved symptomsand reduced major adverse cardiovascular events, but thisstudy was of moderate size. However, future adequatelypowered studies are merited to evaluate the clinical bene-fit in patients with HFREF sufficiently. Furthermore, therationale for the use of CoQ10 in HEPEF is merited and awell-conducted randomized controlled trial will be requiredto demonstrate efficacy and safety in this population.

H

The effect of coenzyme Q10 on morbidity and mortality in chronic heart failure: results from Q-SYMBIO: a randomized double-blind trial

S. A. Mortensen, F. Rosenfeldt, A. Kumar, P. Dolliner, K. J. Filipiak, D. Pella, U. Alehagen, G. Steurer, G. P. Littarru; Q-SYMBIO Study Investigators

JACC Heart Fail. 2014;2:641-649

74



A new living coral reef with an area of 28 km2

is discovered in the territorial waters of Iraq;a biodegradable battery that could be used

for medical implants inside the body is created; and Kryptodrakon is classified as the oldest pterodactyloid pterosaur discovered to date

2014

75



he use of b-blockers for patients with chronicheart failure with reduced ejection fraction(HFREF) was instituted after a series of mecha-nistic studies and large randomized controlledtrials that showed a significant reduction in the

rates of morbidity and mortality. International guidelinesrecommend the use of b-blockers in symptomatic patientswith HFREF, and this has had a class 1A recommendation.Atrial fibrillation and heart failure often coexist, causingsubstantial cardiovascular morbidity and mortality. b-Block-ers are indicated in patients with symptomatic HFREF;however, the efficacy of these drugs in patients with con-comitant atrial fibrillation is uncertain.

In this meta-analysis, authors used individual-patient datato assess the efficacy of b-blockers in patients with heartfailure and sinus rhythm compared with atrial fibrillation.They extracted individual patient data from 10 randomizedcontrolled trials comparing b-blockers with placebo in heartfailure. The presence of sinus rhythm or atrial fibrillationwas ascertained from the baseline electrocardiograph. Theprimary outcome of the study was all-cause mortality andthe analysis was performed by intention to treat. Outcomedata were meta-analyzed with an adjusted Cox proportion-al hazards regression.

They used data from 18 254 patients, and, of these, 13 946(76%) had sinus rhythm and 3066 (17%) had atrial fibrilla-tion at baseline and the remainder had other rhythms, suchas paced beats or heart block. Crude death rates over amean follow-up of 1.5 years (SD, 1.1) were 16% (2237 of13 945) in patients with sinus rhythm and 21% (633 of3064) in patients with atrial fibrillation. b-Blocker therapyled to a significant reduction in all-cause mortality in pa-tients with sinus rhythm (hazard ratio [HR], 0.73; 95% CI,0.67-0.80; P<0.001), but not in patients with atrial fibrilla-tion (HR, 0.97; 95% CI, 0.83-1.14; P=0.73), with a significantP value for interaction of baseline rhythm (P=0.002). Thelack of efficacy for the primary outcome was noted in allsubgroups of atrial fibrillation, including age, sex, left ven-tricular ejection fraction, New York Heart Association class,heart rate, and baseline medical therapy.

The authors concluded that, based on these results, b-block-ers should not be used preferentially over other heartrate–control medications and should not be regarded asstandard therapy to improve prognosis in patients withconcomitant HFREF and atrial fibrillation. However, basedon this study, one should not change clinical practice, asthere is no clear explanation of these findings and usingb-blockers does not appear to be harmful as is reflected inthis study. Taking a closer look at this data, one finds thatpatients with atrial fibrillation were different from patientsin sinus rhythm, for example, atrial fibrillation patientswere older, more likely to be men, had worse symptoms,and were commonly treated with a combination of digoxinand amiodarone, which could interact with b-blockers.Other explanations include potential impact of unmeasuredconfounding factors, such as a conduction-system disease(eg, pauses or pacemaker use) or potential differential responses in patients with milder symptoms vs those witha more advanced disease. These potential explanationsrequire further exploration.

Efficacy of b blockers in patients with heart failure plus atrialfibrillation: an individual-patient data meta-analysis

D. Kotecha, J. Holmes, H. Krum, D. G. Altman, L. Manzano, J. G. Cleland, G. Y. Lip, A. J. Coats, B. Andersson, P. Kirchhof, et al; Beta-Blockers in Heart Failure Collaborative Group

Lancet. 2014;384:2235-2243

T

Massimo Tamburini, an Italian motorcycle designerfor Cagiva, Ducati, and MV Agusta, dies at age 70from lung cancer; the Swedish princess Leonore,Duchess of Gotland is born; and Prince Harrylaunches the Invictus Games, a Paralympic-stylesporting championship for wounded soldiers

2014

76



entral sleep apnea (CSA) is characterized bycycles of apnea and hyperpnea during sleepdue to abnormalities in regulation of breath-ing within respiratory centers in the brainstem.CSA is common in patients with heart failure

(HF), with a 20% to 45% prevalence rate, and its presenceis reported to be a marker of HF severity. It is also describedin some studies to be independently associated with in-creased morbidity and mortality in patients with HF.

Adaptive servo-ventilation (ASV) is a form of positive pres-sure ventilation with a variable pressure algorithm thatdelivers back-up breaths and high pressure during apneaand lower pressure during hyperpnea, resulting in resolu-tion of the apnea-hypopnea index (AHI) to normal levelsin most cases. ASV treats CSA more effectively than otherforms of positive pressure, such as continuous positiveairway pressure (CPAP)

The SERVE-HF trial (treatment of SlEep-disoRdered breath-ing with predominant central sleep apnea by adaptive servo-VEntilation in patients with HF) investigated the effects of adding ASV (AutoSet CS, ResMed) to guideline-basedmedical treatment on survival and cardiovascular out-comes in patients who had HF with reduced ejection fractionand predominantly CSA. This was a time-to-event analysiswith the primary outcome being the first event of deathfrom any cause, lifesaving cardiovascular intervention (car-diac transplantation, implantation of a ventricular assistdevice, resuscitation after sudden cardiac arrest, or appro-priate lifesaving shock), or unplanned hospitalization forworsening heart failure. In SERVE-HF, 1325 were random-ized to ASV or optimal medical therapy with a median 31-month follow-up duration (range, 0 to 80).

This trial unexpectedly demonstrated that, despite effec-tively treating CSA (AHI dropped from 31.2 per hour atbaseline to 6.6 per hour at 12 months), ASV had no impacton the primary end point of the trial (54.1% and 50.8%, re-spectively; hazard ratio [HR], 1.13; 95% CI, 0.97-1.31; P=0.10).Surprisingly, ASV was associated with harm as there wasan increase in all-cause mortality (HR, 1.28; 95% CI, 1.06-

1.55; P=0.01) driven by an increased risk of cardiovasculardeath (HR, 1.34; 95% CI, 1.06-1.55; P=0.006). The increasein cardiovascular death was also driven mainly by an in-crease in sudden cardiac death (the mechanism by whichsudden cardiac death occurred is unclear); therefore fur-ther analysis from SERVE-HF is eagerly awaited.

In contrast with the findings of smaller studies and themeta-analyses that showed improvements in surrogatemarkers, such as brain natriuretic peptide, left ventricularejection fraction, and quality of life scores with ASV in pa-tients with HFREF and CSA, the results of SERVE-HF weresurprising and have now generated further controversy inthe way CSA is viewed, such that the presence of CSA maybe viewed as a compensatory mechanism in HF, which mayhave favorable effects, and perhaps treating it may not be beneficial. For example, the presence of hyperpnea following an apnea may lead to improved lung expansion,recruitment of collapsed alveoli in a congested lung, andimproved oxygenation. However, further studies are re-quired to explore this hypothesis.

Adaptive servo-ventilation for central sleep apnea in systolicheart failure

M. R. Cowie, H. Woehrle, K. Wegscheider, C. Angermann, M. P. d’Ortho, E. Erdmann, P. Levy, A. K. Simonds, V. K. Somers, F. Zannad, H. Teschler

N Engl J Med. 2015;373:1095-1105

C

Hitoshi Saito, a Japanese judoka who won two consecutive gold medals at the Olympic games,

dies at age 54 from cholangiocarcinoma;Princess Charlotte of Cambridge, daughter

of Prince William, Duke of Cambridge, is born; and Hurricane Patricia becomes the most intense

hurricane ever recorded in the WesternHemisphere, with winds of 345 km/hour

and a pressure of 879 mbar

2015



he STICH study (Surgical Treatment for IschemicHeart Failure) consisted of two components—a surgical revascularization component and asurgical ventricular reconstruction component.The surgical revascularization component was

designed to test the hypothesis that coronary artery bypass grafting (CABG) plus guideline-directed medicaltherapy for coronary artery disease, heart failure (HF), andleft ventricular dysfunction would improve survival overthat with medical therapy alone. In the analysis of datafrom the surgical revascularization component at a medianfollow-up of 56 months, no significant difference in the rateof all-cause mortality between the CABG group and themedical-therapy group was observed, although the ratesof death from cardiovascular causes and of death from anycause or hospitalization for cardiovascular causes werelower among patients in the CABG group. In the presentstudy, the authors report the results of the STICH Exten-sion Study (STICHES), which was conducted to evaluatethe long-term, 10-year effects of CABG in patients with ischemic cardiomyopathy.

A total of 1212 patients with an ejection fraction ≤35% andcoronary artery disease amenable to CABG were randomlyassigned to undergo CABG plus medical therapy (CABGgroup, 610 patients) or medical therapy alone (medical-therapy group, 602 patients). The primary outcome wasdeath from any cause. Major secondary outcomes includeddeath from cardiovascular causes and death from any causeor hospitalization for cardiovascular causes. The medianduration of follow-up, including the current extended fol-low-up study, was 9.8 years.

A primary outcome event occurred in 359 patients (58.9%)in the CABG group and 398 patients (66.1%) in the medical-therapy group (hazard ratio [HR] with CABG vs medicaltherapy, 0.84; 95% CI, 0.73-0.97; P=0.02 by log-rank test).A total of 247 patients (40.5%) in the CABG group and 297patients (49.3%) in the medical-therapy group died fromcardiovascular causes (HR, 0.79; 95% CI, 0.66-0.93; P=0.006by log-rank test). Death from any cause or hospitalizationfor cardiovascular causes occurred in 467 patients (76.6%)

in the CABG group and in 524 patients (87.0%) in the med-ical-therapy group (HR, 0.72; 95% CI, 0.64-0.82; P<0.001by log-rank test).

Thus, patients with ischemic cardiomyopathy who under-went surgical revascularization and medical therapy hadbetter long-term outcomes than those who were treatedwith medical therapy alone, with the occurrence of lowerrates of death from any cause, death from cardiovascularcauses, and death from any cause or hospitalization forcardiovascular causes over 10 years. A possible explanationfor the results include the fact that the majority of patientsrandomly assigned to undergo CABG received a left inter-nal mammary artery (LIMA) graft (91.1%) vs 9.9% of patientsin the earlier trials of CABG.

In summary, the results of the STICHES study support asignificant benefit of CABG plus medical therapy overmedical therapy alone with respect to the rate of deathfrom any cause among patients with ischemic cardiomyo-pathy. It is not known whether percutaneous coronaryrevascularization vs medical therapy alone would result inbenefits similar to those that were observed with CABG,and future studies are required to address this question.

Coronary-artery bypass surgery in patients with ischemic cardiomyopathy

E. J. Velazquez, K. L. Lee, R. H. Jones, H. R. Al-Khalidi, J. A. Hill, J. A. Panza, R. E. Michler, R. O. Bonow, T. Doenst, M. C. Petrie, et al; STICHES Investigators

N Eng J Med. 2016;374:1511-1520

T

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David Bowie, an English singer, songwriter, actor, and record producer, dies at age 69 from

liver cancer; Joaquín Guzmán, widely regarded as the world’s most powerful drug

trafficker, is recaptured following his escape from a maximum security prison; and the World Health Organization announces

an outbreak of the Zika virus

2016

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