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Thessaloniki, October 30, 2015

Comorbidities in Heart Failure

Filippos Triposkiadis, MD, FESC, FACCProfessor of CardiologyDirector, Department of CardiologyLarissa University HospitalLarissa, Greece

Definition of Comorbidity

Several definitions have been suggested for comorbidity based on differentconceptualizations of a single core concept: the presence of more than 1distinct conditions in an individual. Although always used as a person-levelconstruct, 4 major types of distinctions are made:• the nature of the health conditions• the relative importance of the co-occurring conditions• the chronology of presentation of the conditions• the expanded conceptualizations

Feinstein AR. J Chronic Dis. 1970;23:455-468Angold A, et al. J Child Psychol Psychiatry. 1999;40:57-87

Valderas JM, et al. Ann Fam Med 2009;7:357-363

Chronologic Aspects of Comorbidity

Time span

Sequence

Comorbidity Constructs

Patient’s complexity

Non health-related individual attributes

Morbidity burden

Disease 1 (index) Disease 2 Disease n

Comorbidity of index disease

Multimorbidity

Sex Age Frailty

Health-related individual attributes

Risk factor 1 Risk factor 2

Risk factor 1

Risk factor 2

No etiologicalassociationThere is no etiologicalassociation between thediseases.

Direct causationOne of the diseases maycause the other, eg,Disease 1 (D1) = diabetesmellitus, Disease 2 (D2) =cataracts.

Associated risk factorsThe risk factors for eachdisease are correlated, eg,Risk Factor 1 (RF1) = smoking;Risk Factor 2 (RF2) = alcohol;D1 = chronic pulmonaryobstructive disease;D2 = liver cirrhosis.

Risk factor 1 Risk factor 2

Etiological Models of Comorbid Diseases

Disease 1

Disease 2

Disease 2 Disease 3

Disease 1 Disease 2 Disease 3

HeterogeneityThe risk factors for eachdiseases are notcorrelated, but eachone of them can causeeither disease, eg, RF1= smoking; RF2 = age;D1 = ischemic heartdisease; D2 = lungcancer.

Risk factor 3

IndependenceThe presence of the diagnostic features of each disease is actuallydue to a third distinct disease, eg, D1 = hypertension; D2 = tensionheadache; D3 = pheochromocytoma.

Disease 1 Disease 2

Cardio-Kidney-Damage (C-K-D)

El Nahas M. Kidney International 2010; 78: 14-18

Prevalence of Comorbiditiesin Heart Failure

Multimorbidity in Heart Failure:A Community Perspective

Chamberlain AM, et al. The American Journal of Medicine 2015; 128: 38-45

Prevalence of Individual Chronic Conditionsin HFpEF and HFrEF

Co-Morbidities in Patients with Heart Failure:the European Heart Failure Pilot Survey

van Deursen, et al. European Journal of Heart Failure 2014; 16: 103–111

A total of 3226 European outpatients with chronic HF were included in this analysis of the European Society ofCardiology (ESC) Heart Failure Pilot Survey. The following co-morbidities were considered: diabetes, hyper- andhypothyroidism, stroke, COPD, sleep apnoea, chronic kidney disease (CKD), and anaemia.

Overall (I-squared = 33.6%, p = 0.068)

Tribouilloy

MEDICARE

EFFECT

SENIORS

RELAX-AHF

OPTIMIZEEURO HF

ADHERE

Worchester

ECHOESVeteransOlmsteadFramingham

DIAMOND-CHF

1.49 (1.30, 1.70)

3.08 (1.70, 5.59)

1.85 (1.05, 3.26)

1.42 (0.79, 2.55)

1.27 (0.73, 2.22)

1.83 (1.05, 3.21)

1.31 (0.64, 2.71)

OR (95% CI)

0.39 (0.18, 0.85)

3.14 (1.70, 5.81)

1.84 (1.05, 3.24)

2.53 (0.99, 6.45)

1.13 (0.64, 1.99)

1.63 (0.88, 3.03)1.44 (0.82, 2.52)

1.56 (0.81, 3.00)

1.50 (0.80, 2.82)

1.25 (0.70, 2.26)

1.13 (0.65, 1.98)1.50 (0.83, 2.71)1.44 (0.68, 3.06)1.13 (0.65, 1.98)

1.12 (0.58, 2.14)

100.00

Weight

4.405.69

6.374.993.156.37

1.49 (1.30, 1.70)

3.08 (1.70, 5.59)

1.85 (1.05, 3.26)

1.42 (0.79, 2.55)

1.27 (0.73, 2.22)

1.83 (1.05, 3.21)

1.31 (0.64, 2.71)

OR (95% CI)

0.39 (0.18, 0.85)

3.14 (1.70, 5.81)

1.84 (1.05, 3.24)

2.53 (0.99, 6.45)

1.13 (0.64, 1.99)

1.63 (0.88, 3.03)1.44 (0.82, 2.52)

1.56 (0.81, 3.00)

1.50 (0.80, 2.82)

1.25 (0.70, 2.26)

1.13 (0.65, 1.98)1.50 (0.83, 2.71)1.44 (0.68, 3.06)1.13 (0.65, 1.98)

1.12 (0.58, 2.14)

100.00

Weight

4.405.69

6.374.993.156.37

1.1 1 10

HYPERTENSION

Comorbidities in HFpEF vs. HFrEF

Tryposkiadis K, Triposkiadis F, 2015

OPTIMIZE

DIAMOND-CHF

Worchester

Veterans

MEDICARE

RELAX-AHF

EURO HF

EFFECT

ADHERE

Tribouilloy

SENIORS

CHSECHOES

OlmsteadFramingham

0.48 (0.42, 0.55)

0.52 (0.30, 0.92)

0.39 (0.21, 0.71)

0.44 (0.25, 0.78)

0.50 (0.28, 0.88)

0.55 (0.31, 1.01)

0.43 (0.23, 0.81)

0.41 (0.22, 0.77)

OR (95% CI)

0.57 (0.32, 1.00)

0.57 (0.33, 1.00)

0.65 (0.36, 1.16)

0.32 (0.17, 0.62)

0.54 (0.31, 0.95)

0.56 (0.30, 1.04)

0.63 (0.36, 1.12)

0.45 (0.19, 1.06)

0.54 (0.30, 0.95)

0.39 (0.21, 0.72)0.20 (0.11, 0.38)

0.73 (0.42, 1.27)

0.56 (0.32, 0.99)0.34 (0.19, 0.61)

100.00

Weight

4.906.58

4.785.93

0.48 (0.42, 0.55)

0.52 (0.30, 0.92)

0.39 (0.21, 0.71)

0.44 (0.25, 0.78)

0.50 (0.28, 0.88)

0.55 (0.31, 1.01)

0.43 (0.23, 0.81)

0.41 (0.22, 0.77)

OR (95% CI)

0.57 (0.32, 1.00)

0.57 (0.33, 1.00)

0.65 (0.36, 1.16)

0.32 (0.17, 0.62)

0.54 (0.31, 0.95)

0.56 (0.30, 1.04)

0.63 (0.36, 1.12)

0.45 (0.19, 1.06)

0.54 (0.30, 0.95)

0.39 (0.21, 0.72)0.20 (0.11, 0.38)

0.73 (0.42, 1.27)

0.56 (0.32, 0.99)0.34 (0.19, 0.61)

100.00

Weight

4.906.58

4.785.93

1.1 1 10

MYOCARDIAL INFARCTION

RELAX-AHF

OPTIMIZE

Tribouilloy

Veterans

DIAMOND-CHFEURO HF

MEDICARE

Olmstead

CHSGWTG

EFFECT

SENIORSDOSE

ADHERE

Framingham

1.36 (1.17, 1.58)

1.70 (0.95, 3.06)

1.69 (0.97, 2.97)

1.27 (0.69, 2.32)

1.25 (0.70, 2.26)

1.00 (0.56, 1.79)

1.18 (0.62, 2.24)1.12 (0.58, 2.14)

1.31 (0.73, 2.37)

0.95 (0.53, 1.73)

3.35 (1.17, 9.62)1.32 (0.73, 2.42)

1.49 (0.80, 2.78)

1.09 (0.61, 1.95)2.53 (1.41, 4.52)

1.30 (0.64, 2.64)

1.16 (0.62, 2.16)

1.45 (0.76, 2.75)

OR (95% CI)

100.00

5.765.84

1.446.25

7.374.87

Weight

1.36 (1.17, 1.58)

1.70 (0.95, 3.06)

1.69 (0.97, 2.97)

1.27 (0.69, 2.32)

1.25 (0.70, 2.26)

1.00 (0.56, 1.79)

1.18 (0.62, 2.24)1.12 (0.58, 2.14)

1.31 (0.73, 2.37)

0.95 (0.53, 1.73)

3.35 (1.17, 9.62)1.32 (0.73, 2.42)

1.49 (0.80, 2.78)

1.09 (0.61, 1.95)2.53 (1.41, 4.52)

1.30 (0.64, 2.64)

1.16 (0.62, 2.16)

1.45 (0.76, 2.75)

OR (95% CI)

100.00

5.765.84

1.446.25

7.374.87

Weight

1.1 1 10

ATRIAL FIBRILLIATION

ADHERE

OPTIMIZE

ECHOES

Framingham

SENIORS

Tribouilloy

Veterans

Worchester

MEDICARE

EFFECT

RELAX-AHF

DIAMOND-CHF

EURO HF

Olmstead

0.95 (0.83, 1.08)

1.24 (0.65, 2.35)

1.23 (0.70, 2.15)

0.95 (0.52, 1.76)

1.18 (0.67, 2.07)

0.49 (0.22, 1.10)

1.05 (0.57, 1.94)

0.76 (0.40, 1.46)

0.85 (0.45, 1.61)

1.00 (0.53, 1.88)

1.23 (0.70, 2.15)

0.77 (0.43, 1.37)

1.20 (0.66, 2.18)

0.88 (0.50, 1.56)

0.74 (0.41, 1.32)

0.96 (0.55, 1.67)

0.96 (0.53, 1.72)

0.79 (0.45, 1.37)

0.64 (0.30, 1.37)

OR (95% CI)

1.28 (0.73, 2.24)

0.90 (0.48, 1.69)

0.92 (0.52, 1.63)

100.00

Weight

0.95 (0.83, 1.08)

1.24 (0.65, 2.35)

1.23 (0.70, 2.15)

0.95 (0.52, 1.76)

1.18 (0.67, 2.07)

0.49 (0.22, 1.10)

1.05 (0.57, 1.94)

0.76 (0.40, 1.46)

0.85 (0.45, 1.61)

1.00 (0.53, 1.88)

1.23 (0.70, 2.15)

0.77 (0.43, 1.37)

1.20 (0.66, 2.18)

0.88 (0.50, 1.56)

0.74 (0.41, 1.32)

0.96 (0.55, 1.67)

0.96 (0.53, 1.72)

0.79 (0.45, 1.37)

0.64 (0.30, 1.37)

OR (95% CI)

1.28 (0.73, 2.24)

0.90 (0.48, 1.69)

0.92 (0.52, 1.63)

100.00

Weight

1.1 1 10

DIABETES MELLITUS

Worchester

Veterans

ADHERE

EFFECT

DIAMOND-CHF

Olmstead

EURO HF

0.93 (0.76, 1.14)

OR (95% CI)

0.84 (0.48, 1.49)

0.89 (0.51, 1.54)

1.00 (0.53, 1.88)

1.17 (0.67, 2.04)

1.20 (0.60, 2.39)

0.45 (0.24, 0.83)

0.92 (0.51, 1.63)

1.25 (0.49, 3.16)

0.82 (0.24, 2.79)

1.17 (0.67, 2.05)

100.00

Weight

0.93 (0.76, 1.14)

OR (95% CI)

0.84 (0.48, 1.49)

0.89 (0.51, 1.54)

1.00 (0.53, 1.88)

1.17 (0.67, 2.04)

1.20 (0.60, 2.39)

0.45 (0.24, 0.83)

0.92 (0.51, 1.63)

1.25 (0.49, 3.16)

0.82 (0.24, 2.79)

1.17 (0.67, 2.05)

100.00

Weight

1.1 1 10

SENIORS

Olmstead

EFFECT

Veterans

1.34 (1.03, 1.76)

1.73 (0.83, 3.62)

OR (95% CI)

1.00 (0.49, 2.03)

1.24 (0.65, 2.35)

1.17 (0.67, 2.04)

2.39 (1.06, 5.39)

1.27 (0.69, 2.32)

100.00

Weight

1.34 (1.03, 1.76)

1.73 (0.83, 3.62)

OR (95% CI)

1.00 (0.49, 2.03)

1.24 (0.65, 2.35)

1.17 (0.67, 2.04)

2.39 (1.06, 5.39)

1.27 (0.69, 2.32)

100.00

Weight

1.1 1 10

ANAEMIA

EFFECT

Worchester

RELAX-AHF

DIAMOND-CHF

Veterans

Tribouilloy

ADHERE

MEDICARE

Olmstead

1.19 (0.97, 1.46)

0.43 (0.16, 1.17)

1.33 (0.73, 2.44)

1.28 (0.69, 2.37)

1.00 (0.47, 2.13)

1.50 (0.77, 2.93)

1.39 (0.76, 2.55)

0.94 (0.47, 1.87)

1.21 (0.66, 2.24)

OR (95% CI)

1.15 (0.63, 2.07)

1.43 (0.79, 2.58)

100.00

Weight

1.19 (0.97, 1.46)

0.43 (0.16, 1.17)

1.33 (0.73, 2.44)

1.28 (0.69, 2.37)

1.00 (0.47, 2.13)

1.50 (0.77, 2.93)

1.39 (0.76, 2.55)

0.94 (0.47, 1.87)

1.21 (0.66, 2.24)

OR (95% CI)

1.15 (0.63, 2.07)

1.43 (0.79, 2.58)

100.00

Weight

1.1 1 10

COPD/ASTHMA

Clinical Significance ofComorbidities

Clinical Course and Available Therapiesin Heart Failure

Allen LA, et al. Circulation 2012;125:1928-1952

Co-Morbidities in Patients with Heart Failure:the European Heart Failure Pilot Survey

van Deursen, et al. European Journal of Heart Failure 2014; 16: 103–111

0 comorbidities

1-3 comorbidities

> 3 comorbidities

Follow up time (days)

0 comorbidities

1-3 comorbidities

> 3 comorbidities

0 100 200 300

0.6Cum

0 100 200 300

Endothelium

Cardiomyocytes

ONOO- NO

VCAM E-selectinROS

TGF-β

Fibroblasts Myofibroblasts

Leukocytes

Collagen

• IL-6• TNF-α• sST2• Pentraxin 3

Fpassive PKG

Hypertrophy

Myocardial Remodeling in HFPEFImportance of Comorbidities

Paulus WJ, Tschoepe C. JACC 2013; 62:263-71

• Hypertension• Overweight/Obesity• Diabetes Mellitus• Kidney disease• Iron deficiency• COPD

Endothelium

Cardiomyocytes

Myocardial Remodeling in HFREF

Autophagy Apoptosis Necrosis

Collagen

• Ischemia• Infection• Toxicity

Inflammation Links Heart Failurewith Coexisting Morbidities

Triposkiadis F, et al. Heart Fail Rev 2012;17:355-66

Management of NoncardiacComorbidities in Heart Failure

The CARRESS-HF Trial: Ultrafiltration inDecompensated HF with Cardiorenal Syndrome

188 patients with ADHF, worsened renal function, and persistent congestion were randomly assigned to astrategy of stepped pharmacologic therapy (94 patients) or ultrafiltration (94 patients).

Bart BA, et al.N Engl J Med 2012;367:2296-304

Iron Supplementation in PatientsWith Heart Failure and Iron Deficiency

Qian C, et al. Can J Cardiol 2015, in press

More vs. Less Intensive Glycaemic Controlon Myocardial Infarction and Heart Failure

Turnbull FM, et al. Diabetologia 2009; 52: 2288–98

To Lose Weight or Not to Lose Weight,That Is the Big Question—in

Obesity-Related Heart Failure

Peterson LR. Diabetes 2015;64:1509–1510

COPD in Heart Failure: AccurateDiagnosis and Treatment

In conclusion: bronchodilators may improve symptoms in HF in the short term, even in the absence of COPD, but negative cardiovascularside effects may prevail during long- or even short-term therapy. When patients need bronchodilation for pulmonary symptomimprovement and reduction of the risk of exacerbations, long-acting anticholinergics seem to be preferred over beta-2-agonists inpatients with concurrent HF, although both drugs were related to severe side effects especially in patients with underlying cardiovasculardiseases. In any case, after initiation of bronchodilators, physicians should carefully monitor symptom improvements and side effectsin patients with HF, and eventually consider drug discontinuation.

Güder G, et al. European Journal of Heart Failure 2014;16: 1273–82

Adaptive Servo-Ventilation for CentralSleep Apnea in Systolic Heart Failure

1325 patients with a left ventricular ejection fraction of 45% or less, an apnea–hypopnea index (AHI) of 15 or more events(occurrences of apnea or hypopnea) per hour, and a predominance of central events were randomly assigned to receiveguideline-based medical treatment with adaptive servo-ventilation or guideline based medical treatment alone (control).

Cowie MR, et al. N Engl J Med 2015;373:1095-105

Conclusions

• Multimorbidity is common in HF, with more than 80% of HF patientshaving 2 or more additional chronic conditions in a recent communitycohort.

• HFpEF is associated with more additional conditions compared withHFrEF. However, the patterns of co-occurring conditions are similarbetween HFpEF and HFrEF.

• Although noncardiac comorbidities adversely affect prognosis, there isno evidence that specific comorbidity treatments are associated with alower incidence of major cardiovascular events in HF.

• The lack of effect of several comorbidity treatments on HF outcomemay be due to the fact that interventions have more likely been appliedin those with more severe HF, drug adverse effects or HF deteriorationby the treatment effect per se.

Several definitions have been suggested for comorbidity based on different conceptualizations ofa single core concept: the presence of more than 1 distinct condition in an individual. Althoughalways used as a person-level construct, 4 major types of distinctions are made:• the nature of the health condition• the relative importance of the co-occurring conditions• the chronology of presentation of the conditions• the expanded conceptualizations

Time span

Sequence

Point of time

Period of time

Valderas JM, et al.Ann Fam Med 2009;7:357-363

Ratio of Observed to Expected Co-Occurrence ofChronic Conditions in HF Patients

Prevalence of HF and Proportionwith Preserved LVEF

McMurray and Pfeffer. Lancet 2005; 365:1877-89

Secular Trends in thePrevalence of HFpLVEF

Owan, et al. N Engl J Med 2006;355:251-9

All consecutive patients hospitalized with decompensated HF at Mayo Clinic Hospitals, from 1987 through 2001 were studied. Atotal of 6076 patients with HF were discharged over the 15-year period; data on LVEF were available for 4596 of these patients(76%). Of these, 53 % had a reduced LVEF and 47 %t had a preserved LVEF. Secular trends in type of HF, associated CV disease,and survival were defined.

Survival in HFpEF vs. HFrEF

Owan, et al. N Engl J Med 2006;355:251-9

European Heart Journal2012;33: 750–1757

Distribution of Deaths inStudies of HFpEF

Chan MMY, Lam CSP. European Journal of Heart Failure 2013; 5:604–613

Myocardial Dysfunction and Remodeling inHFrEF and Advanced HFrEF

Distribution of Deaths inHFpEF vs. HFrEF

Chan MMY, Lam CSP. European Journal of Heart Failure 2013; 5:604–613

Multimorbidity in Heart Failure:A Community Perspective

Men Women

Distribution of Mode of Death in HFpEF

I-PRESERVEZile MR, et al.Circulation 2010;121:1393–1405

CHARM-PreservedSolomon SD, et al.Circulation 2004; 110:2180–2183

TIME-CHF Study: Classification by Causesvs. Modes of Death in HFpEF

Rickenbacher P, et al. Eur J Heart Fail 2012;14:1218–1229

Causes of Death Modes of Death

Prevalence of CAD and Percentageof Non-cardiovascular Deaths

Henkel DM, et al. Circ Heart Fail 2008;1:91–97Rickenbacher P, et al. Eur J Heart Fail 2012;14:1218–1229.

HF with LVEF > 50%:HFpEF or Diastolic Heart Failure?

McMurray JJV, et al. European Heart Journal 2012; 33: 1787–1847

28%12%

Patterns of Left Ventricular Hypertrophy inHFpEF

Katz DH, et al. Am J Cardiol 2013; 112: 1158–64

Yancy CW, et al. JACC 2013; 62:e147–239

Generation of EFs 60% from Fibers thatShorten 15%

Circumferentialfiber Spiral

Longitudinalfiber

EF=15 %

EF=30 % EF=60 %

Sallin EA. Biophys J 1969; 9: 954-64

Shortening and Thickening of a Single Circumferentially LayeredCylindrical Model

de Simone G, Devereux RB. Eur J Echocardiography 2002; 3: 192–198

Alignment of the Myofibers within theVentricular Wall

Anderson, et al. Eur J Cardiothorac Surg 2005; 28:517–25

Myofiber Architecture of LV and Models forUnderstanding LV Function

Sengupta, et al. J Am Coll Cardiol 2008; 1:366–76

“Wringing” Motion of the Left VentricleDuring Systole

Technology and Health Care 1997; 5:45-52

LV Twist and Strain in HFpEF vs. HFrEF

Control HFpEF HFrEF

LV twist(degrees)

CircumferentialStrain (%)

LongitudinalStrain (%)

RadialStrain (%)

Wang, et al. Eur Heart J 2008;29:1283–9

Speckle Strain Echocardiography PredictsOutcome in Patients with HFrEF and HFpEF

420 pts with HF by Framingham criteria and either LV EF <50% (n=320), or elevated LV filling pressure by Doppler in thesetting of LVEF ≥50% (n=100), were enrolled. Speckle tracking was used to measure strain and strain rate in multiple vectors.The primary endpoint was HF hospitalization or cardiovascular death.

Stampehl MR, et al. Echocardiography 2015;32:71–78

Cox Survival Curves

Aortic Stenosis with Preserved LVEF

Prediction of Mortality

Kusunose K, et al.Circ Cardiovasc Imaging 2014;7:938-945

HFpEF: Transitory Stage to HFrEFor Distinct Phenotype ?

Komajda M, Lam CSP. European Heart Journal 2014; 35: 1022–1032

Longitudinal Changes in LVEF in HFpEF and HFrEFAmong a community cohort of incident HF patients diagnosed from 1984 to 2009 in Olmsted County, Minnesota, all EFs assessed(echocardiography) were obtained from initial HF diagnosis until death or last follow-up (March 2010). Mixed effects models fit a unique linearregression line for each person using serial EF data. Compiled results allowed estimates of the change in EF over time in HFpEF and HFrEF. Among1233 HF patients (48.3% male, mean age 75.0 years, mean follow-up 5.1 years), 559 (45.3%) had HFpEF at diagnosis.

Prognostic Value of Change in EF over Time

Dunlay SM, et al. Circ Heart Fail 2012;5:720-726

The Natural History of Left VentricularGeometry in the Community

Evaluation of 4,492 observations (2,604 unique Framingham Heart Study participants attending consecutive examinations) to categorizeLV geometry at baseline and after 4 years. Four groups were defined on the basis of the sex-specific distributions of LVM and RWT(normal: LVM and RWT <80th percentile; concentric remodeling: LVM <80th percentile but RWT 80th percentile; eccentrichypertrophy: LVM 80th percentile but RWT < 80th percentile; and concentric hypertrophy: LVM and RWT 80th percentile).

Lieb W, et al. J Am Coll Cardiol Img 2014;7:870–8

Transition Rates of LV Geometric PatternDuring a Mean Follow-Up of 4 Years

Lieb W, et al. J Am Coll Cardiol Img 2014;7:870–8

HFpEF: Heterogeneity andComorbidities

Heterogeneity of HFpEF

Senni M, et al. European Heart Journal 2014; 35 :2797–2811

Patient Characteristics andComorbidities in HFpEF

Age, years 75Female sex,% 60Hypertension,% 55-86Coronary arterydisease, %

COPD or asthma,% 31-38Renal insufficiency,% 26-52Anemia,% 22-53Diabetes,% 36-45Obesity,% 33-51

Edelmann F, et al. Clin Res Cardiol 2011;100:755-64Mentz RJ, et al. J Am Coll Cardiol 2014; 64:2281–93

Etiological Models of Comorbid Disease

Mechanisms of PulmonaryHypertension in HFpEF

Guazzi M. Circ Heart Fail 2014;7:367-377

Definition and Classification of Group 2Pulmonary Hypertension

Guazzi M, et al. J Heart Lung Transplant 2015, in press

Right Ventricular Function in Heart FailureWith Preserved Ejection Fraction

HFpEF (Framingham HF criteria, LVEF ≥50%) pts (n=562) from Olmsted County, Minnesota, underwent echocardiography at HFdiagnosis and follow-up for cause-specific mortality and HF hospitalization. RV function was categorized by tertiles of TAPSE and bysemiquantitative (normal, mild RVD, or moderate to severe RVD) 2-dimensional assessment.

Mohammed S, et al. Circulation. 2014;130:2310-2320

Kaplan–Meier Survival Curves in HFpEFAccording to the Level of RV function or TR

Mohammed S, et al. Circulation. 2014;130:2310-2320

Treatment

Trial Therapy Inclusion criteria N Follow-up

Primary endpoint Trial result

CHARM-preservedLancet 2003;362(9386):777-81

Candesartan NYHA II-IVLVEF>40%Prior cardiachospitalization

3023 3years

CV death or HFhospitalization

Negative (22% vs.24%;P=0.118)

PEP-CHFEur Heart J 2006;27:2338-45

Perindopril Age>70Diastolic dysfunctionLV wall motion index> 1.4Prior HF hospitalization

850 2.1years

All-cause death andHF hospitalization

Negative (25.1% vs.23.6%; P=0.545)

I-PRESERVENEJM 2008;359:2456-67

Irbesartan NYHA II-IVLVEF>45%Prior HF hospitalization

4128 4.1years

All cause death or CVhospitalization

Negative (36% vs.37%; P=0.35)

ALDO-DHFJAMA 2013;309:781-791

Spironolactone NYHA II-IIILVEF>50%Diastolic dysfunction

422 1year

Change in E/E’Change in peak VO2

Mixed results:E/E’: -0.6 vs. +0.8(P<0.001)VO2: +0.5 vs. +0.5ml/kg/min (P=0.81)

TOPCATNEJM 2014;370:1383-1392

Spironolactone NYHA II-IVLVEF>45%Prior HF hospitalization orelevated BNP

3445 3.25years

CV death, abortedcardiac arrest, or HFhospitalization

Negative (18.6% vs.20%;P=0.14)

Trials Targeting RAAS in HFpEF

Therapy Trial Name Design Inclusion Criteria N Primary outcomemeasure

Results/Status

PDE-5 inhibitor RELAXRedfield MM, etal. JAMA 2013;309:1268–1277

Sildenafil vs.placebo

LVEF>50% 216 Change in peak VO2 at 6months

No difference

I f channelinhibitor

Kosmala, et al.J Am Coll Cardiol2013; 62:1330–1338.

Ivabradine vs.placebo

LVEF>50%Diastolic dysfunction

61 Change in peak VO2 Increase in peak VO2with ivabradine (3.0 vs.0.4 ml/kg/min; P=0.003)

Angiotensinreceptorneprilisyninhibitor

PARAMOUNTSolomon SD, et al.Lancet 2012;380:1387–1395.

PARAGON

LCZ696 vs.valsartan

LVEF>45%NT-proBNP> 400 pg/ml

LVEF>45%Elevated NT-proBNP orHF hospitalization

Change in NT-proBNP at3 months

Cumulative number ofCV death and HFhospitalization

Ratio of change inproBNP forLCZ696/valsartan 0.77(p=0.005)

Enrolling

sGC inhibitor SOCRATES-PRESEVED

Vericiguat vs.placebo

LVEF>45%Worsening HF

470 Change in NT-proBNPand LAVI

Enrolling

Renaldenervation

DIASTOLE

RESPECT-HF

Renaldenervation vs.OMT

LVEF>50%Diastolic dysfunctionSBP > 140/90 mmHg

ADHF with LVEF> 50%E/E’ > 15 or NT-proBNP> 220 pg/ml

CV death, abortedcardiac arrest, or HFhospitalization

Change in LAVI or LVMIon cMRI at 6 moths.

Enrollinh

Enrolling

Interatrialseptal shuntdevice

REDUCE LAP-HF Single arm trialof IASD system(DC Devices)

Age > 40 yearsLVEF>40%Elevated PCWP/LVEDPthat is greater than CVP

100 Incidence of death,stroke, MI or systemicembolic event at 6months

Enrolling

Recently Completed or CurrentInvestigations of Novel Therapies In HFpEF

Current Treatment of HFpEF

Abbate A, et al. Int J Cardiol 2015;179:430-40

Senni M, et al. European Heart Journal 2014; 35 :2797–2811

Matching Key HFpEF Phenotypes toSelect Therapeutic Interventions

Novel Biomarkers in Congestive Heart Failureand Potential Roles in Management

Shah KS, Maisel AS. Heart Failure Clin 2014; 10: 471–479

Conclusions

HFpEF is a common disease characterized by significant morbidity and mortality.

HFpEF is not solely a diastolic disease but is also characterized by disturbances ofmyocardial systolic deformation.

Whether HFpEF and HFrEF are two distinct entities or two ends of a commonspectrum remains a matter of debate.

Comorbidities such as anemia and pulmonary disease tend to be more prevalent inHFpEF, but diabetes and renal disease and burdens are similar in HFpEF and HFrEF .Comorbidities similarly increase morbidity and mortality in HFpEF and HFrEF.

RV dysfunction is common in HFpEF patients, is associated with clinical andechocardiographic evidence of more advanced HF, and are predictive of pooreroutcomes.

An urgent unmet need remains to improve our understanding of the mechanisms ofHFpEF and to develop better diagnostic and therapeutic strategies for this condition.

comorbidities in heart failurestatic.livemedia.gr/hcs2/documents/al17319_us147... · co-morbidities...

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