new strategies in the management of heart failure dr. hassan chamsi pasha md, frcp(lond), frcp(ire),...

New Strategies in the Management New Strategies in the Management of Heart Failureof Heart Failure

Dr. Hassan Chamsi Pasha MD, FRCP(Lond), FRCP(Ire),

FRCP(Glasg), FACC

Head, Non–Invasive Cardiology

King Fahd Armed Forces Hospital

Heart failureHeart failure

Approximately 4.6 million Americans currently have heart failure.

400,000 new cases occur each year. Prevalence of the disease increases with

age, affecting approximately 1% of persons in their fifth decade and nearly 10% of those aged 80 to 89.

South Med J 2001 ,94(2):166-174

Heart failureHeart failure

Contributes directly or indirectly to approximately 260,000 deaths annually.

Primary diagnosis in 870,000 hospital discharges. Five-year survival after the diagnosis is only 25% in

men and 38% in women. In more severe disease, 1-year mortality approaches

30-50%. For all patients, median survival is 1.7 years in men

and 3.2 years in women. Annual cost exceeding $34 billion.

Pharmacotherapy 20(7):787-804, 2000.

One third of patients who are hospitalized for heart failure either die or require readmission within 60 days of hospital discharge.

One half are readmitted within 90 days.

Mechanisms of Heart FailureMechanisms of Heart Failure

Disease progression is related to structural changes in the heart and blood vessels that lead to ventricular remodeling.

Remodeling process is characterized by alterations in the size and shape of the left ventricle and is triggered by activation of endogenous neurohormonal systems, primarily the renin-angiotensin system (RAS) and the sympathetic nervous system (SNS).

Goals of TreatmentGoals of Treatment

The primary goal of treatment has shifted from symptomatic relief to slowing or arresting disease progression.

Neurohormonal abnormalities, not hemodynamic abnormalities, are responsible for disease progression

Usual Treatment TodayUsual Treatment Today

AIMS OF HEART FAILURE MANAGEMENT

TO IMPROVE SYMPTOMS DIURETICS DIGOXIN ACE INHIBITORS

TO IMPROVE SURVIVAL ACE INHIBITORS BLOCKERS ORAL NITRATES PLUS HYDRALAZINE SPIRONOLACTONE

Davies et al. BMJ 2000;320:428-431

HF: Mortality Remains HighHF: Mortality Remains High

ACEI RISK REDUCTION 35% (MORTALITY AND HOSPITALIZATIONS)1

BLOCKERS RISK REDUCTION 38% (MORTALITY AND HOSPITALIZATIONS)2

ORAL NITRATES AND HYDRALAZINEBENEFIT VS. PLACEBO; INFERIOR TO ENALAPRIL (MORTALITY)

HOWEVER: 4-YEAR MORTALITY REMAINS ~40%

Davies et al. BMJ 2000;320:428-431 (metanalysis: 32 trials, n=7105) 2 Gibbs et al. BMJ 2000;320:495-498 (metanalysis: 18 trials, n=3023)

Nonpharmacologic interventionsNonpharmacologic interventions

smoking cessation. Weight reduction Avoidance of alcohol. Limiting sodium intake (no more than 3 g

daily). Daily weight. Contact physician if body weight increases by

2 lb or more.

Benefits of ACE inhibitor therapy may not become apparent for 1 or 2 months after initiation of treatment.

Approximately 90% of patients with heart failure tolerate long-term ACE inhibitor therapy.

Aspirin-ACE Inhibitor InteractionAspirin-ACE Inhibitor Interaction

Studies are largely contradictory, but do reiterate the possibility of an interaction.

Low dosages (</= 100 mg/day) of aspirin appear to be safer than higher dosages.

Pharmacotherapy 20(6):698-710, 2000

B blockersB blockers

Four randomized, double-blind, placebo-controlled clinical trials:

mortality reduced 65% by carvedilol, 34% by metoprolol, 33% by bisoprolol; trials were ended early. Bucindolol: no significant effect on mortality.

[Am J Health-Syst Pharm 58(02):140-145, 2001.

MERIT-HF studyMERIT-HF study

3991 patients with heart failure from 313 centers in 14 countries randomly assigned to metoprolol CR/XL or placebo, in addition to their standard heart failure regimens.

Metoprolol CR/XL reduced the risk:

By 19%, for all-cause mortality or all-cause hospitalizations

By 31%, for total mortality or hospitalizations due to worsening heart failure

By 32%, for death or heart transplant by

By 39%, for cardiac death or nonfatal MI

By 32%, for mortality and hospitalization or emergency department visit due to worsening heart failure

Hjalmarson et al.J AMA 2000; 283: 1295-1302

MERIT-HF trial

JAMA 2000; 283: 1295-1302

CarvedilolCarvedilol

Four US studies: 1,094 patients with mild, moderate, or severe

heart failure receiving standard therapy with a diuretic, an ACE inhibitor, and digoxin.

Overall mortality in carvedilol group was 3.2% vs 7.8%, a reduction of 65%.

27% reduction in hospitalization 38% reduction in the combined risk of

hospitalization or death.

COPERNICUS trialCOPERNICUS trial

Enrolled 2289 patients with severe HF (LVEF <25%), randomized to carvedilol in a target dose of 25 mg bid for up to 29 months.

Trial was stopped early for efficacy.

COPERNI CUS: Effect of carvedilol on the combined risk of morbidity and mortality

Death or hospitalization for HF

0.000004

p valueEndpoint

COPERNICUS and CAPRICORN

0.00004

Death or hospitalization for a CV reason

0.76Death or hospitalization for any reason

Relative risk reduction

0.00002

Odds ratio

27% 0.73

COPERNI CUS: Hospitalizations

Days per hospitalization

p valueEndpoint

0.0005

Number of hospitalizations

Total days in hospital

Reduction with carvedilol

0.001727%

CAPRICORN trialCAPRICORN trial

Examined the effect of carvedilol in patients with left ventricular dysfunction (LVEF < 40%) after an MI, with or without HF.

CAPRI CORN: Primary endpoints

p valueEndpoint

367 (37%)All-cause mortality or CV hospitalization

0.77 (0.60-0.98)All-cause mortality

Relative risk reduction

151 (15%)

Odds ratio

0.92 (0.80–1.07)

CAPRI CORN

All-cause mortality and nonfatal MI

p valueEndpoint

HF hospitalization

0.74Sudden death

Hazard ratio

Nonfatal MI

0.2150.86

Packer :

“Instead of prescribing carvedilol to such patients in the midst of their acute illness, it would be prudent first to take measures to stabilize their clinical condition"

N Engl J Med 2001; 344(22):1651-8.

Packer The use of carvedilol for severe HF would prevent

approximately 70 deaths per 1000 patients treated for 1 year

This compares with 20-40 deaths prevented with ACE inhibitors or beta blockers in mild to moderate HF, and with about 50 deaths prevented with an aldosterone antagonist in severe HF.

N Engl J Med 2001; 344(22):1651-8.

CIBIS-IICIBIS-II

Cardiac Insufficiency Bisoprolol Study II (CIBIS-II) compared a ß-blocker-containing regimen with standard therapy alone (diuretic plus ACE inhibitor) in 2,647 patients with NYHA class III or IV heart failure

Bisoprolol:

34% reduction in mortality

32% reduction in hospitalization. Lancet 1999; 353:9-13

BEST trialBEST trial

The Beta-blocker Evaluation of Survival Trial. Randomized 2708 patients with NYHA Class

III (92%) or IV (8%) HF and an ejection fraction of 35% or lower to bucindolol or placebo.

Mortality was not significantly different between the two groups .

May 31, 2001 issue of the New England Journal of Medicine.

BEST results

p valueEndpoint

Bucinodol and carvedilol in HF

0.0429%

Death or heart transplant

CV death

Placebo

42% <0.001

Hazard ratioBucindolol

BEST investigators. N Engl J Med 2001; 344(22):1659-67.

Hospitalized due to CHF

Death 33%

Heart transplant 3%

COMET TRIALCOMET TRIAL

The ongoing Carvedilol and Metoprolol European Trial, which involves 3,000 patients with NYHA class II to class IV heart failure, is testing the hypothesis that multiple-receptor blockade with carvedilol offers a therapeutic advantage over selective adrenergic blockage with metoprolol.

ß-blocker therapyß-blocker therapy

Although ejection fraction continues to improve at the highest dosage of Carvedilol (25 mg twice daily or 50 mg twice daily in heavier patients), significant treatment effect (two thirds or more of maximum mortality benefit) is seen at 6.25 mg twice daily.

Continue at a minimum dosage of 6.25 mg twice daily and do not abandon therapy if higher doses are not tolerated.

beta-Blocker withdrawal: beta-Blocker withdrawal: The song of OrpheusThe song of Orpheus

Morimoto : 13 patients with dilated cardiomyopathy who were

receiving long-term beta-blockade; Investigators withdrew the therapy to see if the patients

would continue to do well. Seven of the 13 patients deteriorated, including 4 who

died either suddenly or of progressive pump dysfunction.

Am Heart J 1999;138:387-9.

ATLAS study ATLAS study

Increasing ACE inhibitor doses from low to high confers relatively modest absolute reductions in mortality (8%).

Eur Heart J 1998; 19(suppl):142

Adding ß-blockade to intermediate doses of ACEI reduces mortality by 30% or more.

Lancet 1999; 353:9-13

Lancet 1999; 353:2001-2007

To optimally slow disease progression, it may, therefore, be preferable to add ß-blockade to moderate doses of ACE inhibitors, then increase the ACE inhibitor dose later, titrating upward as each successive dose is tolerated.

Taking the ACE inhibitor 2 hours after the carvedilol or taking carvedilol with food may reduce this hypotensive effect.

A temporary reduction in the dose of the ACE inhibitor may also be required.

Am J Cardiol 1999; 83(suppl 2A):1A-38A

-Blockers underutilized in heartfailure: major side effects

N/A 5%Impotence

N/A 8%Depression

12% 9%Diarrhea

9% 17%Bradycardia

13% 22%Hyperglycemia

9% 22%Hypertension

22% 27%Dyspnea

33% 35%Dizziness

25% 61%Fatigue

10% 64%Weight gain

US carvedilol studyStudy populationSide effect

Dr Ghazanfar Khadin et al, 49th AnnualScientific Session of the ACC

ELITEELITE Study Study

Evaluation of Losartan in the Elderly (ELITE) study:

722 patients to compare effects of losartan and captopril on renal function.

losartan associated with a 46% lower risk of mortality than captopril.

Lancet 1996; 2:47-54

ELITE StudyELITE Study

The study was not powered to investigate mortality, and after adjustment for the multiplicity of end points, no difference was seen in frequency of hospitalization or combined morbidity and mortality risk

Pharmacotherapy 20(7):787-804, 2000

RESOLVD studyRESOLVD study

Randomized Evaluation of Strategies for Left Ventricular Dysfunction (RESOLVD) study involved 768 patients.

No significant differences in the rate of cardiac events among patients treated with candesartan, enalapril, or the combination.

Eur Heart J 1998; 19(suppl):

VALVALSARTAN SARTAN HeHeart art FFailure ailure TTrialrial

LONG-TERM CARDIAC MORBIDITY & MORTALITY TRIAL

CHRONIC STABLE HEART FAILURE PATIENTS

VALSARTAN ADDED TO USUAL HEART FAILURE THERAPY (ACEIS; DIURETICS; DIGOXIN; BLOCKERS)

• 5,010 PATIENTS • 300 CENTERS IN 16 COUNTRIES

HF PATIENTS>18 YR; EF <40%;

NYHA II-IV

906 DEATHS (EVENTS RECORDED)

VALSARTAN40 MG BID

TITRATED TO160 MG BID

RANDOMIZED TO

RECEIVING USUAL THERAPY INCLUDING ACEI, DIURETICS, DIGOXIN, BLOCKERS (STRATIFIED RANDOMIZATION)

Val-HeFT DESIGNVal-HeFT DESIGN

Placebo

Cohn et al. J Card Fail 1999;5:155-160

All Cause MortalityAll Cause Mortality

VALSARTAN PLACEBO

TIME SINCE RANDOMIZATION (MONTHS)

P = 0.8

0 3 6 9 12 211815 24 27

13.3%RISK REDUCTION

P= 0.009

COMBINED ALL CAUSE MORTALITY AND MORBIDITY

VALSARTAN PLACEBO

3 6 9 12 211815 24 27TIME SINCE RANDOMIZATION (MONTHS)

TIME SINCE RANDOMIZATION (MONTHS)

27.5%RISK

REDUCTIONP =0.00001

HF HOSPITALIZATION

VALSARTAN PLACEBO

3 6 9 12 211815 24 27TIME SINCE RANDOMIZATION (MONTHS)

0TIME SINCE RANDOMIZATION (MONTHS)

SECONDARY VARIABLES CHANGE FROM BASELINE

012345

QUALITY OF LIFE(MLWHF* SCORE)†

EF (%)†

PLACEBO VALSARTAN

p= 0.001WORS

BETTER

p = 0.005

N=1557 N=1544 N=2509 N=2499

† ENDPOINT ANALYSIS

* MINNESOTA LIVING WITH HEART FAILURE

0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 1.1 1.2 1.3 1.4

% PatientsAll Patients 100

6547 < 6553

Male 80Female 20EF < 27 50EF 27 50

ACEI (Yes) 93ACEI (No) 7BB (Yes) 35BB (No) 65IHD (Yes) 57IHD (No) 43

FAVORS VALSARTAN FAVORS PLACEBO

COMBINED MORBIDITY/MORTALITYCOMBINED MORBIDITY/MORTALITYIN SUBGROUPSIN SUBGROUPS

ARBs offer an alternative to ACE inhibitors in the management of hypertension, especially for ACE-inhibitor-intolerant patients. ACE inhibitors remain the drugs of choice for patients with heart failure, left ventricular dysfunction after MI, and diabetic nephropathy; ARBs offer these patients an alternative when ACE inhibitor therapy is not tolerated.

Am J Health-Syst Pharm 2001: 58(8):671-683

Combination therapyCombination therapy

The addition of an ARB offers more complete angiotensin II receptor blockade of the RAS than can be obtained by ACE inhibitors alone.

Combination therapy preserves the benefits of bradykinin potentiation offered by ACE inhibitors while providing potential antitrophic influences of AT2 receptor stimulation

May play an increased role in the treatment of chronic HF in the future.

Am Heart J 2000 : 140(3):361-366

Aldosterone AntagonistsAldosterone Antagonists

Randomized Aldactone Evaluation Study involved 1,663 patients with severe heart failure (NYHA class III or IV) of ischemic or nonischemic origin.

Most patients received dosages of 25 mg daily in addition to the conventional background therapy

N Engl J Med 1999; 341:709-717

Aldosterone Inhibition and Heart Aldosterone Inhibition and Heart Failure: Too Good to Be True?Failure: Too Good to Be True?

The Randomized Aldactone Evaluation Study (RALES) h stunningly positive results.

Spironolactone, available for more than 40 years

Reduce the mortality rate by 30% in patients with advanced heart failure.

Hospitalization rate for worsening heart failure was reduced by 35%.

American Heart Journal 2001,1:141

DIG trialDIG trial

Digitalis Investigation Group (DIG), the National Institutes of Health .

To study to digoxin's effect on survival and morbidity in 7788 patients who remained symptomatic while taking diuretics and ACE inhibitors

No significant difference when deaths from all cardiovascular causes (29.9% digoxin vs 29.5% placebo, RR=1.10, p=0.78)

DIG trialDIG trial

Digoxin significantly reduced the rate of hospitalizations (26.8%) compared with placebo (34.7%, RR=0.72, p<0.001).

Admissions were fewer when all cardiovascular reasons were combined, including myocardial infarction and supraventricular arrhythmias (49.9% vs 54.4, RR=0.87, p<0.001).

Intermittent inotropic infusion therapy reported excess mortality with dobutamine. Dobutamine infusions were titrated to produce an optimal hemodynamic profile; mean dosages were 8.1 µg/kg/minute (maximum 15 µg/kg/min).

Death occurred in 32% (10/31) of dobutamine-treated patients compared with 14% (4/29) of placebo-treated patients over 24 weeks.

Causes of death assumed to result from arrhythmias (sudden cardiac death).

Lower dosages of inotropes may be associated with improvements in quality of life with lower risk of mortality.

Long-term therapy with phosphodiesterase inhibitors (e.g., milrinone, venarinone) :excess mortality

Intermittent intravenous inotropic agent may be of value in improving the quality of life or as a bridge to cardiac transplantation.

Catecholamine infusions have been associated with excess mortality.

Cardiac transplantation, left ventricular assist devices, and total artificial hearts are limited by technical, logistic, and cost issues

Pharmacotherapy 20(7):787-804, 2000.

Hydralazine-isosorbide dinitrate should be considered in patients with contraindications to ACE inhibitors. The major limitation with the combination is the frequency of adverse effects at dosages recommended for heart failure.

Calcium Channel AntagonistsCalcium Channel Antagonists

May worsen heart failure Trials of verapamil, diltiazem, and nifedipine

showed detrimental effects in heart failure. Vasoselective dihydropyridines, such as

amlodipine and felodipine :no negative effects.

PRAISE trialPRAISE trial

Amlodipine 10 mg/day or placebo to 1153 patients with class III-IV disease. All patients also received digoxin, a diuretic, and an ACE Inhibitor.

No difference was observed in all-cause mortality or combined end points of death and adverse clinical events in the two groups (p=0.07).

Amlodipine and felodipine have few or no beneficial effects..

DDD pacingDDD pacing

Intraventricular conduction delay may hamper the ability of the heart to contract in an organized manner, with contraction of different segments occurring at less than optimal times

DDD pacing of the right sided chambers may be beneficial in selected dilated cardiomyopathy patients

Change in outcome measures with active pacing in MUSTI C

Hospitalizations <0.05

p valueOutcome measure

Cazeau et al. N Engl J Med 2001; 344: 873-80.

MUSTIC

<0.001

Quality of life score

Mean (+SD) distance walked

Peak oxygen uptake

% change

<0.001

Diastolic Heart FailureDiastolic Heart Failure

Half of heart failure subjects in the community have normal LV systolic function.

Major contributor to hospital admissions, but is often overlooked in studies that focus only on patients with impaired systolic function

Hypertension, coronary artery disease, the normal aging process, obesity, and diabetes mellitus are associated with diastolic dysfunction

Cardiology Clinics 2000 :18 ,3

Diastolic heart failureDiastolic heart failure

Currently, there are no therapies that specifically affect the rate of calcium sequestration or protein phosphorylation, which would produce specific therapy for diastolic failure.

Therapy currently is based on the underlying cardiovascular disorder and the use of pharmacologic agents that appear to specifically influence known pathophysiologic abnormalities

Optimal treatment of diastolic heart failure has not yet been defined.

Goals of Therapy for Diastolic Heart Goals of Therapy for Diastolic Heart FailureFailure

Treat underlying cardiovascular disease:Coronary artery diseaseHypertensionDiabetesAtrial fibrillation

Avoid volume depletion ( may predispose to:

Orthostatic symptomsTachycardiaStimulation of vasodepressor syncope

Facilitate diastolic filling time

Slow heart rate. beta Blockade

Avoid chronotropic/inotropic stimulation. with agents, such as:

DigoxinTheophylline

Ephedrine and decongestantsCaffeine

Reverse or minimize ventricular hypertrophy:

Afterload reductionAngiotensin II blockade

Cardiology ClinicsVolume 18 • Number 3 • August 2000

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Heart Failure Society Guidelines: A Heart Failure Society Guidelines: A Model of Consensus and ExcellenceModel of Consensus and Excellence

Committee Members: Kirkwood F. Adams, Jr., MD, Chair, Kenneth L. Baughman, MD Marvin A. Konstam, MD, William G. Dec, MD Peter Liu, MD, Uri Elkayam, MD Barry M. Massie, MD, Alan D. Forker, MD J. Herbert Patterson, PharmD, Mihai Gheorghiade, MD Marc A. Silver, MD, Denise Hermann, MD Lynne Warner Stevenson, MDExecutive Council: Arthur M. Feldman, MD, PhD, President, Jay N. Cohn, MD Bertram Pitt, MD, Gary S. Francis, MD Marc A. Silver, MD, Barry Greenberg, MD Edmund Sonnenblick, MD, Marvin A. Konstam, MD John Strobeck, MD, PhD, Carl Leier, MD Richard Walsh, MD, Beverly H. Lorell, MD Salim Yusuf, MBBS, PhD, Milton Packer, MD