Heart Failure

ROBERT SAMUEL MCKELVIE, BSC, MSC, M.D., PH.D., FRCPC, McMaster University, Hamilton, Ontario, Canada

See editorial on page 27.

Questions Addressed

• What are the effects of nondrug treatments in heart failure?
• What are the effects of drug and invasive treatments in heart failure?
• What are the effects of angiotensin-converting enzyme (ACE) inhibitors in people at high risk of heart failure?
• What are the effects of treatments for diastolic heart failure?

Summary of Interventions Beneficial Angiotensin-converting enzyme (ACE) inhibitors Angiotensin II receptor blockers Digoxin (improves morbidity in people already receiving diuretics and ACE inhibitors) Beta blockers Spironolactone in severe heart failure Likely to be beneficial Multidisciplinary interventions Exercise Amiodarone Implantable cardiac defibrillators Unlikely to be beneficial Calcium channel blockers Unknown effectiveness Anticoagulation Antiplatelet agents Likely to be ineffective or harmful Positive inotropes (nondigitalis) Non-amiodarone antiarrhythmic drugs To be covered in future issues of Clinical Evidence Vasodilators Coronary revascularization Atheroma risk factor modification

Definition

Heart failure occurs when abnormality of cardiac function causes failure of the heart to pump blood at a rate sufficient for metabolic requirements, or maintains cardiac output only with a raised filling pressure. It is characterized clinically by breathlessness, effort intolerance, fluid retention, and poor survival. It can be caused by systolic or diastolic dysfunction and is associated with neurohormonal changes.¹ Left ventricular systolic dysfunction (LVSD) is defined as a left ventricular ejection fraction (LVEF) below 0.40. It can be symptomatic or asymptomatic. Defining and diagnosing diastolic heart failure can be difficult. Recently proposed criteria include: (1) clinical evidence of heart failure; (2) normal or mildly abnormal left ventricular systolic function; and (3) evidence of abnormal left ventricular relaxation, filling, diastolic distensibility, or diastolic stiffness.² The clinical utility of these criteria is limited by difficulty in standardizing assessment of the last criterion.⁷

Incidence/Prevalence

The incidence and prevalence of heart failure increase with age. In those younger than 65 years, the incidence is one per 1,000 men a year and 0.4 per 1,000 women a year. In those older than 65 years, incidence is 11 per 1,000 men a year and five per 1,000 women a year. In those younger than 65 years, the prevalence of heart failure is one per 1,000 men and one per 1,000 women; in those older than 65 years, the prevalence is 40 per 1,000 men and 30 per 1,000 women.³ The prevalence of asymptomatic LVSD is 3 percent in the general population.^4,5,6 The mean age of people with asymptomatic LVSD is lower than that for symptomatic individuals. Heart failure and asymptomatic LVSD are more common in men.^4,5,6 The prevalence of diastolic heart failure in the community is unknown. The prevalence of heart failure with preserved systolic function in people in the hospital with clinical heart failure varies from 13 to 74 percent.^7,8 Less than 15 percent of people younger than 65 years with heart failure have normal systolic function, whereas the prevalence is about 40 percent in people older than 65 years.⁷

Etiology/Risk Factors

Coronary artery disease is the most common cause of heart failure.³ Other common causes include hypertension and idiopathic dilated congestive cardiomyopathy. After adjustment for hypertension, the presence of left ventricular hypertrophy remains a risk factor for the development of heart failure. Other risk factors include cigarette smoking, hyperlipidemia, and diabetes mellitus.⁴ The common causes of left ventricular diastolic dysfunction are coronary artery disease and systemic hypertension. Other causes are hypertrophic cardiomyopathy, restrictive or infiltrative cardiomyopathies, and valvular heart disease.⁸

Prognosis

The prognosis of heart failure is poor, with five-year mortality ranging from 26 to 75 percent.³ Up to 16 percent of people are readmitted with heart failure within six months of first admission. In the United States, it is the leading cause of hospital admission among people older than 65 years.³ In people with heart failure, a new myocardial infarction increases the risk of death (relative risk: 7.8; 95 percent confidence interval [CI]: 6.9 to 8.8); 34 percent of all deaths in people with heart failure are preceded by a major ischemic event.⁹ Sudden death, mainly caused by ventricular arrhythmias, is responsible for 25 to 50 percent of all deaths, and is the most common cause of death in people with heart failure.¹⁰ The presence of asymptomatic LVSD increases an individual's risk of having a cardiovascular event. One large prevention trial found that, for a 5 percent reduction in ejection fraction, the risk ratio for mortality was 1.20 (95 percent CI: 1.13 to 1.29), for hospital admission for heart failure it was 1.28 (95 percent CI: 1.18 to 1.38), and for development of heart failure it was 1.20 (95 percent CI: 1.13 to 1.26).⁴ The annual mortality of patients with diastolic heart failure varies in observational studies (1.3 to 17.5 percent).⁷ Reasons for this variation include age, the presence of coronary artery disease, and variation in the partition value used to define abnormal ventricular systolic function. The annual mortality for left ventricular diastolic dysfunction is lower than that found in patients with systolic dysfunction.¹¹

Clinical Aims

To relieve symptoms; to improve quality of life; to reduce morbidity and mortality with minimum adverse effects.

Clinical Outcomes

Functional capacity (assessed by the New York Heart Association [NYHA] functional classification or, more objectively, by using standardized exercise testing or the six-minute walk test)¹²; quality of life (assessed with questionnaires)¹³; mortality; adverse effects of treatment. Proxy measures of clinical outcome (e.g., LVEF, hospital readmission rates) are used here only when clinical outcomes are unavailable.

Evidence-Based Medicine Findings SEARCH DATE: CLINICAL EVIDENCE UPDATE SEARCH AND APPRAISAL OCTOBER 2000

Nondrug Treatments

MULTIDISCIPLINARY INTERVENTIONS
We found conflicting evidence. One systematic review has found that multidisciplinary approaches to nutrition, patient counseling, and education reduce hospital admissions, may improve quality of life and enhance patient knowledge. However, the review excluded a large randomized controlled trial (RCT), which found that multidisciplinary follow-up increased readmission rates.

EXERCISE
RCTs have found that prescribed exercise training improves functional capacity and quality of life. One recent RCT has also found that exercise significantly reduces adverse cardiac events.

Drug and Invasive Treatments

ANGIOTENSIN-CONVERTING ENZYME (ACE) INHIBITORS
Two systematic reviews and recent RCTs have found that ACE inhibitors reduce mortality, admission to hospital for heart failure, and ischemic events in people with heart failure. Relative benefits are similar in different groups of people, but absolute benefits are greater in people with severe heart failure.

ANGIOTENSIN II RECEPTOR BLOCKERS
One RCT has found that angiotensin II receptor antagonists improve symptom indices compared with placebo. RCTs found no evidence that angiotensin II receptor blockers altered functional capacity or symptoms compared with ACE inhibitors, but the trials were too small to rule out clinically important differences. We found moderate evidence from one RCT that angiotensin II receptor blockers are as effective as ACE inhibitors in reducing all-cause mortality.

POSITIVE INOTROPIC AGENTS
We found no evidence that positive inotropic drugs, other than digoxin, reduce mortality and morbidity in people with heart failure, and most RCTs found that they increased mortality. One well-designed RCT found that digoxin decreased the rate of hospital admissions and cointervention for worsening heart failure in people already receiving diuretics and ACE inhibitors, although it found no evidence of an effect on mortality.

BETA BLOCKERS
We found strong evidence from systematic reviews of RCTs that adding beta blockers to standard treatment with ACE inhibitors in people with moderate heart failure reduces the rate of death or hospital admission. The reviews found less robust evidence that beta blockers improve exercise capacity.

CALCIUM CHANNEL BLOCKERS
We found no evidence that calcium channel blockers are of benefit in people with heart failure.

ALDOSTERONE RECEPTOR ANTAGONISTS
One recent large RCT of people with severe heart failure (on usual treatment including an ACE inhibitor) has found that adding an aldosterone receptor antagonist (spironolactone) further decreases mortality.

ANTIARRHYTHMIC DRUG TREATMENT
Systematic reviews found weak evidence that amiodarone reduces total mortality in people with heart failure. Other antiarrhythmic agents may increase mortality in people with heart failure.

IMPLANTABLE CARDIAC DEFIBRILLATORS
Three RCTs have found good evidence that the implantable cardiac defibrillator (ICD) reduces mortality in people with heart failure who have experienced a cardiac arrest. The review found conflicting evidence for prophylactic implantation of ICDs in people at risk of arrhythmia.

ANTICOAGULATION
We found no RCTs of anticoagulation in people with heart failure. We found conflicting evidence from two large, retrospective cohort studies.

ANTIPLATELET AGENTS
We found no RCTs. Retrospective analyses have included too few events to establish or exclude a clinically important effect of antiplatelet agents in people with heart failure. In people not taking ACE inhibitors, we found limited evidence from one retrospective cohort analysis that the incidence of thromboembolic events in people with heart failure was low and not significantly improved with antiplatelet therapy. It is unclear from limited evidence from two retrospective cohort analyses whether there are additional reductions in the incidence of thromboembolic events from adding ACE inhibitor therapy to antiplatelet therapy in people with heart failure. It is unclear whether adding antiplatelet therapy to ACE inhibitor treatment in people with heart failure is beneficial.

ACE Inhibitors in People at High Risk of Heart Failure

RCTs have found good evidence that ACE inhibitors can delay development of symptomatic heart failure and reduce the frequency of cardiovascular events in people with asymptomatic LVSD and in people with other cardiovascular risk factors for heart failure.

Treatments for Diastolic Heart Failure

We found no randomized controlled trials in people with diastolic heart failure.

Adapted with permission from McKelvie RS. Heart failure. Clin Evid 2001;5:43-62.

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REFERENCES

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2. Working Group Report. How to diagnose diastolic heart failure: European Study Group on Diastolic Heart Failure. Eur Heart J 1998;19:990-1003.
3. Cowie MR, Mosterd A, Wood DA, et al. The epidemiology of heart failure. Eur Heart J 1997;18:208-25.
4. McKelvie RS, Benedict CR, Yusuf S. Prevention of congestive heart failure and management of asymptomatic left ventricular dysfunction. BMJ 1999;318:1400-2.
5. Bröckel U, Hense HW, Museholl M, Döring A, Riegger GA, Schunkert H. Prevalence of left ventricular dysfunction in the general population [Abstract]. J Am Coll Cardiol 1996;27(suppl A):25.
6. Mosterd A, deBruijne MC, Hoes A, Deckers JW, Hofman A, Grobbee DE. Usefulness of echocardiography in detecting left ventricular dysfunction in population-based studies (the Rotterdam study). Am J Cardiol 1997;79:103-4.
7. Vasan RS, Benjamin EJ, Levy D. Congestive heart failure with normal left ventricular systolic function. Arch Intern Med 1996; 156:146-57.
8. Davie AP, Francis CM, Caruana L, Sutherland GR, McMurray JV. The prevalence of left ventricular diastolic filling abnormalities in patients with suspected heart failure. Eur Heart J 1997;18:981-4.
9. Yusuf S, Pepine CJ, Garces C, et al. Effect of enalapril on myocardial infarction and unstable angina in patients with low ejection fractions. Lancet 1992;340:1173-8.
10. Gheorghiade M, Benatar D, Konstam MA, Stoukides CA, Bonow RO. Pharmacotherapy for systolic dysfunction: a review of randomized clinical trials. Am J Cardiol 1997;80(suppl 8B): 14-27H.
11. Gaasch WH. Diagnosis and treatment of heart failure based on LV systolic or diastolic dysfunction. JAMA 1994;271:1276-80.
12. 12. Bittner V, Weiner DH, Yusuf S, et al, for the SOLVD Investigators. Prediction of mortality and morbidity with a 6-minute walk test in patients with left ventricular dysfunction. JAMA 1993;270:1702-7.
13. Rogers WJ, Johnstone DE, Yusuf S, et al, for the SOLVD Investigators. Quality of life among 5,025 patients with left ventricular dysfunction randomized between placebo and enalapril. The studies of left ventricular dysfunction. J Am Coll Cardiol 1994;23:393-400.

This is one in a series of chapters excerpted from Clinical Evidence, published by the BMJ Publishing Group, Tavistock Square, London, United Kingdom. Clinical Evidence is published in print twice a year and is updated monthly online. The complete text for this topic, as well as additional information, is available to subscribers at www.clinicalevidence.com. This series is part of AFP's CME. See "Clinical Quiz" on page 23.

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