What are the effects of nondrug treatments?
One systematic review and subsequent randomized controlled trials (RCTs) showed that multi-disciplinary interventions reduced all-cause mortality, all-cause hospitalizations, and hospitalizations for heart failure compared with conventional care.
LIKELY TO BE BENEFICIAL
Two systematic reviews showed that exercise training reduced death rates compared with usual care, although this reduction was not statistically significant in one review. Two systematic reviews showed that exercise training improved exercise performance compared with usual care.
What are the effects of drug and invasive treatments?
Systematic reviews and RCTs showed that angiotensin-converting enzyme (ACE) inhibitors reduced ischemic events, mortality, and hospitalizations for heart failure compared with placebo. Relative benefits were similar in different groups, although absolute benefits were greater in persons with severe heart failure. The next section of this chapter compares ACE inhibitors with angiotensin-II receptor blockers.
Angiotensin-II Receptor blockers
One systematic review showed that angiotensin-II receptor blockers reduced mortality and hospitalization for heart failure compared with placebo in persons with New York Heart Association functional class II to IV heart failure. They were effective alternatives in persons who were intolerant to ACE inhibitors. One systematic review showed no significant difference between angiotensin-II receptor blockers and ACE inhibitors in all-cause mortality or hospitalizations. One systematic review showed that angiotensin-II receptor blockers plus ACE inhibitors reduced cardiovascular mortality and hospitalizations for heart failure compared with ACE inhibitors alone. Effects on all-cause mortality were unclear.
Digoxin (improves Morbidity in Persons Receiving Diuretics and ace inhibitors)
One systematic review showed that, compared with placebo, digoxin reduced hospitalizations and clinical deterioration in persons in sinus rhythm; however, the review showed no significant difference between digoxin and placebo in mortality rate.
Systematic reviews included strong evidence that adding a beta blocker to an ACE inhibitor decreased mortality and hospitalization in symptomatic persons with heart failure of any severity. Limited evidence from a subgroup analysis of one RCT showed no significant effect on mortality in black persons.
One systematic review and one subsequent RCT showed that cardiac resynchronization improved functional capacity, reduced hospitalization for heart failure, and reduced all-cause mortality compared with standard care.
LIKELY TO BE BENEFICIAL
Spironolactone in Persons with Severe Heart failure
One large RCT including persons with severe heart failure who were taking diuretics, ACE inhibitors, and digoxin showed that adding spironolactone reduced mortality after two years compared with adding placebo.
Eplerenone (in Persons Receiving Medical Treatment for Myocardial Infarction Complicated by Left Ventricular Dysfunction and Heart Failure)
One large RCT including persons receiving medical treatment (e.g., ACE inhibitors, angiotensin receptor blockers, diuretics, beta blockers, coronary reperfusion therapy) for recent myocardial infarction complicated by left ventricular dysfunction and clinical heart failure showed that adding the aldosterone receptor antagonist, eplere-none, reduced mortality compared with adding placebo.
Implantable Cardiac Defibrillators in Persons at High Risk of Arrhythmia
One systematic review showed that implantable cardiac defibrillators reduced mortality in persons with heart failure who have experienced a near-fatal ventricular arrhythmia or are at high risk of sudden death. A second systematic review showed that implantable cardiac defibrillators reduced mortality in persons with heart failure caused by nonischemic cardiomyopathy.
LIKELY TO BE IN EFFECTIVE OR HARMFUL
Positive Inotropic Drugs (other Than Digoxin)
RCTs including persons with heart failure showed that positive inotropic drugs other than digoxin (i.e., ibopamine, milrinone, and vesnarinone) increased mortality over six to 11 months compared with placebo. One systematic review including persons with heart failure showed that intravenous adrenergic inotropes increased mortality compared with placebo or control, although the increase was not significant. The review provided insufficient evidence about effects on symptoms and suggested that the use of these drugs may not be safe.
Calcium Channel blockers
One systematic review showed no significant difference between second-generation dihydropyridine calcium channel blockers and placebo in mortality rates. RCTs comparing other calcium channel blockers with placebo also provided no evidence of benefit. Calcium channel blockers have been shown to exacerbate heart failure symptoms or increase mortality after myocardial infarction in persons with concomitant pulmonary congestion or left ventricular dysfunction.
Nonamiodarone Antiarrhythmic Drugs
Evidence from one systematic review including persons treated for myocardial infarction suggested that nonamiodarone antiarrhythmic drugs (other than beta blockers) may increase mortality in persons with heart failure.
Systematic reviews provided weak evidence that amiodarone reduces mortality compared with placebo. However, we were unable to firmly conclude how amiodarone affects persons with heart failure.
Anticoagulant vs. Antiplatelet Therapy
Preliminary results of one RCT showed no significant difference between warfarin and no antithrombotic treatment or between warfarin and aspirin in the combined outcome of death, myocardial infarction, and stroke after 27 months. However, the RCT may have lacked power to detect clinically important differences. Further research is needed to determine the effects of antiplatelet treatment combined with ACE inhibitors.
What are the effects of ACE inhibitors in persons at high risk of heart failure?
Angiotensin-II Receptor blockers
One RCT showed that candesartan, an angiotensin-II receptor blocker, reduced the combined outcome of cardiovascular death and hospitalization for heart failure compared with placebo, although the difference was not significant. The RCT showed no significant difference between the two groups in cardiovascular death, although candesartan reduced hospitalization compared with placebo.
We found no RCTs examining the effects of other treatments in persons with diastolic heart failure.
Heart failure occurs when abnormal cardiac function does not allow the heart to pump blood at a sufficient rate for metabolic requirements under normal filling pressure. The clinical characterization of heart failure is breathlessness, effort intolerance, fluid retention, and poor survival. Diuretic therapy often can relieve fluid retention and resultant congestion. However, in general, diuretic therapy should not be used alone and, if required, it should be combined with the pharmacologic therapies outlined in this chapter. Heart failure can be caused by systolic or diastolic dysfunction and is associated with neurohormonal changes.1 Left ventricular systolic dysfunction (LVSD) may be symptomatic or asymptomatic and is defined as a left ventricular ejection fraction less than 0.40. 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 However, the assessment of some of these criteria is not standardized.
Incidence and Prevalence
The incidence and prevalence of heart failure increase with age. Studies of heart failure in the United States and Europe showed that the annual incidence of heart failure in patients younger than 65 years is one out of 1,000 for men and 0.4 out of 1,000 for women. The annual incidence in patients older than 65 years is 11 out of 1,000 for men and five out of 1,000 for women. The prevalence of heart failure in patients younger than 65 years is one out of 1,000 for men and women, and the prevalence for patients older than 65 years is 40 out of 1,000 for men and 30 out of 1,000 for women.3 The prevalence of asymptomatic LVSD is 3 percent in the general population.4–6 The mean age of persons with asymptomatic LVSD is lower than that for symptomatic persons. Heart failure and asymptomatic LVSD are more common in men.4–6 The prevalence of diastolic heart failure in the general population is unknown. The prevalence of heart failure with preserved systolic function in persons hospitalized for clinical heart failure is 13 to 74 percent.7,8 Fewer than 15 percent of persons younger than 65 years with heart failure have normal systolic function, whereas the prevalence of heart failure with preserved systolic function is about 40 percent in persons older than 65 years.7
Coronary artery disease is the most common cause of heart failure.3 Hypertension and idiopathic dilated congestive cardiomyopathy also are common causes. After adjustment for hypertension, the presence of left ventricular hypertrophy remains a risk factor for heart failure. Other risk factors include cigarette smoking, hyperlipidemia, and diabetes mellitus.4 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
Heart failure is associated with a poor prognosis and a five-year mortality rate of 26 to 75 percent.3 Up to 16 percent of patients are rehospitalized for heart failure within six months of their initial hospitalization for heart failure. In the United States, heart failure is the leading cause of hospitalization of persons older than 65 years.3 In persons with heart failure, a new myocardial infarction increases the risk of death (relative risk [RR] = 7.8; 95% confidence interval [CI], 6.9 to 8.8). About one third of deaths in persons with heart failure are preceded by a major ischemic event.9 Sudden death, mainly caused by ventricular arrhythmia, is responsible for 25 to 50 percent of all deaths and is the most common cause of death in persons with heart failure.10 Asymptomatic LVSD increases the risk of a cardiovascular event. One large prevention trial showed that the risk of heart failure, hospitalization for heart failure, and death increased linearly with decreasing ejection fraction (for each 5 per-cent reduction: for mortality RR = 1.20; 95% CI, 1.13 to 1.29; for hospitalization RR = 1.28; 95% CI, 1.18 to 1.38; for heart failure RR = 1.20; 95% CI, 1.13 to 1.26).4 The annual mortality for persons with diastolic heart failure has varied in observational studies (1.3 to 17.5 percent).7 Reasons for this variation include patient age, 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 for systolic dysfunction.11