Drugs for heart failure

Heart failure is a disease with two major forms: (1) heart failure with left ventricular (LV) systolic dysfunction, and (2) diastolic heart failure, also known as heart failure with preserved LV ejection fraction. In this chapter, discussion is limited to the first form. Accordingly, for the rest of this chapter, the term heart failure (HF) will be used to denote the first form only.

Heart failure is a progressive, often fatal disorder characterized by ventricular dysfunction, reduced cardiac output, insufficient tissue perfusion, and signs of fluid retention (eg, peripheral edema, shortness of breath). The disease affects nearly 5 million Americans and, every year, is responsible for 12 to 15 million office visits, 6.5 million hospital days, and about 300,000 deaths. Of those who have HF, 24% are likely to die within 1 year, and 65% within 5 years. Heart failure is primarily a disease of the elderly, affecting 2% to 3% of those at age 65 and more than 80% of those over age 80. In 2008, direct and indirect healthcare costs of HF were estimated at more than $35 billion. With improved evaluation and care, many hospitalizations could be prevented, quality of life could be improved, and life expectancy could be extended.

In the past, HF was commonly referred to as congestive heart failure. This term was used because HF frequently causes fluid accumulation (congestion) in the lungs and peripheral tissues. However, because many patients do not have signs of pulmonary or systemic congestion, the term heart failure is now preferred.

In order to understand HF and its treatment, you need a basic understanding of hemodynamics. In particular, you need to understand the role of venous pressure, afterload, and Starling’s mechanism in determining cardiac output. You also need to understand the roles of the baroreceptor reflex, the RAAS, and the kidneys in regulating arterial pressure. If your understanding of these concepts is a little hazy, you can refresh your memory by reading Chapter 43 (Review of Hemodynamics).

In response to stretching of the atria and dilation of the ventricles, the heart releases two natriuretic peptides: atrial natriuretic peptide (ANP) and B-natriuretic peptide (BNP). As discussed in Chapter 43, these hormones promote dilation of arterioles and veins, and also promote loss of sodium and water through the kidneys. Hence, they tend to counterbalance vasoconstriction caused by the SNS and angiotensin II, as well as retention of sodium and water caused by the RAAS. However, as HF progresses, the effects of ANP and BNP eventually become overwhelmed by the effects of the SNS and RAAS.

Levels of circulating BNP are an important index of cardiac status in HF patients, and hence can be a predictor of long-term survival. High levels of BNP indicate poor cardiac health, and hence predict a lower chance of survival. Conversely, low levels of BNP indicate better cardiac health, and hence predict a higher chance of survival. This information can be helpful when assessing the hospitalized patient at discharge: The lower the BNP level, the greater the chances of long-tem survival.

The vicious cycle of “compensatory” physiologic responses

As discussed above, reduced cardiac output leads to compensatory responses: (1) cardiac dilation, (2) activation of the SNS, (3) activation of the RAAS, and (4) retention of water and expansion of blood volume. Although these responses represent the body’s attempt to compensate for reduced cardiac output, they can actually make matters worse: Excessive heart rate can reduce ventricular filling; excessive arterial pressure can lower cardiac output; and excessive venous pressure can cause pulmonary and peripheral edema. Hence, as depicted in Figure 48–2, the “compensatory” responses can create a self-sustaining cycle of maladaptation that further impairs cardiac output and tissue perfusion. If cardiac output becomes too low to maintain sufficient production of urine, the resultant accumulation of water will eventually be fatal. The actual cause of death is complete cardiac failure secondary to excessive cardiac dilation and cardiac edema.

Figure 48–2 The vicious cycle of maladaptive compensatory responses to a failing heart.

Signs and symptoms of heart failure

The prominent signs and symptoms of HF are a direct consequence of the pathophysiology just described. Decreased tissue perfusion results in reduced exercise tolerance, fatigue, and shortness of breath; shortness of breath may also reflect pulmonary edema. Increased sympathetic tone produces tachycardia. Increased ventricular filling, reduced systolic ejection, and myocardial hypertrophy result in cardiomegaly (increased heart size). The combination of increased venous tone plus increased blood volume helps cause pulmonary edema, peripheral edema, hepatomegaly (increased liver size), and distention of the jugular veins. Weight gain results from fluid retention.

Classification of heart failure severity

There are two major schemes for classifying HF severity. One scheme, established by the New York Heart Association (NYHA), classifies HF based on the functional limitations it causes. A newer scheme, proposed jointly by the American College of Cardiology (ACC) and the American Heart Association (AHA), is based on the observation that HF is a progressive disease that moves through stages of increasing severity.

The NYHA scheme, which has four classes, can be summarized as follows:

• Class I—No limitation of ordinary physical activity

• Class II—Slight limitation of physical activity: normal activity produces fatigue, dyspnea, palpitations, or angina

• Class III—Marked limitation of physical activity: even mild activity produces symptoms

• Class IV—Symptoms occur at rest

The ACC/AHA scheme, which also has four stages, can be summarized as follows:

• Stage A—At high risk for HF but without structural heart disease or symptoms of HF

• Stage B—Structural heart disease but without symptoms of HF

• Stage C—Structural heart disease with prior or current symptoms of HF

• Stage D—Advanced structural heart disease with marked symptoms of HF at rest, and requiring specialized interventions (eg, heart transplant, mechanical assist device)

The ACC/AHA scheme was unveiled in treatment guidelines issued in 2001. The 2005 version of that document—ACC/AHA 2005 Guideline Update for the Evaluation and Management of Chronic Heart Failure in the Adult—and its 2009 focused update are discussed below under Management of Heart Failure.

Please note that the ACC/AHA scheme is intended to complement the NYHA scheme, not replace it. The relationship between the two is shown graphically in Figure 48–3.

Figure 48–3 American College of Cardiology/American Heart Association (ACC/AHA) Stage and New York Heart Association (NYHA) Classification of Heart Failure.

Overview of drugs used to treat heart failure

For routine therapy, heart failure is treated with three types of drugs: (1) diuretics, (2) agents that inhibit the RAAS, and (3) beta blockers. Other agents (eg, digoxin, dopamine, hydralazine) may be used as well.

Diuretics

Diuretics are first-line drugs for all patients with signs of volume overload or with a history of volume overload. By reducing blood volume, these drugs can decrease venous pressure, arterial pressure (afterload), pulmonary edema, peripheral edema, and cardiac dilation. However, excessive diuresis must be avoided: If blood volume drops too low, cardiac output and blood pressure may fall precipitously, thereby further compromising tissue perfusion. For the most part, benefits of diuretics are limited to symptom reduction. As a rule, these drugs do not prolong survival. The basic pharmacology of the diuretics is discussed in Chapter 41.

Thiazide diuretics.

The thiazide diuretics (eg, hydrochlorothiazide) produce moderate diuresis. These oral agents are used for long-term therapy of HF when edema is not too great. Since thiazides are ineffective when GFR is low, these drugs cannot be used if cardiac output is greatly reduced. The principal adverse effect of the thiazides is hypokalemia, which increases the risk of digoxin-induced dysrhythmias (see below).

High-ceiling (loop) diuretics.

The loop diuretics (eg, furosemide) produce profound diuresis. In contrast to the thiazides, these drugs can promote fluid loss even when GFR is low. Hence, loop diuretics are preferred to thiazides when cardiac output is greatly reduced. Administration may be oral or IV. Because they can mobilize large volumes of water, and because they work when GFR is low, loop diuretics are drugs of choice for patients with severe HF. Like the thiazides, these drugs can cause hypokalemia, thereby increasing the risk of digoxin toxicity. In addition, loop diuretics can cause severe hypotension secondary to excessive volume reduction.

Potassium-sparing diuretics.

In contrast to the thiazides and loop diuretics, the potassium-sparing diuretics (eg, spironolactone, triamterene) promote only scant diuresis. In patients with HF, these drugs are employed to counteract potassium loss caused by thiazide and loop diuretics, thereby lowering the risk of digoxin-induced dysrhythmias. Not surprisingly, the principal adverse effect of the potassium-sparing drugs is hyperkalemia. Because angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) also carry a risk of hyperkalemia, caution is needed if these drugs are combined with a potassium-sparing diuretic. Accordingly, when therapy with an ACE inhibitor or ARB is initiated, the potassium-sparing diuretic should be discontinued. It can be resumed later if needed.

One potassium-sparing diuretic—spironolactone—prolongs survival in patients with HF primarily by blocking receptors for aldosterone, not by causing diuresis. This drug and a related agent—eplerenone—are discussed below under Aldosterone Antagonists.

Drugs that inhibit the RAAS

The RAAS plays an important role both in cardiac remodeling and in the hemodynamic changes that occur in response to reduced cardiac output. Accordingly, agents that inhibit the RAAS can be highly beneficial. Four groups of drugs are available: ACE inhibitors, ARBs, direct renin inhibitors (DRIs), and aldosterone antagonists. Of the four, the ACE inhibitors have been studied most thoroughly in HF. The basic pharmacology of the RAAS inhibitors is presented in Chapter 44.

ACE inhibitors

ACE inhibitors (eg, captopril, enalapril) are a cornerstone of HF therapy. These drugs can improve functional status and prolong life. In one trial, the 2-year mortality rate for patients taking enalapril was 47% lower than the rate for patients taking placebo. Other large, controlled trials have shown similar benefits. Accordingly, in the absence of specific contraindications, all patients with HF should receive one of these drugs. Although ACE inhibitors can be used alone, they are usually combined with a beta blocker and a diuretic.

How do ACE inhibitors help? They block production of angiotensin II, decrease release of aldosterone, and suppress degradation of kinins. As a result, they improve hemodynamics and favorably alter cardiac remodeling.

Hemodynamic benefits.

By suppressing production of angiotensin II, ACE inhibitors cause dilation of arterioles and veins and they decrease release of aldosterone. Resulting benefits in HF are as follows:

• Arteriolar dilation improves regional blood flow in the kidneys and other tissues and, by reducing afterload, it increases stroke volume and cardiac output. Increased renal blood flow promotes excretion of sodium and water.

• Venous dilation reduces venous pressure, and thereby reduces pulmonary congestion, peripheral edema, preload, and cardiac dilation.

• Suppression of aldosterone release enhances excretion of sodium and water, while causing retention of potassium.

Interestingly, suppression of angiotension II production diminishes over time, suggesting that long-term benefits are the result of some other action.

Impact on cardiac remodeling.

With continued use, ACE inhibitors have a favorable impact on cardiac remodeling. Elevation of kinins is largely responsible. This statement is based in part on the observation that, in experimental models, giving a kinin receptor blocker decreases beneficial effects on remodeling. Also, we know that suppression of angiotensin II production diminishes over time, and hence reduced angiotensin II cannot fully explain long-term benefits.

Adverse effects.

The principal adverse effects of the ACE inhibitors are hypotension (secondary to arteriolar dilation), hyperkalemia (secondary to decreased aldosterone release), intractable cough, and angioedema. In addition, these drugs can cause renal failure in patients with bilateral renal artery stenosis. If taken during pregnancy—especially the second and third trimesters—ACE inhibitors can cause fetal injury. Accordingly, if pregnancy occurs, these drugs should be discontinued. Because of their ability to elevate potassium levels, ACE inhibitors should be used with caution in patients taking potassium supplements or a potassium-sparing diuretic (eg, spironolactone, triamterene).

Dosage.

Adequate dosage is critical: Higher dosages are associated with increased survival. Results of the Assessment of Treatment with Lisinopril and Survival (ATLAS) trial indicate that the doses needed to increase survival are higher than those needed to produce hemodynamic changes. Unfortunately, in everyday practice, dosages are often too low: Providers frequently prescribe dosages that are large enough to produce hemodynamic benefits, but are still too low to prolong life. Target dosages associated with increased survival are summarized in Table 48–1. These dosages should be used unless side effects make them intolerable.

TABLE 48–1

Inhibitors of the Renin-Angiotensin-Aldosterone System Used in Heart Failure

Drug	Initial Daily Dose	Maximum Daily Dose
ACE Inhibitors
Captopril [Capoten]	25 mg 3 times	50–150 mg 3 times
Enalapril [Vasotec]	2.5 mg once	10–20 mg twice
Fosinopril [Monopril]	5–10 mg once	40 mg once
Lisinopril [Zestril, Prinivil]	2.5–5 mg once	20–40 mg once
Quinapril [Accupril]	5 mg twice	20 mg twice
Ramipril [Altace]	1.25–2.5 mg twice	10 mg once
Trandolapril [Mavik]	1 mg once	4 mg once
Angiotensin II Receptor Blockers
Candesartan [Atacand]	4 mg once	32 mg once
Losartan [Cozaar]	12.5–25 mg once	150 mg once
Valsartan [Diovan]	40 mg twice	160 mg twice
Aldosterone Antagonists
Eplerenone [Inspra]	25 mg once	50 mg once
Spironolactone [Aldactone]	12.5–25 mg once	25 mg once

Angiotensin II receptor blockers

In patients with HF, the effects of ARBs are similar to those of ACE inhibitors—but not identical. Hemodynamic effects of both groups are much the same. Clinical trials have shown that ARBs improve LV ejection fraction, reduce HF symptoms, increase exercise tolerance, decrease hospitalization, enhance quality of life, and, most importantly, reduce mortality. However, because ARBs do not increase levels of kinins, their effects on cardiac remodeling are less favorable than those of ACE inhibitors. For this reason, and because clinical experience with ACE inhibitors is much greater than with ARBs, ACE inhibitors are generally preferred. For now, ARBs should be reserved for HF patients who cannot tolerate ACE inhibitors, usually owing to intractable cough. (Because ARBs do not increase bradykinin levels, they do not cause cough.)

Aldosterone antagonists

In patients with HF, aldosterone antagonists—spironolactone [Aldactone] and eplerenone [Inspra]—can reduce symptoms, decrease hospitalizations, and prolong life. These benefits were first demonstrated with spironolactone in the Randomized Aldactone Evaluation Study (RALES). Similar results were later obtained with eplerenone. Current guidelines recommend adding an aldosterone antagonist to standard HF therapy (ie, a diuretic, an ACE inhibitor or ARB, and a beta blocker), but only in patients with moderately severe or severe symptoms.

How do aldosterone antagonists help? Primarily by blocking aldosterone receptors in the heart and blood vessels. To understand these effects, we need to review the role of aldosterone in HF. In the past, researchers believed that all aldosterone did was promote renal retention of sodium (and water) in exchange for excretion of potassium. However, we now know that aldosterone has additional—and more harmful—effects. Among these are

• Promotion of myocardial remodeling (which impairs pumping)

• Promotion of myocardial fibrosis (which increases the risk of dysrhythmias)

• Activation of the SNS and suppression of norepinephrine uptake in the heart (both of which can promote dysrhythmias and ischemia)

• Promotion of vascular fibrosis (which decreases arterial compliance)

• Promotion of baroreceptor dysfunction

During HF, activation of the RAAS causes levels of aldosterone to rise. In some patients, levels reach 20 times normal. As aldosterone levels grow higher, harmful effects increase, and prognosis becomes progressively worse.

Drugs can reduce the impact of aldosterone by either decreasing aldosterone production or blocking aldosterone receptors. ACE inhibitors, ARBs, and DRIs decrease aldosterone production; spironolactone and eplerenone block aldosterone receptors. Although ACE inhibitors and ARBs can reduce aldosterone production, they do not block it entirely. Furthermore, production is suppressed only for a relatively short time. Hence, when ACE inhibitors or ARBs are used alone, detrimental effects of aldosterone can persist. However, when an aldosterone antagonist is added to the regimen, any residual effects are eliminated. As a result, symptoms of HF are improved and life is prolonged.

Aldosterone antagonists have one major adverse effect: hyperkalemia. The underlying cause is renal retention of potassium. Risk is increased by renal impairment and by using an ACE inhibitor or ARB. To minimize risk, potassium levels and renal function should be measured at baseline and periodically thereafter. Potassium supplements should be discontinued.

Spironolactone—but not eplerenone—poses a significant risk of gynecomastia (breast enlargement) in men, a condition that can be both cosmetically troublesome and painful. In the RALES trial, 10% of males experienced painful breast enlargement.

Direct renin inhibitors

As discussed in Chapter 44, DRIs can shut down the entire RAAS. In theory, their benefits in HF should equal those of the ACE inhibitors and ARBs. At this time, only one DRI is available. This drug—aliskiren [Tekturna]—is approved for hypertension, but is not yet approved for HF.