Heart Failure

ABSTRACT: Angiotensin-converting enzyme (ACE) inhibitor therapy is recommended for all patients with heart failure (HF) and a reduced ejection fraction. It is generally initiated in the hospital at low doses as inotropic therapy is tapered. Angiotensin II receptor blockers may be a suitable alternative for patients who cannot tolerate ACE inhibitors. For patients who cannot tolerate either class of drug, a combination of hydralazine and a nitrate is recommended. ß-Blockers are first-line therapy for patients with current or previous symptoms of HF and reduced left ventricular function, as well as all patients hospitalized for HF. An aldosterone antagonist may be added to the regimen of patients with moderately severe to severe symptoms and reduced ejection fraction whose renal function and potassium concentration can be monitored.

More than a half million new cases of heart failure (HF) are diagnosed each year. The prevalence of the disease increases dramatically with age, and morbidity remains high, in part because better therapies have increased the number of survivors. The mortality for patients admitted to the hospital for the first time with HF is 12% at 1 month, 33% at 1 year, and as high as 50% at 5 years.¹

Therapies that target the overstimulated compensatory mechanisms in patients with HF have led to significant reductions in morbidity and mortality. In this article, I review the treatment options for patients with HF based on the latest guidelines.

ACUTE DECOMPENSATED HF
Despite improvements in therapy, acute decompensated HF is common. Patients with this condition can be readily classified in 1 of 4 clinical hemodynamic profiles (Figure), depending on perfusion status and signs of congestion.² Evidence of congestion includes orthopnea and paroxysmal nocturnal dyspnea, jugular venous distention, pulmonary rales, a third heart sound, ascites, and peripheral edema. Perfusion status is determined by evaluation for cool extremities, mental status changes, a narrow pulse pressure, pulsus alternans, prerenal azotemia and oliguria, hypotension, and low serum sodium levels. The 2 basic hemodynamic parameters are the presence or absence of elevated filling pressure (wet or dry) and perfusion that is sufficient or diminished (warm or cold).

Treatment options. Patients with signs of congestion are treated with diuretics and agents that lower preload and afterload, such as nitroglycerin, nitroprusside, and nesiritide. Patients with low cardiac output are treated with positive inotropic agents, such as dobutamine or milrinone. The intravenous agents recommended for acute decompensated HF and their impact on hemodynamic variables are shown in Table 1.³

Inotropes are not indicated for the routine treatment of patients hospitalized for HF because of concern that these agents may increase the risk of death. They are appropriate for patients in cardiogenic shock or for those whose condition is refractory to treatment with standard diuretics and other HF therapies. Inotropic support can be used as a bridge to more definitive therapy for end-stage HF, such as cardiac transplantation. Inotropes may also be used palliatively for patients with end-stage disease.

Nesiritide is indicated for patients who present with dyspnea and evidence of congestion. This agent lowers filling pressures and relieves symptoms. It should not be used in cardiogenic shock or in any patient with systolic blood pressure below 90 mm Hg.

The Vasodilation in the Management of Acute Congestive Heart Failure (VMAC) trial studied patients who presented to the hospital with breathlessness at rest or with minimal activity as a result of acute decompensated HF. They were randomized to treatment with nesiritide or nitroglycerin.⁴ Nesiritide rapidly reduced the pulmonary capillary wedge pressure and relieved some self-reported symptoms more effectively than nitroglycerin. There was no difference in hypotension between the 2 groups. Although nesiritide has been associated with azotemia, this is more common with higher doses and in persons with low systolic blood pressure.

Once acute decompensation is alleviated, chronic HF medications can be started or titrated to full doses as tolerated. The goals of treatment are to relieve symptoms, enhance exercise tolerance, prevent further deterioration of cardiac function, and prolong life. Options include angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), ß-blockers, and aldosterone antagonists.

ACE INHIBITORS
The onset of HF is characterized by a fall in perfusion pressure that stimulates the release of renin from the juxtaglomerular cells in the kidney. Renin produces angiotensin I from angiotensinogen. ACE then converts angiotensin I to the octapeptide angiotensin II. Angiotensin II, a potent vasoconstrictor that stimulates the release of catecholamines and aldosterone, is an important growth promoter at the myocardial level and is involved in the development of left ventricular hypertrophy. Initially, the action of angiotensin II, catecholamines, and aldosterone restores adequate cardiac output and perfusion pressure by volume expansion, vasoconstriction, and direct stimulation of the myocardium. Over time, however, overstimulation by the renin-angiotensin and sympathetic nervous systems leads to cardiac fibrosis and worsening HF.

Evidence from the trials. Inhibition of the renin-angiotensin system reduces morbidity and mortality in HF. The Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS) evaluated the ACE inhibitor enalapril versus placebo in patients with severe congestive HF whowere already taking diuretics and digoxin.⁵ The study concluded that the addition of enalapril reduced mortality and morbidity by slowing the progression of HF. Subsequent trials, such as the Studies of Left Ventricular Dysfunction (SOLVD), verified the benefit of ACE inhibition in patients at earlier stages of HF, including asymptomatic patients with a low ejection fraction.⁶ A meta-analysis of 32 randomized controlled ACE inhibitor trials showed similar reductions in mortality with several other ACE inhibitors.⁷

ACE inhibitor therapy is a class I recommendation in the American College of Cardiology/American Heart Association (ACC/AHA) guidelines for HF and should be considered in all patients with a reduced ejection fraction.⁸ These agents are typically started in the hospital in patients with acute decompensated HF as soon as pulmonary edema is relieved and the blood pressure can tolerate the medication. ACE inhibitors may be started gradually at low doses as the inotropic therapy is tapered.

ARBs
An ARB may be a suitable alternative for patients in whom adverse events such as angioedema and excessive cough preclude the use of ACE inhibitors. ARBs competitively and selectively bind to the AT₁ receptor, which inhibits the action of angiotensin II. This leads to a reduction in systemic vascular resistance and a decrease in aldosterone release, which helps reduce afterload and prevent salt and water retention. ARBs should be used with caution in patients who are hypotensive or who have renal dysfunction and are at risk for hyperkalemia.

Evidence from the trials. The Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM)-Alternative study investigated whether candesartan would improve clinical outcomes in symptomatic HF patients intolerant of ACE inhibitors.⁹ Intolerance manifested as cough, hypotension, renal dysfunction, or angioedema. Candesartan reduced the incidence of cardiovascular death and hospital admissions for HF. The relative risk reduction with candesartan was similar to the risk reduction reported for enalapril in the SOLVD trial, which suggests that an ARB is an equivalent alternative to an ACE inhibitor in ACE-intolerant patients. Moreover, subgroup analysis of the Valsartan Heart Failure Trial (Val-HeFT) of the small subset of patients not treated with an ACE inhibitor showed that the ARB valsartan reduced morbidity and mortality in ACE inhibitor- intolerant patients.¹⁰

Combination therapy. Although ACE inhibitors have been shown to reduce morbidity and mortality in HF, there has been concern that long-term tolerance to these agents may reduce benefit over time. Combining an ARB with an ACE inhibitor may theoretically give further benefit by reducing the production of angiotensin II as well as blocking its effects at the receptor.

The CHARM Low Left Ventricular Ejection Fraction Trial studied patients with symptomatic chronic HF and a reduced ejection fraction at high risk for acute decompensatedHF despite therapy with an ACE inhibitor, b-blocker, and aldosterone antagonist.¹¹ The addition of candesartan significantly reduced mortality and HF hospitalizations, although 23.1% of the patients had to discontinue the drug because of increased creatinine levels, hypotension, or hyperkalemia (compared with 18.8% discontinuation in the placebo arm). In contrast, post hoc observation in Val-HeFT suggested an adverse effect in the subgroup of patients who received valsartan, an ACE inhibitor, and a b-blocker.¹²

Because of concern about adverse effects, the ACC/AHA guidelines do not recommend using the combination of an ACE inhibitor, an ARB, and an aldosterone antagonist in patients with symptomatic HF and a reduced ejection fraction (class III).⁸

Another alternative. Patients who cannot tolerate an ACE inhib- itor or an ARB may be treated with a combination of hydralazine and a nitrate. This recommendation is based on the Veterans Administration Cooperative Vasodilator-Heart Failure Trial (V-HeFT), which showed a favorable effect of this combination on left ventricular function and mortality.¹³ When the combination was compared with enalapril, however, the ACE inhibitor proved more effective.¹⁴

Retrospective analysis of HF trials suggested that black patients might have a clinically significant response to the hydralazine/isosorbide combination; this led to the development of the African-American Heart Failure Trial (A-HeFT).¹⁵ In this trial of African American patients with advanced HF, a fixed-dose combination of isosorbide dinitrate and hydralazine was added to standard therapy that included ACE inhibitors and ß-blockers. An improvement in survival observed in the hydralazine/isosorbide group led to an early halting of the trial.

The ACC/AHA guidelines recommend the addition of hydralazine and a nitrate in patients with HF and a reduced ejection fraction who are already taking an ACE inhibitor and a ß-blocker and who have persistent symptoms.⁸

ß-BLOCKERS
Once contraindicated in patients with left ventricular systolic dysfunction, ß-blockers have become first-line therapy in patients with HF.¹⁶ Three major mortality studies of ß-blockers in HF verified a mortality benefit when these agents were added to a standard HF regimen.^17-19 Based on these trials, the ACC/AHA guidelines recommend using 1 of the 3 ß-blockers proved to reduce mortality (bisoprolol, carvedilol, or sustained-release metoprolol succinate) in stable patients with current or previous symptoms of HF and reduced left ventricular ejection fraction.⁸

If metoprolol is chosen, the guidelines recommend that only sustained-release metoprolol succinate be prescribed, because that preparation was used in the Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF).¹⁹ Metoprolol was compared with carvedilol in the Carvedilol or Metoprolol European Trial (COMET), which found an absolute 5.7% survival benefit in the carvedilol arm.²⁰ The COMET trial, however, used the shorter-acting metoprolol tartrate and a lower target dose (50 mg of metoprolol tartrate twice daily compared with 200 mg of sustained-release metoprolol succinate once daily in MERIT-HF), which may have accounted for the superiority of carvedilol in this trial. This concern has led to the recommendation that the long-acting formulation of metoprolol be used in HF. It is important to keep this in mind when prescribing this ß-blocker, because many of the generic formulations use the shorter-acting tartrate preparation.

Table 2 lists the relative contraindications for ß-blocker use. Patients admitted to the hospital with acute decompensated HF must be stabilized before they begin ß-blocker therapy. If a patient who is being treated with ß-blockers is admitted with acute decompensated HF that requires inotropic support, the ß-blockers are usually withheld until the patient is stable and the inotropes are gradually discontinued.

Special care is warranted for patients whose HF appears to be adrenergically driven; they require stimulation of the adrenergic system to support blood pressure and perfusion. These patients typically present with tachycardia and hypotension. ß-Blocker therapy can lead to hemodynamic collapse in such patients.

ß-Blockers should be started at very low doses and titrated slowly to the full doses that were shown in large mortality trials to be most beneficial. Initial and target doses of the 3 recommended ß-blockers are listed in Table 3.

Patients with severe HF. ß-Blockers should be started in the hospital in all patients with HF, regardless of HF class, unless contraindicated. Patients with severe HF derive substantial benefit from b-blocker therapy. The Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) trial evaluated carvedilol in more than 2000 patients with class IV HF and a left ventricular ejection fraction of less than 25%.²¹ Carvedilol was begun at the starting dose after patients were stabilized out of the ICU and inotropic medications were discontinued. The study showed a 35% reduction in mortality in the carvedilol group.

The ß-blocker dose can gradually be escalated to the full target dose, usually over a period of several weeks after the patient has been discharged. It is important to try to achieve the target dose to obtain the full benefit of therapy. It is probably better to have patients on full doses of the b-blocker than full doses of an ACE inhibitor. If the patient is hypotensive,it is best to lower the dosage of the ACE inhibitor and possibly the diuretic to achieve a full dose of the ß-blocker.

ALDOSTERONE ANTAGONISTS
Aldosterone promotes the retention of sodium and water and is released in response to the declining perfusion pressure resulting from HF. The feedback of aldosterone on the heart can promote myocardial fibrosis and cause progression of HF. In the Randomized Aldactone Evaluation Study, spironolactone, an aldosterone-receptor blocker, was added to standard therapy (an ACE inhibitor, loop diuretics, and digoxin) in patients with HF.²² The trial was discontinued early because interim analysis showed a significant reduction in the relative risk of death in the spironolactone group. The incidence of hyperkalemia was minimal. Because of the risk of hyperkalemia, especially in patients with renal insufficiency, potassium levels need to be monitored frequently to avoid possible adverse events.

In the ACC/AHA guidelines, the addition of an aldosterone antagonist is a class I recommendation in carefully selected patients with moderately severe to severe symptoms and reduced ejection fraction who can be carefully monitored for preserved renal function and normal potassium concentration.⁸ Gynecomastia develops in some men with prolonged use of spironolactone. Eplerenone can be substituted in these patients.

DIGOXIN
The authors of the ACC/AHA guidelines reevaluated the addition of digoxin to the regimen of patients with HF and concluded that the narrow risk/benefit ratio and lack of mortality advantage do not warrant a class I recommendation for this agent.⁸ Digoxin may be used in patients who continue to have signs and symptoms of HF despite standard therapy, or for control of atrial fibrillation.

PREVENTION
A more aggressive approach to cardiac risk factor identification and treatment is needed if we hope to stem the growing epidemic of HF. The ACC/AHA guidelines define patients with Stage A HF as those at high risk for HF who have no structural heart disease or symptoms of HF.⁸ Hypertension is the most common underlying condition preceding the development of HF, especially in African Americans. Patients with atherosclerosis, diabetes, obesity, and metabolic syndrome, and those who use cardiotoxins or who have a strong family history of HF are at increased risk of HF.

Every patient encounter is an opportunity to evaluate for cardiac risk factors and ensure that patients are being treated with the appropriate preventive agents according to guideline recommendations. It is reasonable to consider treatment of at-risk patients with agents that have also been shown to be useful once HF develops. The ACC/AHA guidelines recommend ACE inhibitors in patients at high risk for HF who have a history of atherosclerotic vascular disease, diabetes, or hypertension with associated risk factors.⁸