ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; ARNI, angiotensin receptor inhibitor plus neprilysin inhibitor; BP, blood pressure; HF, heart failure; HR, heart rate; LVH, left ventricular hypertrophy; NT-proBNP, N-terminal pro-brain natriuretic peptide; PDE, phosphodiesterase.
particularly hazardous if the patient is to be given digitalis. Hypokalemia can be treated with potassium supplementation or through the addition of an ACE inhibitor or a potassium-sparing diuretic such as spironolactone. Spironolactone or eplerenone should probably be considered in all patients with moderate or severe heart failure, since both appear to reduce both morbidity and mortality.
In patients with left ventricular dysfunction but no edema, an ACE inhibitor should be the first drug used. Several large studies have shown clearly that ACE inhibitors are superior to both placebo and to vasodilators and must be considered, along with diuretics, as first-line therapy for chronic heart failure. However, ACE inhibitors cannot replace digoxin in patients already receiving the glycoside because patients withdrawn from digoxin deteriorate while on ACE inhibitor therapy.
By reducing preload and afterload in asymptomatic patients, ACE inhibitors (eg, enalapril) slow the progress of ventricular dilation and thus slow the downward spiral of heart failure. Consequently, ACE inhibitors are beneficial in all subsets of patients—from those who are asymptomatic to those in severe chronic failure. This benefit appears to be a class effect; that is, all ACE inhibitors appear to be effective.
The angiotensin II AT1 receptor blockers (ARBs, eg, losartan) produce beneficial hemodynamic effects similar to those of ACE inhibitors. However, large clinical trials suggest that when used alone, ARBs are best reserved for patients who cannot tolerate ACE inhibitors (usually because of cough). In contrast, the ARB valsartan combined with the neprilysin inhibitor sacubitril (Entresto) has additional benefit in HFrEF and is recommended in 2016 guidelines.
Vasodilator drugs can be divided into selective arteriolar dilators, venous dilators, and drugs with nonselective vasodilating effects. The choice of agent should be based on the patient’s signs and symptoms and hemodynamic measurements. Thus, in patients with high filling pressures in whom the principal symptom is dyspnea, venous dilators such as long-acting nitrates will be most helpful in reducing filling pressures and the symptoms of pulmonary congestion. In patients in whom fatigue due to low left ventricular output is a primary symptom, an arteriolar dilator such as hydralazine may be helpful in increasing forward cardiac output. In most patients with severe chronic failure that responds poorly to other therapy, the problem usually involves both elevated filling pressures and reduced cardiac output. In these circumstances, dilation of both arterioles and veins is required. A fixed combination of hydralazine and isosorbide dinitrate is available as isosorbide dinitrate/hydralazine (BiDil), and this is currently recommended for use in African Americans.
Beta blocker therapy in patients with heart failure is based on the hypothesis that excessive tachycardia and adverse effects of high catecholamine levels on the heart contribute to the downward course of heart failure. The results of clinical trials clearly indicate that such therapy is beneficial if initiated cautiously at low doses, even though acutely blocking the supportive effects of catecholamines can worsen heart failure. Several months of therapy may be required before improvement is noted; this usually consists of a slight rise in ejection fraction, slower heart rate, and reduction in symptoms. As noted above, not all β blockers have proved useful, but bisoprolol, carvedilol, metoprolol, and nebivolol have been shown to reduce mortality.