Inhibitors of the RAAS. As noted, the RAAS plays a key role during the development and worsening of HF.22
Angiotensin-converting enzyme inhibitors (ACE inhibitors) constitute the cornerstone of modern HF pharmacotherapy and have compelling evidence of survival benefit.28 These agents (captopril, enalapril, lisinopril, and ramipril; see Table 2 for dosing) have been shown to be effective therapy for HF and post-MI left ventricular dysfunction.29 They reduce early mortality by approximately 20% in symptomatic HF and can prevent hospitalization, increase exercise tolerance, and reduce adverse events (symptoms).9
Because of these benefits, ACE inhibitors should be firstline therapy in all HF patients with left ventricular dysfunction. They are usually used in combination with a diuretic. In addition, ACE inhibitors should be used in patients with reduced LVEF, even if they are asymptomatic, because these agents prevent progression to clinical HF.
Since ACE inhibitors carry the risk for severe hypotension, caution must be used, especially during treatment initiation. Patients whose systolic blood pressure is < 100 mm Hg, or who are hypovolemic, should be started at a low dosage (captopril, 6.25 mg tid; enalapril, 2.5 mg/d; or other equivalent ACE inhibitor dose); for other patients, these dosages can be doubled at initiation.9 Within days of initiation, but no longer than two weeks later, patients should be screened for hypotension and have both kidney function and potassium levels monitored. The dosage of ACE inhibitors should be increased over one to three months to an effective dosage (eg, captopril, 25 mg tid; enalapril, 10 mg bid; ramipril, 10 mg/d; and lisinopril, 20 mg/d, or other equivalent ACE inhibitor dose).9
Asymptomatic hypotension is not a contraindication to continuation or uptitration of the dosage of ACE inhibitors. Patients may also experience an increase in the serum creatinine or potassium level; likewise, this should not prompt a change in dosage if the elevated level stabilizes. The most common adverse effects of ACE inhibitors are dizziness and cough.9
Angiotensin II-receptor blockers (ARBs) have been shown to be as effective as ACE inhibitors for the management of hypertension, congestive HF, and chronic renal failure.30 ARBs decrease the adverse effects of angiotensin II, but do not have the same effects that ACE inhibitors do on other pathways found in HF (specifically, on bradykinin, prostaglandins, and nitric oxide).29 Candesartan and valsartan have been shown to have benefits in HF and are an equivalent alternative to ACE inhibitors; they are often used when a patient cannot tolerate an ACE inhibitor. Because ARBs and ACE inhibitors affect the RAAS at different points in the pathway, there is a theoretical basis for ARB and ACE inhibitor combination therapy; in clinical studies to date, however, the combination has shown no beneficial effect and rather was associated with more adverse effects.29
Neprilysin inhibitor. Recently, the combination of the neprilysin inhibitor sacubitril and an ARB, valsartan, has surfaced as an alternative to ACE inhibitor or single-agent ARB therapy.31,32 Inhibition of the enzyme neprilysin results in an increase in levels of endogenous vasoactive peptides (eg, natriuretic peptides and bradykinin), which may benefit hemodynamics in patients with HF. However, use of an ARB in combination with sacubitril is necessary to counteract the increase in angiotensin II levels that also results from inhibition of neprilysin.33
Sacubitril–valsartan is typically reserved for patients with mild-to-moderate HF who have either an elevated BNP (≥ 50 pg/mL) or an HF-related hospitalization within the past year. Upon transitioning from an ACE inhibitor (or single-agent ARB), a 36-hour washout period must be observed before starting sacubitril–valsartan to minimize the risk for angioedema. Because therapy with sacubitril–valsartan leads directly to an elevation in the BNP level, using the level of N-terminal pro-brain natriuretic peptide—which is not degraded by neprilysin—to monitor disease progression is recommended.34
ß-blockers. Mainstays of HF pharmacotherapy for almost 20 years because of evidence of survival benefit,35 ß-blockers have shown a reduction in early mortality and an increase in ejection fraction.10,35 The mechanism of action is believed to be a decrease in chronic elevations of catecholamines and sympathetic nervous system activity that may cause progressive myocardial damage. Three ß-blockers have been shown to reduce early mortality: carvedilol, extended-release metoprolol, and bisoprolol.9
Initiation of ß-blockers in stable patients can cause general deterioration; initiation must therefore be done gradually:
- Carvedilol, initiated at 3.125 mg bid, can be increased to 6.25 mg, then 12.5 mg, and then 25 mg, all bid, at intervals of approximately two weeks
- Sustained-release metoprolol can be started at 12.5 mg/d or 25 mg/d and doubled at two weeks to a target of 200 mg/d
- Bisoprolol, initiated at 1.25 mg/d, can be increased incrementally to 2.5 mg/d, 3.75 mg/d, 5 mg/d, 7.5 mg/d, or 10 mg/d at one-to-four-week intervals.9
Patients taking ß-blockers need to monitor their weight at home as an indicator of fluid retention. If HF becomes worse, an increase in the dosage of the accompanying diuretic, a delay in the increase of the ß-blocker, or downward adjustment of the ß-blocker is usually sufficient.
Continue to: Digitalis glycoside