Drug Therapy of Heart Failure in the Elderly

Michael W. Rich, MD

Disclosures

Am J Geriatr Cardiol. 2003;12(4) 

In This Article

Systolic Heart Failure

The vast majority of middle-aged HF patients have impaired left ventricular (LV) systolic function, and most of the HF trials have targeted this population. In contrast, fewer than one half of HF patients over age 75 have significant LV systolic dysfunction;[12,13] moreover, many of the trials expressly excluded patients in this age group. For purposes of this discussion, patients with LV ejection fractions less than 45% will be considered to have systolic HF, whereas patients with an ejection fraction of 45% or greater will be considered to have preserved LV systolic function. It should be recognized, however, that this distinction is artificial, and that there is considerable overlap between systolic and diastolic dysfunction.

ACE inhibitors are the cornerstone of drug therapy for persons with impaired LV systolic function, whether symptomatic or asymptomatic. ACE inhibitors slow the progression of HF, improve exercise tolerance and quality of life, and reduce hospitalizations and mortality.

As shown in Figure 1, a meta-analysis of ACE inhibitor trials found that the absolute benefits were similar in patients older and younger than age 60.[14] A more recent overview that included 1066 patients over age 75 found that although there was no evidence of a differential effect of therapy across age groups, the relative benefits were somewhat less in patients over age 75.[15] Based on these data, all persons with reduced LV ejection fractions should receive ACE inhibitor therapy unless contraindicated.

Effects of angiotensin-converting enzyme inhibitors (ACE-Is) on mortality and heart failure admissions (HF Adms) in older compared with younger patients

ACE inhibitors approved for the treatment of HF in the US are listed in Table III , along with recommended dosages. When possible, an effort should be made to gradually increase the ACE inhibitor dosage to a level commensurate with those proved to be efficacious in clinical trials. However, in older patients unable to tolerate such dosages, there is evidence that lower dosages afford some degree of benefit;[16] i.e., low-dose ACE inhibitor therapy appears to be better than no ACE inhibitor at all.

Adverse effects of ACE inhibitors may include worsening renal function, hyperkalemia, and hypotension, and older patients are at greater risk for these complications. Therefore, dosage titration should be gradual, and serum creatinine and potassium levels should be monitored closely. Mild increases in serum creatinine (<0.5 mg/dL above baseline) and potassium (<5.5 mEq/L) generally do not require cessation of therapy, but continued close observation is warranted. A modest reduction in diuretic dosage, if feasible, may attenuate the adverse effects of ACE inhibitor therapy on renal function and reduce the risk of hypotension. Cough may be a limiting side effect in 5%-10% of patients treated with ACE inhibitors, but there is no evidence that this occurs more frequently in older patients.

ARBs are better tolerated than ACE inhibitors and have been associated with improved outcomes in HF patients unable to take ACE inhibitors due to cough or other side effects.[17] However, equivalency of ARBs to ACE inhibitors with respect to major clinical outcomes has not been established,[18] and ACE inhibitors remain first-line therapy at the present time. On the other hand, ARBs are a suitable alternative in patients unable to tolerate ACE inhibitors. In addition, evidence from the Valsartan Heart Failure Trial (Val-HeFT)[17] indicates that the addition of an ARB to an ACE inhibitor may be associated with improved symptoms and quality of life, as well as fewer HF hospitalizations, in a subgroup of patients not receiving concomitant treatment with a blocker.[17]

In the United States, only valsartan has received Food and Drug Administration approval for treatment of HF. The target dose of valsartan in Val-HeFT was 160 mg b.i.d.[17] The dose of losartan in the Evaluation of Losartan in the Elderly (ELITE II) trial, which compared losartan to captopril in HF patients aged ≥60 years (mean age, 71 years), was 50 mg once daily.[18] Side effects from ARBs are infrequent, but may include hypotension, worsening renal function, hyperkalemia, or allergic reactions.

The combination of hydralazine 75 mg q.i.d. and isosorbide dinitrate 40 mg q.i.d. has been shown to reduce mortality and improve symptoms in patients with systolic HF,[19] but the mortality benefit is less than that of ACE inhibitors.[20] Therefore, this combination should be considered in HF patients unable to take either an ACE inhibitor or an ARB. Of note, neither of the major hydralazine/nitrate trials included patients over age 75. In addition, side effects are relatively common with both of these drugs, and the need for frequent dosing is also a disadvantage of these agents. To date, other vasodilators, including calcium channel blockers,[21] have not been shown to improve outcomes in HF patients, and these agents should be avoided unless there are specific indications for their use.

Short-term blockade decreases cardiac output by reducing heart rate and contractility. Nonetheless, long-term mortality and morbidity benefits of blockers in patients with HF have now been demonstrated in several large prospective randomized trials.[22,23,24,25] In addition, subgroup analyses from these trials, which have included patients up to 80 years of age, indicate that older patients derive at least as much benefit from blockers as younger patients. As a result, blockers are now considered standard therapy for all patients with stable systolic HF in the absence of contraindications (heart rate <45 beats/min, systolic blood pressure <90-100 mm Hg, heart block greater than first degree, active bronchospasm, decompensated HF).

In the United States, carvedilol and metoprolol have been approved for treatment of systolic HF. The starting dose of carvedilol is 3.125 mg b.i.d., and the dose should be increased at no less than 2-week intervals to achieve a maintenance dose of 25 mg b.i.d. The starting dose of metoprolol extended release is 12.5-25 mg once daily, gradually increasing at no less than 2-week intervals to a target dose of 200 mg daily. Although not approved for HF in the United States, bisoprolol has also been shown to be effective for systolic HF,[23] with a starting dose of 1.25 mg once daily titrated to 10 mg once daily.

With proper patient selection and dose titration, the majority of HF patients are able to tolerate blockers. However, initiation and titration of blocker therapy may be associated with a transient increase in HF symptoms, including fatigue and exertional shortness of breath, and such symptoms may occur more frequently in older patients. In mild cases, no treatment or a modest increase in diuretic dose may be all that is necessary, given that these early blocker side effects often resolve after a few weeks. In more severe cases, it may be necessary to reduce the blocker dosage or discontinue therapy.

Digoxin improves symptoms and reduces HF hospitalizations in patients already receiving ACE inhibitors and diuretics, but digoxin has no effect on either cardiovascular or total mortality.[26] Of note, a recent subgroup analysis from the Digitalis Investigation Group (DIG) trial[27] found that the effects of digoxin were similar in HF patients of all ages, including those over age 80. Furthermore, excess side effects directly attributable to digoxin did not increase significantly with age at the relatively modest digoxin dosages (mean serum digoxin concentration 0.9 ng/mL) used in the DIG trial. Based on these findings, low- to moderate-dose digoxin is recommended in patients with systolic HF who remain significantly symptomatic despite other therapy.

The recommended dose of digoxin for older patients with preserved renal function (estimated creatinine clearance >50 cc/min) is 0.125 mg daily without a loading dose. Patients with estimated creatinine clearance <30 cc/min may achieve therapeutic benefit from dosages as low as 0.125 mg one to three times weekly. Although routine monitoring of serum digoxin levels is not required, many clinicians check a level several weeks after initiating therapy, principally to avoid toxicity. Due to age-related changes in volume of distribution and clearance, the therapeutic range for digoxin in older adults is 0.5-1.3 ng/mL.[28] Levels ≥1.5 ng/mL are associated with increased toxicity without enhanced efficacy and should be avoided.[29]

Common side effects related to digoxin therapy include bradycardia, heart block, supraventricular and ventricular tachyarrhythmias, gastrointestinal disturbances, and central nervous system disorders (e.g., visual changes). Suspected digoxin toxicity should prompt cessation of therapy, evaluation of renal function and electrolytes (including calcium and magnesium), and obtaining a serum digoxin level. The medication regimen should also be carefully reviewed for potential digoxin drug interactions (e.g., amiodarone, verapamil).

With the exception of spironolactone (discussed below), diuretics have not been shown to improve HF outcomes and their use is primarily palliative. Nonetheless, diuretics are the most effective agents for managing volume overload and maintaining euvolemia, and they remain a mainstay of HF therapy. Patients with mild HF may be adequately controlled with a thiazide diuretic, but most patients will require a loop diuretic with typical daily dosages of furosemide ranging from 20-200 mg or equivalent. Patients with more severe HF or refractory volume overload may require metolazone 2.5-10 mg daily in addition to high-dose loop diuretics.[30]

Optimal use of diuretics in HF patients incorporates appropriate dietary sodium restriction, usually 2 g/day, along with measurement of daily weights. The patient's target "dry weight" (i.e., euvolemic weight) should be defined, and the diuretic dose should be adjusted to maintain this weight plus-or-minus 2-3 pounds. With a little bit of experience, many patients (including the elderly) can regulate their own diuretic dosages according to fluctuations in their daily weights.

Diuretics often cause potassium and/or magnesium wasting, and these electrolytes should be replenished through dietary means or supplements. Diuretics may also result in worsening renal function, usually related to hypotension or over-diuresis. Renal function should therefore be monitored during diuretic dosage adjustments.

The Randomized Aldactone Evaluation Study (RALES)[31] found that the addition of spironolactone 12.5-50 mg daily to standard therapy with an ACE inhibitor, diuretic, and digoxin led to a 30% reduction in mortality in patients with advanced heart failure (New York Heart Association class III-IV), and the benefits were similar in older and younger patients. Therefore, the addition of low-dose spironolactone is recommended in patients who remain highly symptomatic despite conventional multidrug therapy.

Spironolactone is contraindicated in patients with significant renal insufficiency (serum creatinine ≥2.5 mg/dL) or hyperkalemia (serum potassium ≥5.0 mEq/L), and renal function and serum electrolytes should be assessed within 1-2 weeks after initiating spironolactone therapy. In addition, painful gynecomastia occurs in up to 10% of patients treated with spironolactone.

Figure 2 illustrates current pharmacotherapy for systolic LV dysfunction. All patients with LV ejection fraction of 40% or less should receive an ACE inhibitor unless contraindicated or not tolerated due to side effects, with gradual titration to clinical trial dosages ( Table III ). In symptomatic patients unable to take an ACE inhibitor, an ARB or hydralazine/nitrates should be substituted. A blocker should also be given to all patients with stable, euvolemic class I-IV HF in the absence of contraindications, and the dosage should be gradually titrated upward as tolerated until the maintenance dosages used in clinical trials have been achieved. Diuretics should be added to maintain euvolemia, as defined by the patient's "dry weight," and daily weights should be monitored on a home scale. Digoxin should be added for persistent symptoms despite the above therapy, recognizing that digoxin does not prolong life. Finally, patients with advanced HF despite an aggressive three or four drug regimen should also receive low-dose spironolactone in the absence of contraindications.

Drug therapy of systolic heart failure. Gray areas denote recommended treatments based on prospective randomized clinical trialsACE=angiotensin converting enzymeReprinted with permission from Rich MW. Heart failure in the elderly: strategies to optimize outpatient control and reduce hospitalizations. Am J Geriatr Cardiol. 2003;12(1):19-27.

Failure to achieve adequate symptom control with the above measures should prompt investigation for noncompliance, drug interactions (e.g., nonsteroidal anti-inflammatory drugs), or other factors which could contribute to a poor therapeutic response. In selected older patients who may be candidates for device therapy (e.g., biventricular pacing)[32] or investigational treatments, referral to a HF specialist should be considered.

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