Congestive heart failure is increasingly prevalent and its pharmacotherapy has changed substantially over the last two decades.45 The comprehensiveness and complexity of heart failure therapy justifies its management through skilled specialized heart failure teams that are trained in handling multifaceted pharmacological regimens. The major classes of drugs indicated for chronic heart failure are:
- ACE inhibitors/angiotensin receptor blockers
- aldosterone antagonists
Diuretics are essential for treating and counteracting the "congestive" aspect of congestive heart failure, that is, the tendency toward the development of chronic fluid overload.46 This is particularly the case in patients with peripheral edema, general overhydration, or manifest pulmonary edema. The pathophysiological mechanism for this fluid accumulation is the result of a decreased perfusion of the kidneys, due to a compromised cardiac output. As a result of this hypoperfusion, the endohormonal renin-angiotensin axis is activated, leading to sodium and fluid retention and ultimately fluid overload. Even though no controlled randomized trial has demonstrated the effect of diuretics in heart failure, their routine use is mandatory. Both loop diuretics, thiazides and metolazone, as well as potassium-sparing diuretics, should be considered for this indication, depending on how powerful an anticongestive effect is required.
ACE inhibitors are indicated both in asymptomatic and symptomatic heart failure. These drugs improve survival, diminish symptoms such as shortness of breath, and increase functional capacity.47 In general, ACE inhibitors should be given with care in patients with renal failure and/or hyperkalemia. Side-effects include cough, hypotension, and rarely angioedema. In clinical trials an initial side-effect has been reported to occur in up to 10% of all patients. In these cases angiotensin receptor blockers may safely replace ACE inhibitors. Because various ACE inhibitors have been assessed in large-scale clinical trials to date, it appears that they share a class-effect, and that the earliest ACE inhibitors on the market (enalapril, captopril) as well as the newer, once-daily agents, are indicated in heart failure.
These agents are indicated in patients who are in a stable stage of their disease, regardless of whether the underlying ventricular systolic dysfunction is mild, moderate, or severe. Beta-blockers have shown to improve functional class, reduce symptoms (except during the initial run-
in period of one to two weeks when symptoms may slightly worsen), and substantially decrease mortality. Four compounds have been shown to confer these beneficial effects, namely bisoprolol, metoprolol succinate, and nebivolol, as well as the combined alpha- and beta-blocker carvedilol.48-51 Side-effects are described in the section on anti-ischemic drugs. Therapy with beta-blockers as well as ACE inhibitors should be initiated with the lowest available dose, and should encompass slow, incremental up-titration over time. Based on knowledge gained through the CIBIS-3 study, it is entirely at the physician's discretion to decide whether ACE inhibitors or beta-blocker therapy should be started initially in chronic heart failure patients. In clinical practice, an up-titration scheme will usually be able to encompass both classes of drugs simultaneously.
This family of drugs can replace ACE inhibitors in the case of ACE inhibitor intolerance.52 They exert the same beneficial effects as the ACE inhibitors but with a significantly lower rate of side-effects. Because these drugs were developed relatively recently, they cost much more than ACE inhibitors, and as a result do not replace ACE inhibitors as the first drug of choice. These drugs may be considered in combination with ACE inhibitors in patients who continue to be symptomatic (the so-called "dual blockade"). However, care must be given not to elicit renal failure by this combination.
Aldosterone receptor antagonists are also indicated in congestive heart failure, but only in patients with more severe symptoms (functional NYHA class III or IV).53,54 The indication extends to patients who have left ventricular systolic dysfunction after myocardial infarction. This class of drugs includes spironolactone and eplerenone. Eplerenone is only indicated in post-infarction patients.
This class of drugs, derived from the purple foxglove (Digitalis purpurea), is the oldest among all currently used medications. Its first use in heart failure was described in 1775. Digitalis preparations are indicated in those patients with heart failure who have concomitant atrial fibrillation, or who are persistently symptomatic despite all the above pharmacological approaches. Digoxin and digitoxin both decrease atrioventricular conductance, thus diminishing ventricular heart rate. Even though digitalis has no effect on mortality, its salutary actions lead to reduced hospitaliza-tions and amelioration of symptoms.55 Any form of cardiac block, dysfunction of the atrioventric-ular or sinus node and bradyarrhythmia are important contraindications to digitalis.
A variety of positive inotropic agents direct their effects against decreased ventricular contractile function. Although these compounds represent a conceptually straightforward principle to counteract the mechanisms of reduced ventricular contractility, their use in clinical practice has unfortunately shown that they actually increase mortality in heart failure. Accordingly, none of the existing inotropic stimulants (except for digoxin) are indicated in patients with chronic heart failure.
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