Patients with New York Heart Association (NYHA) functional class IV heart failure are more likely than those with milder disease to exhibit nonfatal adverse reactions to carvedilol and require permanent withdrawal of the drug, in particular during initiation and dose titration. However, they are also more likely to show symptomatic improvement in the long term.
Macdonald et al found that carvedilol was generally well tolerated in heart failure: 71% of their patients tolerated long-term therapy, and 59% showed symptomatic improvement at 3 months, together with significant improvement in left ventricular dimensions and contraction, as measured by echocardiography and the 6-min walk distance. However, they did not offer carvedilol to class IV patients to whom any of the following applied: cardiogenic shock, intractable pulmonary or systemic edema, heart failure requiring intravenous inotropic or mechanical support, resting bradycardia < 50 bpm, systemic hypotension (< 80/50 mm Hg), and asthma.
Carvedilol was well tolerated in the CarvedilOl ProspEctive RaNdomlzed Cumulative Survival (COPERNICUS) study. Fewer patients required permanent discontinuation of treatment because of adverse effects than in the placebo group. Benefit was observed in clinically euvolemic patients not receiving intravenous positive inotropics or vasodilators for heart failure or requiring intensive care. Patients with symptomatic hypotension or severe renal dysfunction were excluded. It is possible that such critically ill patients depend on sympathetic nervous system activation to maintain circulatory homeostasis, in which case sympathetic blockade could be ineffective or precipitate rapid clinical deterioration. Such patients should first be clinically stabilized (with particular respect to volume status) before being started on carvedilol.
Class IV patients are at twice the risk of exacerbation than patients with less severe disease. If they react adversely to the initiation and titration of P-blocker therapy, concurrent therapies should be adjusted to allow p-blockade to continue. Exacerbations generally respond to an increase in diuretic or nitrate therapy. Further uptitration of the P-blocker should only be attempted after the exacerbation has fully resolved. This approach enables long-term P-block-ade to be maintained in a third of patients who develop exacerbations. Indeed, their long-term outcome is similar to that of patients tolerating P-blockade at the first attempt.
Other classic reactions to P-blocker therapy, namely symptomatic bradycardia, hypotension, and fatigue, are infrequent. Most occur during initiation and titration, and over half in the first 2 weeks. The class IV patients most at risk are those with pretreatment hyponatremia. Sackner-Bernstein et al found that hyponatremia was the most powerful predictor of adverse reactions to carvedilol in mod-erate-to-severe heart failure. It correlates closely with neurohumoral activation, particularly of the renin-angiotensin system, and is an independent predictor of mortality in severe heart failure. Hyponatremic patients are also more likely to be hypotensive and to have evidence of impaired peripheral and renal perfusion than normonatrem-ic class IV controls. All class IV patients with hyponatremia or hypotension should be hospitalized for the initiation of carvedilol therapy.
Class IV patients are clearly at greatest risk from carvedilol therapy, but potentially have the most to gain. The magnitude of improvement in left ventricular size and function is similar to, and in the case of the 6-min walk distance actually exceeds, that in patients with milder disease.
The COPERNICUS study demonstrated that long-term carvedilol plus conventional therapy significantly decreased the rate of death and hospitalization in severe heart failure. Benefit was independent of age, gender, cause of heart failure, left ventricular ejection fraction, or recent hospitalization history. It was seen even in patients with a history of recent or recurrent cardiac decompensation or severely depressed cardiac function.
In summary, carvedilol is a useful adjuvant therapy in patients with class IV heart failure. However, close observation during initiation and titration is mandatory.
fi-blocker; efficacy; tolerability; NYHA classification; side effect; prognosis