Pharmacologic Prevention of Anthracycline-Induced Cardiomyopathy :

To define better the efficacy of vasodilator therapy in the treatment of chronic congestive heart failure, we compared the effects of hydralazine and isosorbide dinitrate with those of enalapril in 804 men receiving digoxin and diuretic therapy for heart failure. The patients were randomly assigned in a double-blind manner to receive 20 mg of enalapril daily or 300 mg of hydralazine plus 160 mg of isosorbide dinitrate daily. The latter regimen was identical to that used with a similar patient population in the effective-treatment arm of our previous Vasodilator-Heart Failure Trial. Mortality after two years was significantly lower in the enalapril arm (18 percent) than in the hydralazine-isosorbide dinitrate arm (25 percent) (P = 0.016; reduction in mortality, 28.0 percent), and overall mortality tended to be lower (P = 0.08). The lower mortality in the enalapril arm was attributable to a reduction in the incidence of sudden death, and this beneficial effect was more prominent in patients with less severe symptoms (New York Heart Association class I or II). In contrast, body oxygen consumption at peak exercise was increased only by hydralazine-isosorbide dinitrate treatment (P less than 0.05), and left ventricular ejection fraction, which increased with both regimens during the 2 years after randomization, increased more (P less than 0.05) during the first 13 weeks in the hydralazine-isosorbide dinitrate group. The similar two-year mortality in the hydralazine-isosorbide dinitrate arms in our previous Vasodilator-Heart Failure Trial (26 percent) and in the present trial (25 percent), as compared with that in the placebo arm in the previous trial, (34 percent) and the further survival benefit with enalapril in the present trial (18 percent) strengthen the conclusion that vasodilator therapy should be included in the standard treatment for heart failure. The different effects of the two regimens (enalapril and hydralazine-isosorbide dinitrate) on mortality and physiologic end points suggest that the profile of effects might be enhanced if the regimens were used in combination.

Cardiotoxicity is a recognized complication of doxorubicin therapy, but the long-term effects of doxorubicin are not well documented. We therefore assessed the cardiac status of 115 children who had been treated for acute lymphoblastic leukemia with doxorubicin 1 to 15 years earlier in whom the disease was in continuous remission. Eighteen patients received one dose of doxorubicin (45 mg per square meter of body-surface area), and 97 received multiple doses totaling 228 to 550 mg per square meter (median, 360). The median interval between the end of treatment and the cardiac evaluation was 6.4 years. Our evaluation consisted of a history, 24-hour ambulatory electrocardiographic recording, exercise testing, and echocardiography. Fifty-seven percent of the patients had abnormalities of left ventricular afterload (measured as end-systolic wall stress) or contractility (measured as the stress-velocity index). The cumulative dose of doxorubicin was the most significant predictor of abnormal cardiac function (P less than 0.002). Seventeen percent of patients who received one dose of doxorubicin had slightly elevated age-adjusted afterload, and none had decreased contractility. In contrast, 65 percent of patients who received at least 228 mg of doxorubicin per square meter had increased afterload (59 percent of patients), decreased contractility (23 percent), or both. Increased afterload was due to reduced ventricular wall thickness, not to hypertension or ventricular dilatation. In multivariate analyses restricted to patients who received at least 228 mg of doxorubicin per square meter, the only significant predictive factors were a higher cumulative dose (P = 0.01), which predicted decreased contractility, and an age of less than four years at treatment (P = 0.003), which predicted increased afterload. Afterload increased progressively in 24 of 34 patients evaluated serially (71 percent). Reported symptoms correlated poorly with indexes of exercise tolerance or ventricular function. Eleven patients had congestive heart failure within one year of treatment with doxorubicin; five of them had recurrent heart failure 3.7 to 10.3 years after completing doxorubicin treatment, and two required heart transplantation. No patient had late heart failure as a new event. Doxorubicin therapy in childhood impairs myocardial growth in a dose-related fashion and results in a progressive increase in left ventricular afterload sometimes accompanied by reduced contractility. We hypothesize that the loss of myocytes during doxorubicin therapy in childhood might result in inadequate left ventricular mass and clinically important heart disease in later years.

Functional benefit in heart failure due to idiopathic dilated cardiomyopathy has been observed after beta-blockade, but improvement in survival has not been established in a large-scale randomized trial. This was the main objective of the Cardiac Insufficiency Bisoprolol Study (CIBIS). Six hundred forty-one patients with chronic heart failure of various etiologies and a left ventricular ejection fraction of < 40% entered this placebo-controlled, randomized, double-blind study. Patients were in New York Heart Association functional class III (95%) or IV (5%) at inclusion. All received background diuretic and vasodilator therapy (an angiotensin-converting enzyme inhibitor in 90% of cases). A total of 320 patients was randomized to bisoprolol and 321 to placebo. Mean follow-up was 1.9 years. Bisoprolol was well tolerated without between group difference in premature treatment withdrawals (82 on placebo, 75 on bisoprolol; NS). The observed difference in mortality between groups did not reach statistical significance: 67 patients died on placebo, 53 on bisoprolol (P = .22; relative risk, 0.80; 95% confidence interval, 0.56 to 1.15). No significant difference was observed in sudden death rate (17 on placebo, 15 on bisoprolol) or death related to documented ventricular tachycardia or fibrillation (7 on placebo, 4 on bisoprolol). Bisoprolol significantly improved the functional status of the patients; fewer patients in the bisoprolol group required hospitalization for cardiac decompensation (90 on placebo versus 61 on bisoprolol, P < .01), and more patients improved by at least one New York Heart Association functional class (48 on placebo versus 68 on bisoprolol, P = .04) by the end of follow-up period. These results confirm previous trials evidence that a progressively increasing dose of beta-blocker in severe heart failure confers functional benefit. Subgroup analysis suggested that benefit from beta-blockade therapy was greater for those with nonischemic cardiomyopathy. However, improvement in survival while on beta-blockade remains to be demonstrated.