In COPERNICUS, 2,289 patients with symptoms of heart failure at rest or on minimal exertion were randomized to placebo or carvedilol. Patients had left ventricular ejection fraction <25%, systolic blood pressure 385 mm Hg, and were receiving diuretics, and angiotensin converting enzymes with or without digoxin. The trial was terminated prematurely on account of a marked 35% survival benefit with carvedilol.

In the COPERNICUS population, 132 (5.8%) had systolic blood pressure of 85-95 mm Hg and 264 (11.5%) had a systolic blood pressure of 96-105 mm Hg at randomization. Patients with lower systolic blood pressures (<96 mm Hg) tended to be younger and to have lower ejection fractions. Patients with lower systolic blood pressure had significantly worse prognoses (P < 0.0001 for all cause mortality) than those with higher blood pressures (>125 mm Hg), with about a 50% mortality rate at 2 years. Survival was best in those patients with systolic blood pressure >125 mm Hg. Death or hospitalization for any reason, similarly, occurred in nearly 80% of patients in the lowest (<96 mm Hg) systolic blood pressure group at one year, and was less common (P < 0.0001) progressively with higher systolic blood pressures.

Carvedilol reduced risk of death or risk of death or heart failure hospitalization among all subgroups defined by baseline systolic blood pressure. The magnitude of benefit was independent of systolic blood pressure (interaction P = 0.64 and P = 0.80 for mortality and for death or heart failure hospitalization, respectively). Risk of worsening heart failure increased with lower systolic blood pressure levels in the placebo group. That risk was reduced similarly (interaction P = 0.74) across groups by the addition of carvedilol, indicating that the benefit is entirely independent of blood pressure.

Risk of Outcome Variables (Hazard Ratio) Carvedilol: Placebo

Systolic blood pressure	All cause mortality	Death or heart failure hospitalization
85-95 mm Hg	0.77	0.74
96-105 mm Hg	0.61	0.75
106-115 mm Hg	0.65	0.78
116-125 mm Hg	0.61	0.54
>125 mm Hg	0.60	0.68

The rate of permanent withdrawal decreased with increasing baseline systolic blood pressure similarly for both placebo and carvedilol. While hypotension was reported more frequently with carvedilol than with placebo, the effect was not accentuated at lower systolic blood pressures.

Dr. Rouleau concluded that pretreatment blood pressure is not a determinant of efficacy or safety of carvedilol in patients with severe heart failure, and thus should not be used to exclude patients from treatment with the drug as long as systolic blood pressure is 385 mm Hg. Also, the vasodilatory effects of carvedilol did not adversely affect patients with a low systolic blood pressure and may have contributed to the reduction in risk of worsening heart failure produced by treatment.