N Engl J Med 1987; 314:1429-35
Background Prior to the publication of this study, digoxin and diuretics were the mainstay of chronic heart failure management. No therapy had yet been shown to reduce mortality or improve heart failure outcomes in patients with severe disease. The results of the V-HEFT trial had been published in the prior year, which demonstrated that the vasodilator combination of hydralazine and isosorbide reduced death in patients with chronic, stable heart failure. CONSENSUS was the first study to test whether vasodilator therapy in general, and angiotensin converting enzyme inhibitors in particular could modify heart failure disease trajectory for those with severe disease when used as part of chronic disease management. The CONSENSUS trial was designed to test the hypothesis that Enalapril compared to placebo reduced mortality in patients with severe (NYHA IV) congestive heart failure.
Patients Men and women with severe (NYHA IV) congestive heart failure and cardiomegaly based on heart size >600 ml/m2 in men or >550 ml/m2 in women were recruited from 35 centers in Finland, Norway and Sweden. Measurement of LV function was not required. Patients were excluded if they had 1) acute pulmonary edema, 2) hemodynamically important aortic or mitral valve stenosis, 3) MI within the previous 2 months, 4) unstable angina, 5) planned cardiac surgery, 6) right heart failure due to pulmonary disease, or 7) serum creatinine >3.4 mg/dL.
It is not specified whether patients could be recruited from the inpatient or outpatient setting or both but prior to randomization, a 14-day period was allowed to stabilize patients on digoxin and diuretics. If during this period, their condition improved to NYHA class III or less they were not randomized.
Baseline characteristics The majority of participants were male (70%) and their average age was 70. The average heart rate and blood pressure were 80 bpm and 120/75 mmHg and the average serum creatinine was about 1.5 mg/dL. Coronary artery disease was present in over 70% of participants and nearly 50% had suffered a previous heart attack. Hypertension and diabetes were present in over 20% and atrial fibrillation in 50%. The use of medications at baseline was evenly distributed between groups with nearly all patients being on digoxin and furosemide. About 50% of participants were also taking spironolactone as well as other vasodilator drugs. About 50% of patients had heart failure for more than 4 years.
Procedures Treatment with enalapril or an identical placebo was initially started in the hospital with a dose of 5 mg twice a day. After 1 week it was increased to 10 mg twice a day if the patient did not have symptoms of hypotension or other side effects. According to the clinical response, a further increase in dosage could occur up to a maximum dose of 20 mg twice a day.
Patients were evaluated after 1, 2, 3, 6, and 16 weeks, 6, 9, and 12 months and at the end of the study. In patients with worsening symptoms, additional vasodilator therapy with isosorbide dinitrate, hydralazine, or prazosin, in that sequence was recommended.
Early in the trial the occurrence of symptomatic hypotension led to revision of the protocol after 67 patients had been randomized. No patient’s treatment was unblinded but in patients with 1) serum sodium <130 mg/dL, 2) serum Cr between 1.7 – 3.4 mg/dL, 3) an increase in diuretic dosage within the week prior to randomization or 4) treatment with spironolactone, the initial dose given was 2.5 mg daily. If hypotension or an increase in the serum creatinine did not occur after to 3 to 4 days, the dosage was increased to 2.5 mg twice a day for the remainder of the first week. Thereafter, the previous titration plan was followed.
Endpoints The primary endpoints were stated as 6-month mortality and cause of death. The cause of death was determined by 2 blinded investigators independently. Secondary endpoints were 12-month and overall mortality during the entire trial period, according to the intention-to-treat principle.
A sample size of 400 patients was calculated on the assumption that the 6-month mortality would be 40% in the control group and 24% in the enalapril group (alpha = 0.05, power = 90%, two-tailed test). All randomized patients were included in the mortality analyses. No formal rule was adopted governing the interruption of the trial for the purpose of interim analyses by the Ethical Review Committee.
Results The trial was terminated early by the Ethical Review Committee after only 63% of the target population number had been enrolled for a total of 253 patients – 126 in the placebo group and 127 in the enalapril group. It is reported that at this time the difference in outcomes was sufficient enough to recommend termination. Only 194/253 (77%) patients achieved a 6 month follow up, and 102/253 (40%) achieved a 12 month follow up and this is not broken down by treatment group. Despite these limits, 6-month, 12-month and total mortality data is provided for all 253 patients. Information is not provided on how the trial was conducted after it was terminated and information is not provided on whether the protocol was maintained or not. No details of this are provided in the manuscript and in the discussion, readers are informed that a detailed report from the Ethical Review Committee is available upon request.
Based on what is reported, the mean overall follow up time was 160 days (0.44 years) in the placebo group and 215 days (0.59 years) in the enalapril group. Again, based on the reported results, which include a high percentage of follow up time occurring after study termination, the 6-month death totals were 55 (44%) in the placebo group and 33 (26%) in the enalapril group for a p value of 0.002. The 12-month totals were 66 (52%) in the placebo group and 46 (36%) in the enalapril group for a p value of 0.001. Total mortality was 68 (54%) in the placebo group versus 50 (39%) in the enalapril group for a p value of 0.003. Based on the total mortality, the estimated death rate per 100 patient years in the placebo group was 124 and in the enalapril group was 67 for a difference of 57 deaths per 100 patient years.
Total cardiac death occurred in 64 (51%) of the placebo group and 50 (39%) of the enalapril group for a p value of 0.001. The estimated cardiac death rate per 100 patient years in the placebo group was 116 and 59 in the enalapril group for a difference of 57 cardiac deaths per 100 patient years.
For patients who were alive after results were reported (58 in placebo group and 77 in enalapril group), this was the breakdown of NYHA class for placebo and enalapril groups: for class 4 (34% vs 27%), class 3 (43% vs 49%), class 2 (3% vs 17%), and class 1 (0% vs 4%).
There was no significant difference in overall withdrawals between groups with 18 (14%) in the placebo group and 22 (17%) in the enalapril group; however, hypotension led to the withdrawal of 7 patients in the enalapril group and 0 in the placebo group. In the initial phase of the study, when a starting dose of 5 mg twice a day was used, 4 of the first 34 patients in the enalapril group withdrew due to hypotension (12%); however, after the protocol change, where high-risk patients were started on 2.5 mg daily, only 3 of the remaining 93 patients in the enalapril group withdrew due to hypotension (3%). The number of withdrawals due to deterioration in creatinine were 4 (3%) in the placebo group and 6 (5%) in the enalapril group, respectively.
The average time to withdrawal was 67 days in the placebo group and 75 in the enalapril group and the average survival time following withdrawal was 27 days in the placebo group and 80 in the enalapril group.
After the 1st dose, the fall in SBP was greater in the enalapril group compared to placebo (118 to 98 [20] mmHg vs 121 to 111 [10] mmHg), respectively and mean heart rate was unchanged.
The final mean dose of enalapril was 18.4 mg (<10 mg twice a day) and 27.3 mg. The dose was titrated to maximum level in 28 patients in the enalapril group and 57 patients in the placebo group.
Conclusions The CONSENSUS trial compared enalapril with placebo in patients with NYHA 4 congestive heart failure. The fragility of this patient population is supported by the very high death rates in both groups (this makes the mortality rate per 100 patient years higher than 100); however, enalapril significantly reduced death and increased survival. Results from this trial would seem to apply to very sick outpatients or inpatients admitted with acute decompensations. It should be remembered that stabilization of patients’ conditions with digoxin and diuretics was a requirement. Enthusiasm for these results must be tempered by concerns for bias in the trial.
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