Abstract
Aims
To examine associations of below-target and target dose of enalapril, an angiotensin-converting enzyme (ACE) inhibitor, with outcomes in patients with heart failure and reduced ejection fraction (HFrEF) in the Studies of Left Ventricular Dysfunction (SOLVD) Treatment trial.
Methods and results
Two thousand five hundred and sixty-nine patients with HFrEF (ejection fraction ≤35%) were randomized to below-target (5 – 10 mg/day) dose placebo (n = 1284) or enalapril (n = 1285). One month post-randomization, blind up-titration to target (20 mg/day) dose was attempted for both study drugs in 2458 patients. Among the 1444 patients who achieved dose up-titration (placebo, n = 748; enalapril, n = 696; mean dose for both groups, 20.0 mg/day), target dose enalapril (vs. target dose placebo) was associated with a 9% absolute lower risk of the combined endpoint of heart failure hospitalization or all-cause mortality [adjusted hazard ratio (HR) 0.70; 95% confidence interval (CI) 0.60 – 0.81; P < 0.001] during 4 years of follow-up. Among the 1014 patients who could not achieve target dose (placebo, n = 486; enalapril, n = 528; mean dose for both groups, 8.8 mg/day), below-target dose enalapril (vs. below-target dose placebo) was associated with a 12% absolute lower risk of the combined endpoint of heart failure hospitalization or all-cause mortality (adjusted HR 0.68; 95% CI 0.57 – 0.81; P < 0.001). Among the 1224 patients receiving enalapril, target (vs. below-target) dose had no association with the combined endpoint of heart failure hospitalization or all-cause mortality (adjusted HR 1.04; 95% CI 0.87 – 1.23; P = 0.695).
Conclusion
In patients with HFrEF, the clinical benefits of ACE inhibitors appear to be similar at both below-target and target doses.
Keywords: ACE inhibitors, Target dose, Enalapril, Placebo, Heart failure
Introduction
Heart failure (HF) is a chronic condition and a major source of mortality and morbidity.1 – 4 Angiotensin-converting enzyme (ACE) inhibitors have been shown to reduce the risk of death and hospital admission in patients with HF and reduced ejection fraction (HFrEF). Major HF guidelines recommend initial low-dose ACE inhibitor therapy followed by higher target doses as tolerated.5,6 This recommendation is based in part on the findings from the Treatment arm of the double-blind Studies of Left Ventricular Dys-function (SOLVD) trial, in which patients were randomized to receive 2.5 – 20 mg daily doses of either placebo or enalapril, an ACE inhibitor.7 Although SOLVD was designed to use study drugs at higher target (20 mg/day) doses, the final mean daily dose of either study drug was 11 mg and at the final visit, 49% of patients in either treatment group were receiving target doses.7 Thus, the beneficial effects of enalapril in SOLVD may not be attributed to the use of higher target doses. To the best of our knowledge, comparative associations of the two doses of enalapril used in the SOLVD trial have never been published. The objective of the current analysis is to examine associations of target and below-target dose enalapril with outcomes in the SOLVD Treatment trial.
Methods
Data source and study population
The current study is based on the public-use copy of the SOLVD Treatment trial obtained from the National Heart, Lung, and Blood Institute (NHLBI), which also sponsored the trial. The details of the design, methods, and results of the SOLVD trial have been reported previously.7 Briefly, 2569 patients with HFrEF [ejection fraction (EF) ≤35%], mostly with NYHA class II or III symptoms, who tolerated a pre-randomization stabilization phase with single-blinded enalapril of 5 mg/day for a week were randomized to receive either placebo (n = 1284) or enalapril (n = 1285) at an initial dose of 5 – 10 mg/day in a double-blind fashion.
During the month following randomization, following a protocol-driven up-titration process, study investigators double-blindly up-titrated the dose of both study drugs to a target dose of 20 mg/day if patients did not have symptomatic hypotension or worsening renal function.7,8 The current analysis is restricted to 2458 of the 2569 patients who underwent the dose up-titration process. Overall, 61% (748 of 1234) of patients in the placebo group and 57% (696 of 1224) of patients in the enalapril group received the target (20 mg daily) dose (Figure 1). Overall, 58.7% (1444 of 2458) of patients received the target dose of the study drugs.
Figure 1.
Flow chart for study cohort assembly for the current analysis. In the SOLVD Treatment trial, 2569 patients with heart failure and left ventricular ejection fraction ≤35% were randomized to below-target (5 – 10 mg/day) dose enalapril or matching placebo at baseline. One month post-randomization, double-blind up-titration to target (20 mg/day) dose was attempted per protocol for both study drugs in 2458 patients, based primarily on systolic blood pressure (SBP) and serum creatinine (SCr). Dose up-titration was achieved in 1444 patients and 1014 patients continued on below-target dose. Baseline SBP and SCr and all-cause mortality during 4.6 (average, 2.7) years of follow-up for each group are displayed in their respective cells.
Study outcomes
The primary outcome for the current analysis was all-cause mortality during 4.6 years (average, 2.7 years) of follow-up, which was also the primary outcome in the SOLVD trial.7 Secondary outcomes included cardiovascular and HF mortality, all-cause, cardiovascular, and HF hospitalizations, and the combined endpoint of HF hospitalization or all-cause mortality. All endpoints were classified by study investigators at each centre on the basis of blinded chart reviews and interviews of family members.
Statistical analysis
Baseline characteristics of study participants receiving below-target and target doses of the study drugs were compared separately within the placebo and enalapril groups using Pearson’s χ2 test and Student’s t-test as appropriate. Because doses of both enalapril and placebo were up-titrated double-blindly, we used two separate approaches to examine the dose response in the SOLVD trial. First, we examined the association of enalapril with outcomes separately in the target and below-target groups. This was done first by comparing target dose enalapril with target dose placebo and then by comparing below-target dose enalapril with below-target dose placebo. Second, we examined the association of target dose with outcomes separately in the enalapril and the placebo groups. This was done by comparing target dose enalapril with below-target dose enalapril and then by comparing target dose placebo with below-target dose placebo.
For both approaches, we used multivariable Cox proportional hazard models that were adjusted for all baseline characteristics displayed in Table 1. We used the same models to generate adjusted survival curves for target vs. below-target dose patients, separately for the enalapril and the placebo groups. Because systolic blood pressure and serum creatinine were the two key variables used for dose up-titration eligibility, to examine their confounding effect on the association between dose and primary outcome, we performed additional analysis adjusting for these two variables. We also compared the total number of all-cause, cardiovascular, and HF hospitalizations, and tested for statistical significance as appropriate using Student’s t-test or the Wilcoxon rank sum test. All statistical tests were two-tailed with 95% confidence intervals (CIs) and a P-value <0.05 was considered significant. IBM SPSS Statistics for Windows, version 22.0 (IBM Corp., Armonk, NY, USA) was used for all data analysis.
Table 1.
Baseline characteristics of patients receiving below-target doses vs. target doses of the study drugs in the SOLVD Treatment trial, for the placebo and enalapril groups separately
| Placebo (n = 1234) | Enalapril (n = 1224) | |||||
|---|---|---|---|---|---|---|
| Below-target dose (n = 486) |
Target dose (n = 748) |
P-value | Below-target dose (n = 528) |
Target dose (n = 696) |
P-value | |
| Age (years) | 61 (±10) | 60 (±9) | 0.061 | 60 (±11) | 60 (±10) | 0.662 |
| Female* | 128 (26) | 119 (16) | <0.001 | 102 (19) | 127 (18) | 0.634 |
| African American | 91 (19) | 86 (12) | <0.001 | 95 (18) | 100 (14) | 0.086 |
| Dose of study drugs (mg/day) | 8.8 (±2.3) | 20.0 (±0.0) | <0.001 | 8.8 (±2.2) | 20.0 (±0.0) | <0.001 |
| Current smoker* | 87 (18) | 178 (24) | 0.014 | 127 (24) | 155 (22) | 0.463 |
| New York Heart Association class | ||||||
| I | 60 (12) | 113 (15) | <0.001 | 63 (12) | 110 (16) | 0.083 |
| II | 252 (52) | 428 (57) | 275 (52) | 374 (54) | ||
| III | 152 (31) | 200 (27) | 181 (34) | 205 (30) | ||
| IV | 22 (5) | 7 (1) | 9 (2) | 7 (1) | ||
| Past medical history | ||||||
| Chronic heart failure aetiology | ||||||
| Ischaemic causes | 337 (69) | 556 (74) | 0.118 | 384 (73) | 479 (69) | 0.095 |
| Other causes | 54 (11) | 62 (8) | 59 (11) | 71 (10) | ||
| Unknown causes | 95 (20) | 130 (17) | 85 (16) | 146 (21) | ||
| Acute myocardial infarction | 310 (64) | 492 (66) | 0.474 | 362 (69) | 451 (65) | 0.168 |
| Hypertension | 203 (42) | 307 (41) | 0.800 | 204 (39) | 314 (45) | 0.023 |
| Diabetes mellitus* | 135 (28) | 195 (26) | 0.508 | 118 (22) | 177 (25) | 0.212 |
| Angina pectoris | 188 (39) | 295 (39) | 0.791 | 199 (38) | 247 (36) | 0.428 |
| Atrial fibrillation† | 36 (7) | 46 (6) | 0.386 | 46 (9) | 62 (9) | 0.905 |
| Cardiothoracic ratio >0.5 | 284 (58) | 410 (55) | 0.210 | 307 (58) | 402 (58) | 0.892 |
| Clinical findings | ||||||
| Pulse (beats/min) | 81 (±14) | 79 (±13) | 0.018 | 80 (±14) | 80 (±13) | 0.579 |
| Systolic blood pressure (mmHg) | 121 (±18) | 127 (±16) | <0.001 | 122 (±18) | 128 (±17) | <0.001 |
| Diastolic blood pressure (mmHg) | 75 (±10) | 77 (±10) | <0.001 | 76 (±10) | 78 (±10) | <0.001 |
| Weight (kg) | 76 (±10) | 77 (±9) | 0.003 | 76 (±9) | 77 (±8) | 0.049 |
| Laboratory data | ||||||
| Serum sodium (mEq/L) | 140 (±3) | 140 (±3) | 0.413 | 140 (±3) | 140 (±3) | 0.195 |
| Serum potassium (mEq/L) | 4.3 (±0.47) | 4.3 (±0.45) | 0.688 | 4.2 (±0.44) | 4.3 (±0.46) | 0.334 |
| Serum creatinine (mEq/L) | 1.3 (±0.32) | 1.2 (±0.29) | 0.002 | 1.3 (±0.32) | 1.2 (±0.29) | 0.033 |
| Ejection fraction (%) | 25 (±7) | 25 (±7) | 0.608 | 25 (±7) | 25 (±7) | 0.714 |
| Medications | ||||||
| Beta-blockers | 26 (5) | 62 (8) | 0.050 | 41 (8) | 59 (9) | 0.652 |
| Digitalis† | 305 (63) | 541 (72) | <0.001 | 339 (64) | 464 (67) | 0.369 |
| Diuretics | 3399 (82) | 650 (87) | 0.021 | 444 (84) | 598 (86) | 0.373 |
| Potassium-sparing diuretics | 39 (8) | 76 (10) | 0.207 | 46 (9) | 68 (10) | 0.528 |
| Calcium channel blockers* | 158 (33) | 243 (33) | 0.993 | 141 (27) | 223 (32) | 0.043 |
| Nitrates† | 226 (47) | 312 (42) | 0.097 | 228 (43) | 255 (37) | 0.020 |
| Anti-arrhythmics | 111 (23) | 145 (19) | 0.144 | 116 (22) | 160 (23) | 0.673 |
| Potassium supplements | 233 (48) | 369 (49) | 0.633 | 262 (50) | 360 (52) | 0.466 |
| Anti-coagulants | 93 (19) | 110 (15) | 0.040 | 87 (17) | 106 (15) | 0.553 |
| Anti-platelets | 189 (39) | 230 (31) | 0.003 | 203 (38) | 203 (29) | 0.001 |
Values are mean (±SD) or numbers and proportion of patients (%).
P-value <0.05, when patients in the below-target dose enalapril group were compared with those in the below-target dose placebo group.
P-value <0.05, when patients in the target dose enalapril group were compared with those in the target dose placebo group.
Results
Baseline characteristics
Overall, the 2458 patients included in the current analysis had a mean age (± standard deviation) of 60 (±10) years, a mean EF of 25 (±7)%, 20% were women, and 15% were African American. Baseline characteristics between patients receiving below-target and target dose of the study drugs are presented in Table 1 separately for patients in the placebo and enalapril groups. Mean systolic blood pressure was higher and mean serum creatinine was lower among patients receiving target dose of both placebo and enalapril, reflecting blind dose up-titration (Table 1). Other baseline characteristics are displayed in Table 1.
Overall, the mean dose of the study drugs for patients in the placebo and enalapril groups was 15.6 and 15.2 mg/day, respectively (P = 0.077). The mean dose of the study drugs for patients in the below-target and target dose groups was 8.8 and 20.0 mg/day, respectively, which was similar for both placebo and enalapril groups (Table 1). All patients in the target dose group received a 20 mg/day dose. The vast majority of the patients in the below-target group received 10 mg/day (n = 774); 76% and 77% of patients in the placebo and enalapril groups, respectively, received this dose. Other below-target doses were: 2.5 mg/day (n = 23), 5 mg/day (n = 215), 7.5 mg/day (n = 1), 15 mg/day (n = 1).
Enalapril and all-cause mortality in the original SOLVD cohort
As previously reported, among the 2569 patients enrolled in the SOLVD trial, the primary endpoint of all-cause mortality occurred in 40% and 35% of patients in the placebo and the enalapril groups, respectively [hazard ratio (HR) when enalapril was compared with placebo, 0.84; 95% CI 0.74 – 0.96; P = 0.008).7
Enalapril and all-cause mortality in the dose up-titration cohort
Among the 2458 patients included in the current analysis, all-cause mortality occurred in 39% and 34% of patients receiving placebo and enalapril, respectively (HR associated with enalapril use, 0.83; 95% CI 0.73 – 0.95; P = 0.005).
Enalapril and outcomes within the target dose group
Among patients in the target dose group (n = 1444), all-cause mortality occurred in 38% and 33% of patients receiving target dose placebo and target dose enalapril, respectively (HR associated with target dose enalapril, 0.91; 95% CI 0.83 – 0.99; P = 0.029; Table 2 and Figure 2). This association remained unchanged after multivariable risk adjustment (adjusted HR 0.90; 95% CI 0.82 – 0.98; P = 0.017; Table 2). Target dose enalapril was also associated with a lower risk of HF hospitalization (adjusted HR 0.75; 95% CI 0.68 – 0.83; P < 0.001), and consequently a lower risk of the combined endpoint of HF hospitalization or all-cause mortality (adjusted HR 0.70; 95% CI 0.60 – 0.81; P < 0.001; Table 2). Associations of target dose enalapril (vs. target dose placebo) with other outcomes are displayed in Table 2.
Table 2.
Outcomes by randomization to placebo vs. enalapril in the SOLVD Treatment trial, separately in the target and below-target dose groups
| Target dose (n = 1444) | ||||||
|---|---|---|---|---|---|---|
| Events (%) | Hazard ratio (95% CI); P-value | |||||
| Placebo (n = 748) |
Enalapril (n = 696) |
ARDa | Unadjusted | Age, sex, race adjusted | Multivariable adjustedb | |
| Mortality | ||||||
| All-cause | 287 (38%) | 233 (33%) | −5% | 0.91 (0.83 – 0.99); P = 0.029 |
0.91 (0.83 – 0.99); P = 0.033 |
0.90 (0.82 – 0.98); P = 0.017 |
| Cardiovascular | 257 (34%) | 207 (30%) | −4% | 0.91 (0.83 – 0.99); P = 0.032 |
0.91 (0.83 – 0.99); P = 0.034 |
0.90 (0.81 – 0.98); P = 0.020 |
| Heart failure | 97 (13%) | 82 (12%) | −1% | 0.92 (0.80 – 1.07); P = 0.286 |
0.93 (0.80 – 1.07); P = 0.296 |
0.91 (0.78 – 1.06); P = 0.236 |
| Hospitalization | ||||||
| All-cause | 556 (74%) | 474 (68%) | −6% | 0.88 (0.83 – 0.93); P < 0.001 |
0.88 (0.83 – 0.93); P < 0.001 |
0.87 (0.82 – 0.93); P < 0.001 |
| Cardiovascular | 470 (63%) | 386 (56%) | −7% | 0.88 (0.82 – 0.94); P < 0.001 |
0.88 (0.82 – 0.94); P < 0.001 |
0.87 (0.81 – 0.93); P < 0.001 |
| Heart failure | 270 (36%) | 172 (25%) | −11% | 0.78 (0.71 − 0.86); P < 0.001 |
0.77 (0.70 – 0.85); P < 0.001 |
0.75 (0.68 – 0.83); P < 0.001 |
| Combined endpoint of heart failure hospitalization or all-cause mortality |
415 (55%) | 322 (46%) | −9% | 0.74 (0.64 – 0.85); P < 0.001 |
0.73 (0.63 – 0.85); P < 0.001 |
0.70 (0.60 – 0.81); P < 0.001 |
| Below-target dose (n = 1014) | ||||||
| Events (%) | Hazard ratio (95% CI); P-value | |||||
| Placebo (n = 748) |
Enalapril (n = 696) |
ARDa | Unadjusted | Age, sex, race adjusted | Multivariable adjustedb | |
| Mortality | ||||||
| All-cause | 196 (40%) | 185 (35%) | −5% | 0.91 (0.82 – 1.01); P = 0.068 |
0.92 (0.83 – 1.01); P = 0.091 |
0.90 (0.81 – 1.00); P = 0.057 |
| Cardiovascular | 178 (37%) | 163 (31%) | −6% | 0.90 (0.81 – 1.00); P = 0.047 |
0.90 (0.81 – 1.01); P = 0.064 |
0.89 (0.80 – 0.99); P = 0.039 |
| Heart failure | 66 (14%) | 59 (11%) | −3% | 0.89 (0.75 – 1.06); P = 0.183 |
0.91 (0.76 – 1.09); P = 0.301 |
0.91 (0.75 – 1.10); P = 0.310 |
| Hospitalization | ||||||
| All-cause | 365 (75%) | 375 (71%) | −4% | 0.92 (0.86 – 0.99); P = 0.022 |
0.92 (0.86 – 0.99); P = 0.024 |
0.93 (0.86 – 1.00); P = 0.054 |
| Cardiovascular | 308 (63%) | 302 (57%) | −6% | 0.90 (0.83 – 0.98); P = 0.011 |
0.90 (0.83 – 0.97); P = 0.009 |
0.89 (0.82 – 0.97); P = 0.008 |
| Heart failure | 181 (37%) | 140 (27%) | −10% | 0.79 (0.71 – 0.89); P < 0.001 |
0.80 (0.72 – 0.90); P < 0.001 |
0.79 (0.71 – 0.89); P < 0.001 |
| Combined endpoint of heart failure hospitalization or all-cause mortality |
285 (59%) | 249 (47%) | −12% | 0.71 (0.60 – 0.84); P < 0.001 |
0.71 (0.60 – 0.85); P < 0.001 |
0.68 (0.57 – 0.81); P < 0.001 |
ARD, absolute risk difference; CI, confidence interval.
Estimated by subtracting event rates in the enalapril group from those in the placebo group.
Adjusted for all variables included in Table 1.
Figure 2.
Kaplan – Meier plots for all-cause mortality in patients with heart failure and left ventricular ejection fraction ≤35% in the SOLVD Treatment trial, by randomization to enalapril or placebo, separately within the below-target and target dose groups. HR, hazard ratio; CI, confidence interval.
Enalapril and outcomes within the below-target dose group
Among patients in the relatively smaller below-target dose group (n = 1014), all-cause mortality occurred in 40% and 35% of patients receiving below-target dose placebo and below-target dose enalapril, respectively (HR associated with below-target dose enalapril, 0.91; 95% CI 0.82 – 1.01; P = 0.068; Table 2 and Figure 2). This association remained unchanged after multivariable risk adjustment (adjusted HR 0.90; 95% CI 0.81 – 1.00; P = 0.057; Table 2). Below-target dose enalapril was also associated with a lower risk of HF hospitalization (adjusted HR 0.79; 95% CI 0.71 – 0.89; P < 0.001) as well as the combined endpoint of HF hospitalization or all-cause mortality (HR 0.68; 95% CI 0.57 – 0.81; P < 0.001; Table 2). Associations of below-target dose enalapril (vs. below-target dose placebo) with other outcomes are displayed in Table 2.
Target dose and outcomes within the enalapril group
Among patients in the enalapril group (n = 1224), all-cause mortality occurred in 35% and 33% of patients receiving below-target dose enalapril and target dose enalapril, respectively (HR associated with target dose enalapril, 0.89; 95% CI 0.74 – 1.09; P = 0.26, Table 3). Multivariable-adjusted HR for this association was 1.01 (95% CI 0.82 – 1.24; P = 0.95; Table 3 and Figure 3). HR adjusted for baseline systolic blood pressure and serum creatinine, the two characteristics that were used to determine blind up-titration suitability, was 0.97 (95% CI 0.80 – 1.18; P = 0.76). Target dose enalapril was not associated with the combined endpoint of HF hospitalization or all-cause mortality (HR 1.04; 95% CI 0.87 – 1.23; P = 0.70; Table 3). Associations of target dose enalapril (vs. below-target dose enalapril) with other outcomes are displayed in Table 3.
Table 3.
Outcomes by below-target vs. target doses of the study drugs in the SOLVD Treatment trial, separately in the enalapril and placebo groups
| Enalapril (n = 1224) | ||||||
|---|---|---|---|---|---|---|
| Events (%) | Hazard ratio (95% CI); P-value | |||||
| Below-target dose (n = 528) | Target dose (n = 696) | ARDa | Unadjusted | Age, sex, race adjusted | Multivariable adjustedb | |
| Mortality | ||||||
| All-cause | 185 (35%) | 233 (33%) | −2% | 0.89 (0.74 – 1.09); P = 0.257 |
0.91 (0.75 – 1.10); P = 0.325 |
1.01 (0.82 – 1.24); P = 0.947 |
| Cardiovascular | 163 (31%) | 207 (30%) | −1% | 0.90 (0.74 – 1.11); P = 0.326 |
0.92 (0.75 – 1.13); P = 0.403 |
1.02 (0.83 – 1.27); P = 0.827 |
| Heart failure | 59 (11%) | 82 (12%) | +1% | 0.97 (0.69 – 1.35); P = 0.838 |
0.98 (0.70 – 1.37); P = 0.916 |
1.22 (0.85 – 1.74); P = 0.286 |
| Hospitalization | ||||||
| All-cause | 375 (71%) | 474 (68%) | −3% | 0.87 (0.76 – 0.99); P = 0.037 |
0.87 (0.76 – 1.00); P = 0.048 |
0.91 (0.78 – 1.05); P= 0.173 |
| Cardiovascular | 302 (57%) | 386 (56%) | −1% | 0.90 (0.78 – 1.05); P = 0.175 |
0.90 (0.78 – 1.05); P = 0.191 |
0.94 (0.81 – 1.11); P = 0.478 |
| Heart failure | 140 (27%) | 172 (25%) | −2% | 0.88 (0.70 – 1.10); P = 0.264 |
0.90 (0.72 – 1.12); P = 0.348 |
0.99 (0.78 – 1.25); P = 0.899 |
| Combined endpoint of heart failure hospitalization or all-cause mortality | 249 (47%) | 322 (46%) | −1% | 0.92 (0.78 – 1.09); P = 0.346 |
0.94 (0.80 – 1.11); P = 0.485 |
1.04 (0.87 – 1.23); P = 0.695 |
| Placebo (n = 1234) | ||||||
| Events (%) | Hazard ratio (95% CI); P-value | |||||
| Below-target dose (n = 486) | Target dose (n = 748) | ARDa | Unadjusted | Age, sex, race adjusted | Multivariable adjustedb | |
| Mortality | ||||||
| All-cause | 196 (40%) | 287 (38%) | −2% | 0.91 (0.76 – 1.09); P = 0.284 |
0.92 (0.76 – 1.10); P = 0.349 |
0.96 (0.79 – 1.16); P = 0.666 |
| Cardiovascular | 178 (37%) | 257 (34%) | −3% | 0.89 (0.74 – 1.08); P = 0.250 |
0.91 (0.75 – 1.11); P = 0.347 |
0.94 (0.77 – 1.16); P = 0.579 |
| Heart failure | 66 (14%) | 97 (13%) | −1% | 0.91 (0.66 – 1.24); P = 0.530 |
0.95 (0.69 – 1.30); P = 0.732 |
1.17 (0.82 – 1.66); P = 0.381 |
| Hospitalization | ||||||
| All-cause | 365 (75%) | 556 (74%) | −1% | 0.95 (0.83 – 1.08); P = 0.425 |
0.95 (0.83 – 1.09); P = 0.447 |
1.00 (0.86 – 1.15); P = 0.947 |
| Cardiovascular | 308 (63%) | 470 (63%) | 0% | 0.95 (0.82 – 1.10); P = 0.481 |
0.94 (0.81 – 1.09); P = 0.399 |
0.99 (0.84 – 1.15); P = 0.845 |
| Heart failure | 181 (37%) | 270 (36%) | −1% | 0.92 (0.76 – 1.11); P = 0.357 |
0.93 (0.77 – 1.13); P = 0.454 |
1.03 (0.84 – 1.26); P = 0.772 |
| Combined endpoint of heart failure hospitalization or all-cause mortality | 285 (59%) | 415 (56%) | −3% | 0.89 (0.77 – 1.04); P = 0.129 |
0.89 (0.77 – 1.04); P = 0.143 |
0.93 (0.79 – 1.09); P = 0.374 |
ARD, absolute risk difference; CI, confidence interval.
Estimated by subtracting event rates in the below-target group from those in the target group.
Adjusted for all variables included in Table 1.
Figure 3.
Adjusted survival plots for all-cause mortality in patients with heart failure and left ventricular ejection fraction ≤35% in the SOLVD Treatment trial, by receipt of the below-target vs. the target dose of the study drugs, separately within the enalapril and the placebo groups. Multivariable-adjusted Cox regression model was adjusted for all variables included in Table 1. CI, confidence interval; HR, hazard ratio.
Target dose and outcomes within the placebo group
Among patients in the placebo group (n = 1234), all-cause mortality occurred in 40% and 38% of patients receiving below-target dose placebo and target dose placebo, respectively (HR associated with target dose placebo, 0.91; 95% CI 0.76 – 1.09; P = 0.28; Table 3).
Multivariable-adjusted HR for this association was 0.96 (95% CI 0.79 – 1.16; P = 0.67; Table 3 and Figure 3). As observed in the enalapril group, HR adjusted for baseline systolic blood pressure and serum creatinine was similar to that observed after multivariable adjustment (HR 0.98; 95% CI 0.81 – 1.18; P = 0.79). Associations of target dose placebo (vs. below-target dose placebo) with other outcomes are displayed in Table 3.
Associations with total number of hospitalizations
Among the 2458 patients included in the current analysis, patients in the enalapril group had 32% fewer HF hospitalizations (634 vs. 931 in the placebo group; P < 0.001; Table 4). There was no difference in total number of hospitalizations between the two dose groups receiving enalapril or placebo (Table 4).
Table 4.
Total numbers of hospitalizations for any reason, cardiovascular reason, and heart failure in the SOLVD Treatment trial, by below-target vs. target doses of the study drugs, separately in the enalapril and placebo groups
| Hospitalizations for any reason, total (mean/patient) | Hospitalizations for CV reason, total (mean/patient) | Hospitalization for HF, total (mean/patient) | ||||
|---|---|---|---|---|---|---|
| 2268 (1.9)a | 1562 (1.3)b | 634 (0.5)c | ||||
| Enalapril (n = 1224) |
Below-target dose (n = 528) |
Target dose (n = 696) |
Below-target dose (n = 528) |
Target dose (n = 696) |
Below-target dose (n = 528) |
Target dose (n = 696) |
| 1004 (1.9)d P = 0.465j |
1264 (1.8)e | 679 (1.3)f P = 0.612j |
883 (1.3)g | 281 (0.5)h
P = 0.445j |
353 (0.5)i | |
| Hospitalizations for any reason, total (mean/patient) | Hospitalizations for CV reason, total (mean/patient) | Hospitalization for HF, total (mean/patient) | ||||
| 2738 (2.2)a | 1967 (1.6)b | 931 (0.8)c | ||||
| Placebo (n = 1234) |
Below-target dose (n = 486) |
Target dose (n = 748) |
Below-target dose (n = 486) |
Target dose (n = 748) |
Below-target dose (n = 486) |
Target dose (n = 748) |
| 1110 (2.3)d
P = 0.971j |
1628 (2.2)e | 800 (1.7)f
P = 0.672j |
1167 (1.6)g | 398 (0.8)h
P = 0.682j |
533 (0.7)i | |
CV, cardiovascular; HF, heart failure.
P-values comparing hospitalization for any reason, cardiovascular reason, and heart failure, between placebo and enalapril, overall were derived from Student’s t-tests and were <0.001 for all three outcomes.
P-values comparing hospitalization for any reason, cardiovascular reason, and heart failure, between placebo and enalapril, separately within below-target (d 0.021, f 0.008, and h 0.003) and target (e 0.005, g 0.005, and i 0.002) dose groups.
P-values comparing hospitalization for any reason, cardiovascular reason, and heart failure, between below-target and target dose groups, were derived from the Wilcoxon rank sum (or Mann – Whitney) tests.
Target dose and outcomes in SOLVD, ATLAS, NETWORK, and HEAAL
The design, name and dose of study drugs, demographics, and key outcomes data of the current study and the randomized controlled trials (RCTs) of higher (vs. lower) doses of ACE inhibitors or angiotensin II receptor blockers (ARBs) are presented in Table 5. In none of these RCTs did high dose reduce the risk of death (Table 5).9–11 The composite endpoint of mortality or HF hospitalization was significantly reduced in two of these trials and both were driven by a reduction in the risk of HF hospitalization.9,11
Table 5.
Comparison of studies of dose effect of renin – angiotensin system inhibition in patients with heart failure and reduced ejection fraction
| Study | Design | Drug (n); dose/day (low vs. high); n (low vs. high) | Mean age, women, African American | Primary endpoint | Events, low vs. high dose (%); hazard ratio (95% CI); P-value | Total number (low vs. high dose); P-value | |||
|---|---|---|---|---|---|---|---|---|---|
| All-cause mortality | HF hospitalization | Combined endpoint of HF hospitalization or all-cause | Combined endpoint of CV hospitalization or all-cause | HF hospitalizations | |||||
| SOLVD (n = 2458) |
Post hoc analysis of RCT | Enalapril (n = 1224); <20 vs. 20 mg; 528 vs. 696 |
60 years 19% 16% |
All-cause mortality | 35% vs. 33%; 1.01 (0.82 – 1.24); P = 0.947 |
27% vs. 25%; 0.99 (0.78 – 1.25); P = 0.899 |
47% vs. 46%; 1.01 (0.82 – 1.24); P = 0.947 |
69% vs. 67%; 0.95 (0.82 – 1.01); P = 0.488 |
281 vs. 353; P = 0.712 |
| Placebo (n = 1234); <20 vs. 20 mg; 486 vs. 748 |
61 years 20% 15% |
40% vs. 38%; 0.96 (0.79 – 1.16); P = 0.666 |
37% vs. 36%; 1.01 (0.84 – 1.26); P = 0.772 |
59% vs. 56%; 0.93 (0.79 – 1.09); P = 0.374 |
76% vs. 75%; 0.95 (0.83 – 1.10); P = 0.508 |
398 vs. 533; P = 0.229 |
|||
| ATLAS (n = 3164) | RCT | Lisinopril 2.5 – 5 vs. 32.5 – 35 mg; 1596 vs. 1568 |
64 years 20% 9% |
All-cause mortality | 45% vs. 43%; 0.92(0.82 – 1.03); P = 0.128 |
Not reported | 60% vs. 55%; 0.85 (0.78 – 0.93); P < 0.001 |
74% vs. 71%; 0.92 (0.84 – 0.99); P = 0.036 |
1576 vs. 1199; P = 0.002 |
| NETWORK (n = 1532) |
RCT | Enalapril; 5 vs. 10 vs. 20 mg; 506 vs. 510 vs. 516 |
70 years 35% — |
All-cause mortality, worsening HF or HF hospitalization |
Not reported | Not reported | Not reported | Not reported | Not reported |
| HEAAL (n = 3846) |
RCT | Losartan 50 vs. 150 mg; 1913 vs. 1921 |
66 years 30% 1% |
All-cause mortality or HF hospitalization |
35% vs. 33%; 0.94 (0.84 – 1.04); P = 0.24 |
26% vs. 23%; 0.87 (0.76 – 0.98); P = 0.025 |
12% vs. 11%; 0.90 (0.82 – 0.99); P = 0.027 |
17% vs. 16%; 0.92 (0.85 – 1.01); P = 0.068 |
503 vs. 450; P = 0.025 |
CI, confidence interval; CV, cardiovascular; HF, heart failure; RCT, randomized controlled trial.
The point estimate for risk reduction for HF hospitalization in the ATLAS trial was not provided,9 and in the HEAAL trial there was a significant but modest 1% reduction in HF hospitalization per 100 patient-years of follow-up in the high-dose losartan group.11
Discussion
Findings from this post hoc analysis of the SOLVD data demonstrate that enalapril (vs. placebo) use was associated with a similar lower risk of mortality separately in the below-target and target dose groups, and that the magnitude of the absolute risk reduction in these two dose groups was similar to that observed in the main trial.7 When we examined the association of target (vs. below-target) dose with mortality, we found similar modest non-significant unadjusted associations in both placebo and enalapril groups reflecting selection bias and blind up-titration of the study drugs. This lack of evidence of greater mortality benefit from higher target dose observed in our study is generally consistent with findings from previous RCTs comparing target (vs. below-target) dose of ACE inhibitors or ARBs.9 – 11 The lower risk of combined endpoints observed in some of these trials was driven primarily by a modest reduction in HF hospitalization. Taken together, these findings suggest that target dose ACE inhibitor is not associated with incremental mortality benefit beyond that achieved at below-target dose and that other clinical benefits of target dose, if present, are modest.
By protocol, the blind up-titration of enalapril and placebo in the SOLVD trial was based on patients’ conditions, specifically the absence of symptomatic hypotension and/or impaired kidney function — a process that may have selected patients with a better prognosis in the target dose group. As a result, patients receiving both target dose enalapril and target dose placebo had significantly higher mean systolic blood pressure and lower mean serum creatinine levels at baseline (Table 1), characteristics that have been shown to be associated with better outcomes in patients with HF.12,13 A 2% non-significant absolute reduction in unadjusted mortality in the target dose enalapril (vs. below-target enalapril) group suggests that the risk reduction associated with the higher target dose was at best modest. However, two observations point to another explanation — a potential selection bias. First, the modest association of target dose and mortality disappeared when adjusted for just systolic blood pressure and serum creatinine, and second, similar unadjusted and adjusted associations of target dose and mortality were also observed in the placebo group.
In the SOLVD Treatment trial, enalapril had a strong and significant effect on HF hospitalization.7 We observed that enalapril (vs. placebo) in both target and below-target dose use was associated with a similar lower risk of HF hospitalization, suggesting that a higher target dose did not provide any incremental benefit for this outcome. The lack of dose effect was also supported by our observation that neither target dose of enalapril nor target dose of placebo had any association with HF hospitalization when compared with their below-target dose counterparts (Table 3). However, as explained below, these findings in terms of HF hospitalization are not entirely consistent with findings from some of the RCTs on dosing.9,11
As mentioned before, none of the three RCTs that examined the effect of high (vs. low) doses of ACE inhibitors or ARBs found any mortality benefit.9–11 Two of these RCTs reported a reduction of mortality or HF hospitalization,9,11 which was driven by a modest reduction in the risk of HF hospitalization. However, neither had a placebo group to demonstrate the effect of low dose compared with placebo. Findings from our study suggest that enalapril use at both below-target and target dose of enalapril was associated with a similar lower risk for HF hospitalizations (Table 3). These findings are also consistent with findings from a recent study that observed similar efficacy of sacubitril/valsartan (vs. enalapril) in the below-target dose group (HR 0.80, 95% CI 0.70 – 0.93, P < 0.001) and the target dose group (HR 0.79, 95% CI 0.71 – 0.88, P < 0.001).14
Findings from our study have important clinical implications. The use of higher target doses of ACE inhibitors and ARBs is associated with a modest increase in the risk of adverse effects, including hypotension, dizziness, hyperkalaemia, and elevation of serum creatinine.9,15,16 The use of a higher dose of these drugs may also preclude the initiation or up-titration of beta-blockers and aldosterone antagonists, and switching to an angiotensin receptor – neprilysin inhibitor (ARNI).6,17 Recent updates in HF guidelines recommend the use of an ARNI, a combination of valsartan and sacubitril, to replace ACE inhibitors in ambulatory patients with mild to moderate chronic HFrEF who tolerate a high target dose of ACE inhibitors.6,17
The SOLVD trial was conducted during an earlier era of HF management, which may limit generalization to contemporary HFrEF patients. However, the SOLVD trial remains the cornerstone of the evidence base for the use of ACE inhibitors in patients with HFrEF. Importantly, the use of target dose ACE inhibitors in the SOLVD trial is often cited as a rationale to recommend higher target doses of ACE inhibitors, although data on outcomes in patients receiving below-target and target dose have not been previously published.
Thus, the current analysis based on the SOLVD trial is relevant in clarifying current interpretations of the findings from that trial. Because dose in our study was not determined by randomization, confounding due to selection bias is possible. However, this is not a concern as we did not observe any clinical benefit in patients receiving higher target doses who may have had a lower risk due to selection bias. Finally, the similar associations of below-target and target dose enalapril with mortality observed in our study is consistent with the similar effect of below-target and target dose ACE inhibitors or ARBs on mortality observed in the ATLAS, NETWORK, and HEAAL trials.9–11
In conclusion, in patients with HFrEF enrolled in the SOLVD trial, the use of target dose enalapril (vs. target dose placebo) and below-target dose enalapril (vs. below-target dose placebo) was associated with a similar lower risk of death, HF hospitalization, or the combined endpoint of HF hospitalization or death. We also observed that the use of target dose enalapril (vs. below-target dose enalapril) was not associated with these outcomes or total number of hospitalizations. Taken together with the findings from the ATLAS, NETWORK, and HEAAL trials, these findings suggest that ACE inhibitor use is associated with clinical benefits for those who can tolerate a higher dose as well as for those who cannot tolerate a higher dose or may not be eligible for such a dose, and that incremental clinical benefits associated with a higher dose, if present, are modest.
Acknowledgements
The Studies of Left Ventricular Dysfunction (SOLVD) trial was conducted and supported by the US National Heart, Lung, and Blood Institute (NHLBI) in collaboration with the SOLVD Investigators. This manuscript was prepared using a limited access dataset obtained by the NHLBI and does not necessarily reflect the opinions or views of all SOLVD investigators or the NHLBI. Bertram Pitt, a coauthor in this paper, was the Chairman, SOLVD Executive Committee.
Funding
A.A. was in part supported by the National Institutes of Health through grants (R01-HL085561, R01-HL085561-S, and R01-HL097047) from the National Heart, Lung, and Blood Institute.
Footnotes
Conflict of interest:
S.D.A. discloses the following relationships - consultant to Bayer, Boehringer Ingelheim, Novartis, Servier, Vifor, and Astra. D.L.B. discloses the following relationships - Advisory Board: Cardax, Elsevier Practice Update Cardiology, Medscape Cardiology, Regado Biosciences; Board of Directors: Boston VA Research Institute, Society of Cardiovascular Patient Care; Chair: American Heart Association Quality Oversight Committee; Data Monitoring Committees: Cleveland Clinic, Duke Clinical Research Institute, Harvard Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine, Population Health Research Institute; Honoraria: American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Duke Clinical Research Institute (clinical trial steering committees), Harvard Clinical Research Institute (clinical trial steering committee), HMP Communications (Editor in Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), Population Health Research Institute (clinical trial steering committee), Slack Publications (Chief Medical Editor, Cardiology Today’s Intervention), Society of Cardiovascular Patient Care (Secretary/Treasurer), WebMD (CME steering committees); Other: Clinical Cardiology (Deputy Editor), NCDR-ACTION Registry Steering Committee (Chair), VA CART Research and Publications Committee (Chair); Research Funding: Amarin, Amgen, AstraZeneca, Bristol-Myers Squibb, Chiesi, Eisai, Ethicon, Forest Laboratories, Ironwood, Ischemix, Lilly, Medtronic, Pfizer, Roche, Sanofi Aventis, The Medicines Company; Royalties: Elsevier (Editor, Cardiovascular Intervention: A Companion to Braunwald’s Heart Disease); Site Co-Investigator: Biotronik, Boston Scientific, St. Jude Medical (now Abbott); Trustee: American College of Cardiology; Unfunded Research: FlowCo, Merck, PLx Pharma, Takeda. J.B. discloses the following relationships - consultant to Amgen, Astra-Zeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, CVRx, Janssen, Luitpold, Medtronic, Novartis, Relypsa, Vifor, and ZS Pharma. G.S.F. participated in committees of trials and registries sponsored by Vifor, Novartis, Bayer, Servier. G.C.F. discloses the following relationships - consultant to Amgen, Novartis, Medtronic, St. Jude Medical.
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