Hypotension in landmark randomized controlled trials of guideline-directed medical therapy
| Trial | Medication | Hypotension | SBP drop | SBP cutoff exclusion | Notes |
|---|---|---|---|---|---|
| CONSENSUS6 | Enalapril | 0.05% (0% placebo) | SBP 10 mm Hg lower in both enalapril and placebo | None | 5.5% discontinuation due to hypotension |
| SOLVD7,8 | Enalapril | 14.8% (7.1% placebo) | SBP 4.7 mm Hg lower, vs 4.0 with placebo | 2.2% excluded for symptomatic hypotension during run-in period | During run-in period, 1.2% were at risk of serious hypotension and were hospitalized for 24 hours during the initiation of the drug |
| US Carvedilol Heart Failure Study Group9 | Carvedilol | 9% (4% placebo) | No significant SBP drop | SBP < 85 mm Hg | 0.3% discontinuation due to hypotension |
| COPERNICUS10,11 | Carvedilol | 1.9% (1.6% placebo) | NR | NR | Subjects with lowest blood pressure experienced greatest cardiovascular benefit |
| CIBIS-II12 | Bisoprolol | NR | NR | SBP < 100 mm Hg | Less hospitalizations for hypotension in bisoprolol arm (3 VS 11; P = .03) |
| MERIT-HF13 | Metoprolol | NR | SBP decreased less than placebo (−2.1 VS 3.5; P = .013) | Supine SBP < 100 mm Hg | Relative-risk of primary outcome was lower in the lower SBP tertile; < 1% discontinuation due to hypotension |
| ATLAS14 | Lisinopril | 11% (high-dose group), 7% (low-dose group) | SBP decreased 4.4 mm Hg more in the high-dose group vs low-dose group; P < .001 | No predefined numeric threshold for definition | 0.6% (low-dose group) and 0.8% (high-dose group) discontinuation due to hypotension |
| Val-HeFT15 | Valsartan | NR | At 1-year, SBP 5.2 mm Hg lower, vs 1.3 mm Hg lower with placebo | Titration required standing SBP ≥ 90 mm Hg, absence of symptomatic hypotension, and serum creatinine concentration < 2.0 mg/dL or < 50% higher than baseline concentration | 1.3% (0.8% placebo) discontinuation due to hypotension; P = .124 |
| CHARM-Alternative16 | Candesartan | 14.1% (11.7% placebo) | SBP 4.4 mm Hg lower vs placebo | None | 3.7% (placebo 0.9%) discontinuation due to hypotension; P < .0001 |
| PARADIGM-HF17 | Sacubitril-valsartan | 14% symptomatic (9.2% enalapril), 2.7% symptomatic with SBP < 90 mm Hg (1.4% enalapril) | SBP 3.2 mm Hg lower vs enalapril; P < .001 | SBP < 100 mm Hg at screening, SBP < 95 mm Hg at randomization, or symptomatic hypotension | Double run-in period, likely leading to underestimation of risks; 0.9% (0.7% with enalapril) discontinuation due to hypotension |
| PIONEER-HF18 | Sacubitril-valsartan | 15% symptomatic (12.7% enalapril) | NR | SBP < 100 mm Hg for preceding 6 hours | 2.5% (2.5% with enalapril) rate of discontinuation due to hypotension |
| TRANSITION19 | Sacubitril-valsartan | 12.7% predischarge, 9.5% postdischarge | NR | SBP < 100 mm Hg for preceding 6 hours | 0.7% rate of discontinuation due to hypotension; SBP ≥ 120 mm Hg was predictor of successful titration |
| EPHESUS20 | Eplerenone | NR | No significant difference | None | Mean blood pressure increased by 5 mm Hg in the eplerenone group (vs 8 mm Hg in the placebo); P < .01 |
| EMPHASIS-HF21 | Eplerenone | 3.4% (2.7% placebo) | SBP 2.5 mm Hg lower, vs 0.3 with placebo | None | NR |
| DAPA-HF22 | Dapagliflozin | 0.3% (0.5% placebo) asymptomatic and 0.1% (0.2% placebo) symptomatic | SBP 1.92 mm Hg lower, vs 0.38 with placebo; P = .002 | SBP < 95 mm Hg | NR |
| EMPEROR-Reduced23 | Empagliflozin | 9.4% (8.7% placebo) asymptomatic and 5.7% (5.5% placebo) symptomatic | SBP 2.4 mm Hg lower, vs 1.7 with placebo | Symptomatic hypotension and/or SBP < 100 mm Hg at screening | Baseline SBP and the risk of primary end points were inversely related |
HF = heart failure; NR = not reported; SBP = systolic blood pressure