Table 1.
Summary of major HFrEF treatment clinical trials.
| Year | Reference | Patient Characteristics | Treatment | Mean Follow Up | Primary Endpoint | Secondary Endpoint | Comments |
|---|---|---|---|---|---|---|---|
| Beta blockers | |||||||
| 1994 | CIBIS [18] | 641 patients with chronic HF NYHA III–IV, LVEF < 40% | 1.25–5 mg of bisoprolol vs. placebo | 1.9 years | Mortality with bisoprolol vs. placebo HR 0.80 (95% CI: 0.56–1.15, p = 0.22) |
NS in SCD rate, NS mortality rate related to VT/VF, improved functional status of patients on bisoprolol | |
| 1999 | CIBIS-II [19] | 2647 NYHA III–IV patients, LVEF ≤ 35%, receiving standard therapy with diuretics and ACEi |
Bisoprolol 1.25–10 mg vs. placebo | 1.3 years | All-cause mortality with bisoprolol vs. placebo HR 0.66 (95% CI: 0.54–0.81, p < 0.0001) |
Bisoprolol improved sudden deaths HR 0.56 95% (CI: 0.39–0.80, p = 0.0011) | Terminated early, after the second interim analysis, because of a significant mortality benefit |
| 1999 | MERIT-HF [20] | 3991 patients with chronic HF in NYHA functional class II–IV and with LVEF ≤ 40%, stabilized with optimal standard therapy | Metoprolol CR/XL 12.5 mg (NYHA III–IV) or 25.0 mg once daily (NYHA II), target dose 200 mg up-titrated over 8 weeks vs. placebo | 1 year | All-cause mortality with metoprolol CR/XL vs. placebo HR 0.66 (95% CI 0.53–0.81, p = 0.00009 or adjusted for interim analyses p = 0.0062) |
Metoprolol CR/XL improved sudden deaths HR 0.59 (CI: 0.45–0.78, p = 0.0002) and deaths from worsening HF HR 0.51 (CI: 0.33–0.79, p = 0.0023) | Terminated early because of a significant mortality benefit |
| 2002 | COPERNICUS [21] | 2289 patients with HF symptoms at rest or on minimal exertion and with LVEF < 25% | Carvedilol 3.125 mg twice daily up-titrated to 25 mg twice daily vs. placebo | 10.4 months | Combined risk of mortality or CV hospitalization HR 0.73 (95% CI: 0.63–0.86, p = 0.00002) Combined risk of mortality or HF hospitalization HR 0.69 (95% CI: 0.59–0.81, p = 0.000004) |
Carvedilol improved all-cause LOHS HR 0.73 (p = 0.0005) and LOHS for HF HR 0.6 (p < 0.0001) | |
| ACE Inhibitors | |||||||
| 1987 | CONSENSUS [23] | 253 patients with severe CHF NYHA functional class IV | Enalapril initial dose of 5 mg twice daily to a maximal dose of 20 mg twice daily vs. placebo | 188 days | Overall 6-month mortality with enalapril vs. placebo HR 0.6 (p = 0.002) 1-year mortality with enalapril vs. placebo HR 0.69 (p = 0.001) Mortality at the end of the study with enalapril vs. placebo HR 0.73 (p = 0.003) |
Enalapril improved mortality, reduced heart size, and reduced requirement for other HF medication | Terminated early because of a significant mortality benefit |
| 1992 | SAVE [27] | 2231 patients with LVEF ≤ 40%, but without overt HF or symptoms of myocardial ischemia | Captopril 12.5 mg up-titrated to 50 mg three times daily vs. placebo | 3 years after randomization | All-cause mortality with captopril vs. placebo HR 0.79 (95% CI: 0.65–0.97, p = 0.019) CV death HR 0.79 (95% CI: 0.65–0.95, p = 0.014) MI HR 0.75 (95% CI: 0.6–0.95, p = 0.012) |
Captopril reduced risk for the development of severe HF HR 0.63 (95% CI: 0.5–0.8, p < 0.001), for CHF requiring hospitalization HR 0.78 (95% CI: 0.63–0.96, p = 0.019), and for recurrent MI HR 0.75 (95% CI: 0.6–0.95, p = 0.015) | |
| Angiotensin Receptor Blockers | |||||||
| 2001 | Val-HeFT [28] | 5010 patients with NYHA class II, III, or IV | Valsartan 40 mg twice daily up-titrated to 160 mg of valsartan or placebo twice daily | 23 months | Mortality and morbidity combined endpoint with valsartan vs. placebo HR 0.87 (97.5% CI: 0.77–0.97) Risk with valsartan HR 0.87 (97.5% CI: 0.77–0.97) |
Valsartan reduced the risk of HF hospitalization by 27.5% (p < 0.001), improved NYHA classification in patients, and relieved worsening outcomes (p < 0.001) | Combined endpoints benefit −24% reduction in the rate of adjudicated hospitalizations for worsening HF as a first event in those receiving valsartan |
| 2003 | CHARM [30] | 4576 CHF patients with NYHA class II–IV with LVEF ≤ 40% | Candesartan 4 mg once daily up-titrated to a maximal dose of 32 mg once daily vs. placebo | Median 40 months |
Risk of CV mortality or CHF hospitalization with candesartan vs. placebo HR 0.82 (95% CI: 0.74–0.90) Risk at 1 year, less 30% p < 0.001 Risk at 2 years, less 23% p < 0.001 All-cause mortality at 1 year, less 33% p < 0.001 All-cause mortality at 2 years, less 20% p = 0.001 |
Candesartan improved CHF hospitalization HR 0.76 (95% CI: 0.68–0.85, p < 0.001), CV mortality HR 0.84 (95% CI: 0.75–0.95, p = 0.005) | |
| Mineralocorticoid Receptor Antagonists | |||||||
| 1999 | RALES [31] | 1663 CHF patients in NYHA class III or IV, treated with ACEi and loop diuretic, and had LVEF ≤ 35% | Spironolactone 25 mg once daily up-titrated to 50 mg once daily | 2 years | Mortality with spironolactone vs. placebo HR 0.70 (95% CI: 0.60–0.82, p < 0.001) by a Cox proportional-hazards model Cardiac mortality HR 0.69 (95% CI, 0.58–0.82, p < 0.001) |
Spironolactone reduced the risk of cardiac hospitalization HR 0.70 (95% CI: 0.59–0.82, p < 0.001), and improved the NYHA classification in patients | The trial was discontinued early |
| 2003 | EPHESUS [32] | 6200 patients, 3 to 14 days after acute MI with symptomatic HF and LVEF ≤ 40% | Eplerenone 25 mg per day initially, titrated to a maximum of 50 mg per day vs. placebo | 16 months | All-cause mortality with eplerenone vs. placebo HR 0.85 (p = 0.008), Risk of CV mortality or CV hospitalization HR 0.87 (p = 0.002) Risk of all-cause mortality or any hospitalization HR 0.92 (p = 0.02) |
Eplerenone reduced the risk of SCD HR 0.79 (p = 0.03), reduced the risk of HF hospitalization 0.85 (p = 0.03), and reduced the episodes of HF hospitalization HR 0.77 (p = 0.002) | |
| 2011 | EMPHASIS-HF [33] | 2737 patients > 55 years, with NYHA class II HF and LVEF ≤ 35% | Eplerenone 25 mg per day initially, titrated to a maximum of 50 mg per day vs. placebo | Median 21 months |
All-cause mortality or HF hospitalization with eplerenone vs. placebo HR 0.63 (95% CI: 0.54–0.74, p < 0.001) | Eplerenone reduced all-cause mortality or HF hospitalization HR 0.65 (95% CI: 0.55–0.76, p < 0.001), reduced all-cause mortality HR 0.76 (95% CI: 0.62–0.93, p = 0.008), reduced CV mortality HR 0.76 (95% CI, 0.61–0.94, p = 0.01), and reduced HF hospitalization HR 0.58 (95% CI: 0.47–0.70, p < 0.001) | The trial was discontinued early |
| Nitrates and Hydralazine | |||||||
| 1986 | V-HeFT [34] | 642 chronic CHF patients already taking furosemide and digoxin | 40 mg isosorbide dinitrate and 75 mg hydralazine administered four times daily compared to prazosin (5 mg four times daily) and to a placebo | 2.3 years | For mortality by two years the risk reduction among patients treated with both hydralazine and isosorbide dinitrate was 34 percent (p < 0.028) | The cumulative mortality rates at two years were 25.6 percent in the hydralazine–isosorbide dinitrate group and 34.3 percent in the placebo group; at three years, the mortality rate was 36.2 percent versus 46.9 percent | |
| 2004 | A-HeFT [35] | 1050 black patients who had NYHA class III or IV HF with dilated ventricles | 37.5 mg of hydralazine hydrochloride and 20 mg of isosorbide dinitrate three times daily to a total daily dose of 225 mg of hydralazine hydrochloride and 120 mg of isosorbide dinitrate | 10 months | All-cause mortality with combined hydralazine hydrochloride and isosorbide dinitrate vs. placebo HR 0.57 (p = 0.01) by the log-rank test | Combined hydralazine hydrochloride and isosorbide dinitrate reduced first HF hospitalizations by 33% (p = 0.001) and improved the quality-of-life scores (p = 0.02) | Terminated early because of a significant mortality benefit |
| Angiotensin Receptor Neprilysin Inhibitor | |||||||
| 2014 | PARADIGM-HF [48] | 8442 patients with class II, III, or IV HF and LVEF ≤ 40% | Treatment with either enalapril (at a dose of 10 mg twice daily) or LCZ696 (at a dose of 200 mg twice daily) | Median 27 months |
Risk of CV mortality or HF hospitalization with LCZ696 vs. placebo HR 0.80 (95% CI: 0.73–0.87, p < 0.001) | LCZ696 reduced CV mortality HR 0.80 (95% CI: 0.71–0.89, p < 0.001), reduced HF hospitalization HR 0.79 (95% CI: 0.71–0.89, p < 0.001), and reduced all-cause mortality HR 0.84 (95% CI: 0.76–0.93, p < 0.001) | The trial was discontinued early |
| 2019 | PIONEER-HF [41] | 881 patients with LVEF ≤ 40%, elevated NT-proBNP/BNP, and received a primary diagnosis of acute decompensated HF, including signs and symptoms of fluid overload | The initial dose of sacubitril–valsartan (either 24 mg of sacubitril with 26 mg of valsartan or 49 mg of sacubitril with 51 mg of valsartan as a fixed-dose combination) or enalapril (either 2.5 mg or 5 mg) was administered orally twice daily | 8 weeks | Time-averaged reduction in NT-proBNP with sacubitril–valsartan vs. enalapril HR 0.71 (95% CI: 0.63–0.81, p < 0.001) | NS worsening renal function, hyperkalemia, and symptomatic hypotension between sacubitril–valsartan vs. enalapril; sacubitril-valsartan reduced the rate of rehospitalization HR 0.56 (CI: 0.37–0.84) and reduced composite of serious clinical events HR 0.54 (CI: 0.37–0.79) | |
| Hyperpolarization-activated Cyclic Nucleotide (HCN) Channel Inhibitor | |||||||
| 2010 | SHIFT [36] | 6558 patients with LVEF ≤ 35%, sinus rhythm with heart rate ≥ 70 beats per minute | Ivabradine titrated to a maximum of 75 mg twice daily or matching placebo | Median 22.9 months |
Risk of CV mortality or worsening HF hospitalization with ivabradine vs. placebo HR 0.82 (95% CI: 0.75–0.90, p < 0.0001) Risk of worsening HF hospitalization HR 0.74 (95% CI: 0.66–0.83, p < 0.0001) Risk of HF mortality HR 0.74 (95% CI: 0.58–0.94, p = 0.014) |
Ivabradine reduced serious adverse events (p = 0.025), increased symptomatic bradycardia (p < 0.0001), and increased visual side-effects (p < 0.0001) | |
| Sodium–glucose transport-2 (SGLT2) inhibitors | |||||||
| 2015 | EMPA-REG [60] | 7020 patients with type 2 diabetes with established CV disease | Empagliflozin 10 mg, empagliflozin 25 mg, or placebo (1:1:1) | Primary outcome with empagliflozin vs. placebo HR 0.86 (95.02% CI: 0.74–0.99, p < 0.001 for noninferiority, p = 0.04 for superiority) | Empagliflozin reduced the key secondary outcome HR 0.89 (95% CI: 0.78–1.01, p < 0.001 for noninferiority, p = 0.08 for superiority) | ||
| 2019 | DECLARE TIMI [62] | 17,160 patients, including 10,186 without atherosclerotic CV disease but with risk factors | Dapagliflozin 10 mg or matching placebo | Median 4.2 years |
Risk of mortality from CV causes or HF hospitalization with dapagliflozin vs. placebo HR 0.83 (95% CI: 0.73–0.95, p = 0.005) | Dapagliflozin reduced the incidence of renal composite outcome (>40% decrease in GFR to <60 mL/min/1.73 m2, ESRD, or death from renal or CV cause) HR 0.76 (95% CI: 0.67–0.87) | |
| 2017 | CANVAS [63] | 9734 type 2 diabetes patients and ≥30 years, with a history of symptomatic atherosclerotic CV disease, or ≥50 years with two or more risk factors for CV disease | Canagliflozin 300 mg, 100 mg compared to placebo | 188.2 weeks, median 126.1 weeks |
Primary outcome with canagliflozin vs. placebo HR 0.86 (95% CI: 0.75–0.97, p < 0.001 for noninferiority, p = 0.02 for superiority) | Canagliflozin improved the progression of albuminuria HR 0.73 (95% CI: 0.67–0.79) and improved the composite outcome of a sustained 40% reduction in eGFR, the need for renal replacement therapy, or death from renal causes HR 0.60 (95% CI: 0.47–0.77) | |
| 2019 | DAPA-HF [64] | 4744 patients with LVEF ≤ 40% and NYHA functional class II, III, or IV symptoms | Dapagliflozin 10 mg once daily vs. matching placebo | Median 18.2 months |
Risk of mortality from CV causes or HF hospitalization/visit with dapagliflozin vs. placebo HR 0.74 (95% CI: 0.65–0.85, p < 0.001) | Dapagliflozin reduced HF hospitalizations or CV mortality HR 0.75 (95% CI: 0.65–0.85, p < 0.001) | |
| 2020 | EMPEROR-reduced [65] | 3730 patients with class II, III, or IV HF and LVEF ≤ 40% | Empagliflozin 10 mg once daily or placebo | Median 16 months |
Risk of mortality from CV causes or HF hospitalization with empagliflozin vs. placebo HR 0.75 (95% CI: 0.65–0.86, p < 0.001) The effect of empagliflozin was consistent in patients regardless of the presence or absence of diabetes |
Empagliflozin reduced HF hospitalizations vs. placebo HR 0.70 (95% CI: 0.58–0.85, p < 0.001), slowed the annual decline rate in eGFR (p < 0.001), and reduced the risk of serious renal outcomes | |
| 2021 | SOLOIST-WHF [67] | 1222 type 2 diabetes patients, recently hospitalized due to symptoms of HF, and received treatment with intravenous diuretic therapy | 200 mg of sotagliflozin once daily (with a dose increase to 400 mg, depending on side effects) or placebo | Median 9.2 months |
Rate of primary endpoint events with sotagliflozin vs. placebo HR 0.67 (95% CI: 0.52–0.85, p < 0.001) for an absolute difference of 25.3 events per 100 patient-years (95% CI: 5.1–45.6) | Sotagliflozin reduced CV mortality rates HR 0.84 (95% CI: 0.58–1.22) and reduced all-cause mortality rates, HR 0.82 (95% CI: 0.59–1.14) | |
| 2020 | VERTIS-CV [68] | 8246 type 2 diabetes patients with atherosclerotic CV disease | 5 mg or 15 mg of ertugliflozin or placebo | 3.5 years | Risk of mortality from CV causes or HF hospitalization with ertugliflozin vs. placebo HR 0.88 (95.8% CI: 0.75–1.03, p = 0.11 for superiority) | Ertugliflozin reduced CV mortality HR 0.92 (95.8% CI: 0.77–1.11) and reduced mortality from renal causes, renal replacement therapy, or doubling of the serum creatinine level HR 0.81 (95.8% CI: 0.63–1.04) | Major adverse CV events occurred in 653 of 5493 ertugliflozin patients (11.9%) vs. 327 of 2745 placebo patients (11.9%) (HR, 0.97; 95.6% CI, 0.85–1.11; p < 0.001 for noninferiority) |
| Soluble guanylate cyclase (sGC) stimulator | |||||||
| 2015 | SOCRATES-Reduced [87] | 351 clinically stable patients with LVEF < 45% within 4 weeks of a worsening chronic HF event, defined as worsening signs and symptoms of congestion and elevated natriuretic peptide level, requiring hospitalization or outpatient intravenous diuretic | Placebo or 1 of 4 daily target doses of oral vericiguat (1.25 mg, 2.5 mg, 5 mg, 10 mg for 12 weeks) | 12 weeks | Δlog-transformed NT-proBNP (baseline to week 12) with pooled vericiguat vs. placebo HR 0.885 (90% CI: 0.73–1.08, p = 0.15) | Higher vericiguat doses were associated with greater reductions in NT-proBNP, in a dose–response manner (p < 0.02) | Vericiguat 10 mg reduced rates of any adverse event vs. placebo (71.4% vs. 77.2%, respectively) |
| 2020 | VICTORIA [88] | 5050 patients with chronic HF (New York Heart Association class II, III, or IV) and LVEF < 45% | Vericiguat (target dose, 10 mg once daily) or placebo | Median 10.8 months |
Risk of mortality from CV causes or HF hospitalization with vericiguat vs. placebo HR 0.90 (95% CI: 0.82–0.98, p = 0.02) | Vericiguat reduced HF hospitalizations HR 0.90 (95% CI: 0.81–1.00) and reduced CV mortality HR 0.93 (95% CI: 0.81–1.06) | |
| Cardiac-specific myosin activator | |||||||
| 2016 | ATOMIC-AHF [95] | 606 patients admitted with acute decompensated HF and LVEF ≤ 40%, dyspnea, and elevated plasma concentrations of natriuretic peptides | Received 48-h intravenous infusion of placebo or omecamtiv mecarbil in 3 sequential, escalating-dose cohorts | 30 days | Primary endpoint of dyspnea relief and secondary outcomes with omecamtiv mecarbil (3 dosages) vs. placebo (OM cohort 1, 42%; cohort 2, 47%; cohort 3, 51%; placebo, 41%; p = 0.33) | Omecamtiv mecarbil improved dyspnea relief at 48 h (p = 0.034) and through 5 days (p = 0.038) in the high-dose cohort | NS adverse event profile and tolerability with OM vs. placebo, without increases in ventricular or supraventricular tachyarrhythmias |
| 2016 | COSMIC-HF [96] | 299 patients with stable, symptomatic chronic HF and LVEF ≤ 40% | Received 25 mg oral omecamtiv mecarbil twice daily (fixed-dose group), 25 mg twice daily titrated to 50 mg twice daily guided by pharmacokinetics (pharmacokinetic titration group), or placebo for 20 weeks | 24 weeks | Mean maximum concentration of omecamtiv mecarbil at 12 weeks was 200 ± 71 ng/mL in the fixed-dose group and 318 ± 129 ng/mL in the pharmacokinetic titration group | Omecamtiv mecarbil improved systolic ejection time (95% CI: 18–32, p < 0.0001), stroke volume (CI: 0.5–6.7, p = 0.0217), LVESD (CI: −2.9 to −0.6, p = 0.0027), LVEDD (CI: −2.3 to 0.3, p = 0.0128), heart rate (CI: −5.1 to −0.8, p = 0.0070), and NT-proBNP concentration in plasma (p = 0.0069) | |
| 2021 | GALACTIC-HF [97] | 8256 patients (inpatients and outpatients) with symptomatic chronic HF and LVEF ≤ 35% | Omecamtiv mecarbil (using pharmacokinetic-guided doses of 25 mg, 37.5 mg, or 50 mg twice daily) or placebo | Median 21.8 months |
Risk of CV mortality or HF hospitalization/visit with omecamtiv mecarbil vs. placebo HR 0.92 (95% CI: 0.86–0.99, p = 0.03) | NS CV mortality with omecamtiv mecarbil HR 1.01 (95% CI: 0.92–1.11), and NS in the change from baseline on the Kansas City Cardiomyopathy Questionnaire total symptom score | NS frequency of cardiac ischemic and ventricular arrhythmia events with OM vs. placebo |
AF—atrial fibrillation, SR—sinus rhythm, ACEi—angiotensin-converting enzyme, ARNi—angiotensin receptor–neprilysin inhibitor, eGFR—estimated glomerular filtration rate, MRA—mineralocorticoid receptor antagonist, SGLT2i—sodium–glucose transport protein inhibitor.