Table 4. Evidence of foundational therapies in patients with HFmrEF.
| Drug class/drug name | Trial name | Number of patients | Inclusion LVEF (patient number) | Primary endpoints | Effect on primary endpoint by LVEF, HR (95% CI) (p value) | Pint | Effect on HHF by LVEF, HR (95% CI) (p value) | Pint | ||||||
| ACEI/perindopril | PEP-CHF38 | 850 | < 40% (0) | 41-49% (850) | ≥ 50% (0) | All-cause death + HHF | < 40%, – | 41-49%, HR: 0.69 (0.47-1.01) (p = 0.055) | ≥ 50%, – | – | < 40%, – | 41-49%, HR: 0.63 (0.41-0.97) (p = 0.033) | ≥ 50%, – | – |
| ARB/candesartan | CHARM-Program23 | 7598 | < 40% (4,323) | 41-49% (1,322) | ≥ 50% (1,953) | CV death + HHF | < 40%, HR: 0.82 (0.75-0.91) (p < 0.001) | 41-49%, HR: 0.76 (0.61-0.96) (p = 0.02) | ≥ 50%, HR: 0.95 (0.79-1.14) (p = 0.57) | 0.27 | < 40%, HR: 0.68* (0.58-0.80) (p < 0.001) | 41-49%, HR: 0.48* (0.33-0.70) (p < 0.001) | ≥ 50%, HR: 0.78* (0.59-1.03) (p = 0.08) | 0.60 |
| ARNI | PARADIGM/PARAGON Pooled24 | 13195 | 32.5-42.5% (3,143) | 42.5-52.5% (1,427) | 52.5-62.5% (2,166) | CV death + HHF | 32.5-42.5%, HR: 0.81 (0.69-0.94) (p = 0.005) | 42.5-52.5%, HR: 0.89 (0.73-1.10) (p = 0.28) | 52.5-62.5%, HR: 0.89, (0.74-1.06) (p = 0.05) | 0.05 | 32.5-42.5%, HR: 0.81 (0.69-0.94) (p = 0.005) | 42.5-52.5%, HR: 0.89 (0.73-1.10) (p = 0.28) | 52.5-62.5%, HR: 0.89 (0.74-1.06) (p = 0.05) | 0.15 |
| Beta-blocker | 11 trials/Meta-analysis22 | 14262 | – | 41-49% (5,750) | ≥ 50% (244) | All-cause death or CV death | – | 41-49%, HR: 0.59 (0.34-1.03) (p = 0.066) | ≥ 50%, HR: 1.79 (0.78-4.10) (p = 0.17) | NR | – | 41-49%#, HR: 0.48 (0.24-0.97) (p = 0.04) | ≥ 50%#, HR: 1.77 (0.61-5.14) (p = 0.29) | NR |
| MRA/eplerenone | TOPCAT20 | 1766 | 45 to < 50% (197) | 50 to 55% (289) | 55 to 60% (422) | CV death + HHF | 45 to < 50%, HR: 0.55 (0.33-0.91) | 50 to 55%, HR: 0.83 (0.56-1.25) | 55 to 60%, HR: 0.85 (0.60-1.21) | 0.069 | 45 to < 50%, HR: 0.60 (0.32-1.10) | 50 to 55%, HR: 0.80 (0.65-1.06) | 55 to 60%, HR: 0.70 (047-1.06) | 0.037 |
| SGLT2 inhibitor/empagliflozin | EMPEROR-Preserved11 | 5988 | < 50% (1,983) | 50 to < 60% (2,058) | ≥ 56% (1,947) | CV death + HHF | < 50%, HR: 0.71 (0.57-0.88) | 50 to < 60%, HR: 0.80 (0.64-0.99) | ≥ 56%, HR: 0.87 (0.69-1.10) | NR | NR | NR | NR | NR |
| SGLT2 inhibitor/empagliflozin | EMPEROR-Reduced/EMPEROR-Preserved pooled25 | 9718 | 35-44% (1,272) | 45-54% (2,260) | 55-64% (2,092) | CV death + HHF | 35-44%, HR: 0.82 (0.63-1.05) | 45-54%, HR: 0.74 (0.61-0.91) | 55-64%, HR: 0.78 (0.62-0.97) | NR | 35-44%, HR: 0.72 (0.52-0.98) | 45-54%, HR: 0.66 (0.50-0.86) | 55-64%, HR: 0.70 (0.53-0.92) | 0.32 |
| SGLT2 inhibitor/dapagliflozin | DELIVER12 | 6263 | < 49% (2,116) | 50 to 59% (2,256) | ≥ 60% (1,891) | CV death + WHF | < 49%, HR: 0.87 (0.72-1.04) | 50 to 59%, HR: 0.79 (0.65-0.97) | ≥ 60%, HR: 0.78 (0.62-0.96) | > 0.05 | > 44% and ≤ 51%†, HR: 0.83 (0.64-1.07) | > 51% and ≤ 60%†, HR: 0.66 (0.51-0.84) | ≥ 60%†, HR: 0.88 (0.64-1.22) | > 0.05 |
| SGLT1+2 inhibitor/sotagliflozin | SOLOIST-WHF9 | 1222 | < 50% | ≥ 50% | CV death + total HHF + urgent HF visit | < 50%, HR: 0.72 (0.56-0.94) | ≥ 50%, HR: 0.48 (0.27-0.86) |
* Recurrent heart failure hospitalization; # Cardiovascular death; † Data from Jhund et al.29 Data shown in bold characters are for HFmrEF.
ACEI, angiotensin converting enzyme inhibitor; ARB, angiotensin receptor blocker; ARNI, angiotensin receptor-neprilysin inhibitor; CI, confidence interval; CV, cardiovascular; HF, heart failure; HfmrEF, heart failure with mildly reduced ejection fraction; HHF, heart failure hospitalization; HR, hazard ratio; int, interaction; LVEF, left ventricular ejection fraction; MRA, mineralocorticoid receptor antagonist; NR, not reported; SGLT2 I, sodium-glucose co-transporter 2 inhibitor; WHF, worsening heart failure (heart failure hospitalization + urgent heart failure visit).