Table 1 Characteristics of included RCTs
Trial | Number | Follow-up | Patient | Inclusion criteria | Age (years) | Male (%) | ACEI/ARB | Dosage | Baseline DM (%) | Main outcome |
|---|---|---|---|---|---|---|---|---|---|---|
EVALUATE-HF | 464 | 12 weeks | HFrEF | Age ≥ 50 years, hypertension, CHF, and EF ≤ 40%, NYHA I–III | 67.8 ± 9.8 vs 66.7 ± 8.5 | 355 (77) | Enalapril | 200mg bid vs 10mg bid | Treatment of HFrEF with sacubitril/valsartan, compared with enalapril, did not significantly reduce central aortic stiffness | |
NCT01785472 | 1434 | 8 weeks | Not all-HF | Mean sitting SBP ≥ 140 to < 180 mm Hg | (57.5 ± 10.17, 58.1 ± 9.71) vs 57.4 ± 10.14 | 756 (53) | Olmesartan | 200/400 mg qd vs 20mg qd | 156 (16) vs 77 (16) | Treatment with sacubitril/valsartan once daily is effective and provided superior BP reduction than olmesartan in Asian patients with mild-to-moderate hypertension |
PARAMOUNT | 301 | 3 months | HFpEF | NYHA II–III HFpEF, EF > 45% | 70.9 ± 9.4 vs 71.2 ± 8.9 | 152 (57) | Valsartan | 200mg bid vs 160mg bid | 61 (41) vs 53 (35) | Sacubitril/valsartan has a better effect on reducing BNP and improving LA reverse remodeling and NYHA compared with valsartan in patients with HFpEF |
PIONEER-HF | 875 | 8 weeks | HFrEF | Hemodynamic stabilisation after ADHF and EF ≤ 40% | 61 (51, 71) vs 63 (54, 72) | 635 (72.1) | Enalapril | 200mg bid vs 10mg bid | 79 (18) vs 89 (20) | Among patients with HFrEF who were hospitalised for ADHF, the initiation of sacubitril/valsartan therapy led to a greater reduction in the NT-proBNP concentration than enalapril therapy |
OUTSTEP-HF | 619 | 12 weeks | HFrEF | NYHA II and LVEF ≤ 40% | 66.89 ± 10.74 | 487 (79) | Enalapril | 200mg bid vs 10mg bid | 96 (31) vs 117 (38) | There was no significant benefit of sacubitril/valsartan either 6MWT or in daytime physical activity measured by actigraphy compared with enalapril |
PARALLEL-HF | 223 | 33.9 months | HFrEF | NYHA II–IV and EF ≤ 35% | 69.0 ± 9.7 vs 66.7 ± 10.9 | 192 (86) | Enalapril | 200mg bid vs 10mg bid | 52 (47) vs 52 (46) | In Japanese patients with HFrEF, there was no difference in reduction in the risk of cardiovascular death or HF hospitalisation between sacubitril/valsartan and enalapril |
PARALLAX | 2564 | 24 weeks | HFpEF | NYHA II–IV, EF > 40%, LV hypertrophy or left atrial enlargement with NT-proBNP↑ | 73 ± 8.4 vs 72 ± 8.6 | 1265 (49) | Enalapril/valsartan | 200mg bid vs 10mg bid vs 160mg | 566 (44) vs 589 (46) | Among patients with HFpEF, sacubitril/valsartan treatment compared with standard renin-angiotensin system inhibitor treatment or placebo resulted in a significantly greater decrease in NT-proBNP levels at 12 weeks but did not significantly improve 6MWT at 24 weeks |
PARADIGM-HF | 8442 | 27 months | HFrEF | NYHA II–IV, EF ≤ 40% | 63.8 ± 11.5 vs 63.8 ± 11.3 | 6567 (78) | Enalapril | 200mg bid vs 10mg bid | 1451 (35) vs 1456 (35) | Sacubitril/valsartan was superior to enalapril in reducing the risk of death and of hospitalisation for HFrEF |
PARAGON-HF | 4821 | 26 months | HFpEF | NYHA II–IV, EF ≥ 45% | 72.7 ± 8.3 vs 72.8 ± 8.5 | 2317 (48) | Valsartan | 200mg bid vs 160mg bid | 1046 (44) vs 1016 (43) | Sacubitril/valsartan did not result in a significantly lower rate of total hospitalisations for HF and death from cardiovascular causes among patients with HFpEF |
UK HARP-III | 414 | 12 months | Not all-HF | eGFR ≥ 45 and < 60 mL/min/1.73m2 and uACR > 20; or eGFR ≥ 20 and < 45 mL/min/1.73m2 | 62.0 ± 14.1 vs 63.6 ± 13.4 | 298 (72) | Irbesartan | 200mg bid vs 300mg qd | 81 (39) vs 83 (40) | In people with chronic kidney disease, sacubitril/valsartan is well-tolerated and has similar effects on kidney function and albuminuria to irbesartan |
HFN-LIFE | 335 | 24 weeks | HFrEF | Advanced HFrEF, SBP ≥ 90 mmHg, NT-proBNP ≥ 800 pg/mL or BNP ≥ 250 pg/mL | 60.2 ± 13.4 vs 58.3 ± 13.1 | 245 (73) | Valsartan | 200mg bid vs 160mg bid | 74 (44) vs 83 (49) | In patients with chronic advanced HFrEF, there was no statistically significant difference between sacubitril/valsartan and valsartan with respect to reducing NT-proBNP levels |
AARDVARK | 224 | 2 years | Not all-HF | Abdominal aortic aneurysms, SBP < 150 mmHg | 71.6 ± 6.9 vs 70.7 ± 7.5 | 211 (94.2) | Perindopril | 10mg qd vs 10mg qd | 2 (3) vs 8 (10) | No evidence that in patients with systolic BP of <150 mmHg, the rate of growth of small AAAs is slowed by the administration of the ACE-I perindopril compared with placebo and that modest BP lowering did not beneficially impact on the growth of small AAAs |
NCT00591253 | 412 | 6 weeks | Non-HF | Essential hypertension, SBP 150–180 mm Hg and 24-h mean SBP 130–170 mm Hg | <45: 66 vs 36 46–64: 180 vs 85 >65: 29 vs 17 | 177 (42.9) | Azilsartan | 40/80 mg qd vs 40/80 mg qd | ||
TRAFIC | 58 | 48 weeks | Non-HF | Infected with HIV | 47 vs 50 | 41 (93.2) | Elmisartan | 40-80 mg qd vs 40–80 mg qd | ||
LIFE-HIV | 108 | 12 months | Non-HF | HIV infection, age > 50 years, SBP > 120 mmHg, GFR > 30 mL/min/1.73 m2 | 56 (53, 62) vs 56 (53, 61) | 104 (96) | Losartan | 100 mg qd vs 100 mg qd | 0 (0) vs 0 (0) | Among older PHIV with viral suppression, losartan did not improve blood measures of inflammation nor T-cell immune recovery |
ACTIVE I | 9016 | 4.1 years | Not all-HF | SBP of at least 110 mmHg | 69.5 ± 9.7 vs 69.6 ± 9.7 | 5475 (60.7) | Irbesartan | 300 mg qd vs 300 mg qd | 906 (20) vs 881 (20) | Irbesartan did not reduce cardiovascular events in patients with atrial fibrillation |
I-Preserve | 4126 | 49.5 months | HFpEF | Age ≥ 50 years and NYHA II, III, or IV HF and an EF ≥ 45% | 72 ± 7 vs 72 ± 7 | 1637 (39.7) | Irbesartan | 300 mg qd vs 300 mg qd | 564 (27) vs 570 (28) | Irbesartan did not improve the outcomes of patients with heart failure and a preserved left ventricular ejection fraction |
DIRECT-Prevent | 1420 | 4.7 years | Not all-HF | T1D diagnosed before age of 36 years and in need for continuous insulin treatment within 1 year of diagnosis of diabetes | 29.6 ± 8.0 vs 29.9 ± 8.1 | 805 (56.7) | Candesartan | 32 mg qd vs 32 mg qd | 710 (100) vs 710 (100) | Candesartan reduces the incidence of retinopathy |
DIRECT-Protect 1 | 1902 | 4.8 years | Not all-HF | Aged 18–55 years with T1D diagnosed before age of 36 years and in need for continuous insulin treatment within 1 year of diagnosis of diabetes | 31.5 ± 8.5 vs 31.9 ± 8.5 | 1091 (57.3) | Candesartan | 32 mg qd vs 32 mg qd | 951 (100) vs 951 (100) | We did not see a beneficial effect on retinopathy progression from candesartan |
DIRECT-Protect 2 | 1902 | 4 years | Not all-HF | Aged 37–75 years with T2D diagnosed at age of 36 years or thereafter | 56.9 ± 7.6 vs 56.8 ± 7.9 | 948 (49.8) | Candesartan | 32mg qd vs 32 mg qd | 949 (100) vs 953 (100) | Treatment with candesartan in T2D patients with mild to moderate retinopathy might induce improvement of retinopathy |
ORGENT | 565 | 3.4 years | Not all-HF | Clinical diagnosis of diabetic nephropathy in patients with T2D | 59.1 ± 8.1 vs 59.2 ± 8.1 | 391 (69.1) | Olmesartan | 10/20 mg qd vs 10/20 mg qd | 287 (100) vs 288 (100) | In T2D patients with overt nephropathy and renal insufficiency receiving concomitant antihypertensive agents including ACEI, treatment with olmesartan reduced proteinuria and BP but did not further improve renal outcomes |
Navigator | 4599 | 5.0/6.5 years | Not all-HF | Impaired glucose tolerance and either cardiovascular disease or cardiovascular risk factors to receive nateglinide | 63.7 ± 6.91 vs 63.9 ± 6.88 | 2318 (49.7) | Valsartan | 160 mg qd vs 160 mg qd | 0 (0) vs 0 (0) | Among persons with impaired glucose tolerance and established cardiovascular disease or cardiovascular risk factors, assignment to nateglinide for 5 years did not reduce the incidence of diabetes or the coprimary composite cardiovascular outcomes |
HOPE (no-DM) | 5720 | 4.5 years | Non-HF | Older than 55 years without known diabetes but with vascular disease | 66.3 ± 6.7 vs 65.9 ± 6.9 | 4562 (79.7) | Ramipril | 2.5 mg qd vs 2.5 mg qd | 0 (0) vs 0 (0) | Ramipril is associated with lower rates of new diagnosis of diabetes in high-risk individuals |
MICRO-HOPE | 3577 | 4.5 years | Non-HF | Had evidence of vascular disease plus one other cardiovascular risk factor and not a low EF or HF, and diabetes | 65.3 ± 6.4 vs 65.6 ± 6.6 | 2255 (63.0) | Ramipril | 2.5 mg qd vs 2.5 mg qd | 1808 (100) vs 1769 (100) | Ramipril was beneficial for cardiovascular events and overt nephropathy in people with diabetes. The cardiovascular benefit was greater than that attributable to the decrease in blood pressure |
SCOPE | 4923 | 3.7 years | Not all-HF | Aged 70–89 years, with SBP 160–179 mmHg, and/or DBP 90–99 mmHg, and a MMSE test score > 24 | 76.4 vs 76.4 | 1748 (35.5) | Candesartan | 8 mg qd vs 8 mg qd | 308 (12) 285 (12) | In elderly hypertensive patients, a slightly more effective blood pressure reduction during candesartan-based therapy, compared with control therapy, was associated with a modest, statistically nonsignificant, reduction in major cardiovascular events and with a marked reduction in non-fatal stroke |
DREAM | 5269 | 3 years | Non-HF | Without cardiovascular disease but with impaired fasting glucose levels (after an 8-h fast) or impaired glucose tolerance | 54.7 ± 10.9 vs 54.7 ± 10.9 | 2149 (40.8) | Ramipril | 15 mg qd vs 15 mg qd | 0 (0) vs 0 (0) | Among persons with impaired fasting glucose levels or impaired glucose tolerance, the use of ramipril for 3 years does not significantly reduce the incidence of diabetes or death but does significantly increase regression to normoglycaemia |
TRANSCEND | 5926 | 56 months | Non-HF | Intolerant to ACEI with cardiovascular disease or diabetes with end-organ damage | 66.9 ± 7.3 vs 66.9 ± 7.4 | 3379 (57.0) | Telmisartan | 80 mg qd vs 80 mg qd | 1059 (36) vs 1059 (36) | Telmisartan could be regarded as a potential treatment for patients with vascular disease or high-risk diabetes, if they are unable to tolerate an ACE inhibitor |
CHARM (non-DM) | 5436 | 2–4 years | HF | Complementary populations of patients with symptomatic HF not known to have DM at baseline | 66 ± 11 vs 66 ± 12 | 1685 (31.0) | Candesartan | 32 mg qd vs 32 mg qd | 0 (0) vs 0 (0) | The angiotensin-receptor blocker candesartan appears to prevent diabetes in HF patients |
SOLVD (non-DM) | 291 | 3.4 years | HFrEF | Asymptomatic left ventricular dysfunction with congestive HF (EF ≤ 35%) | 56.1 ± 10.1 vs 56.8 ± 10.0 | 268 (92.1) | Enalapril | 5/20 mg qd vs 5/20 mg qd | 0 (0) vs 0 (0) | Enalapril significantly reduces the incidence of diabetes in patients with left ventricular dysfunction, especially those with impaired fasting plasma glucose |
PEACE | 8290 | 7 years (median, 4.8) | Not all-HF | Stable coronary artery disease and normal or near-normal left ventricular function | 64 ± 8 vs 64 ± 8 | 6798 (82.0) | Trandopril | 4 mg qd vs 4 mg qd | 748 (18) vs 661 (16) | In patients with stable coronary heart disease and preserved left ventricular function who are receiving “current standard” therapy and in whom the rate of cardiovascular events is lower than in previous trials of ACE inhibitors in patients with vascular disease, there is no evidence that the addition of an ACE inhibitor provides further benefit in terms of death from cardiovascular causes, myocardial infarction, or coronary revascularisation |
Jean | 2553 | 2.95 years (median) | Not all-HF | Post-CABG 7 d, stable after operation, 18 y old, LVEF ≥ 40% | 61 ± 10 vs 61 ± 10 | 2229 (87) | Quinapril | 40 mg qd vs 40 mg qd | 121 (9) vs 132 (10) | In patients at low risk of cardiovascular events after CABG, routine early initiation of ACEI therapy does not appear to improve clinical outcome up to 3 years after CABG |