Network meta‐analysis of medical therapy efficacy in more than 90,000 patients with heart failure and reduced ejection fraction

Fig. 1. Network of the comparisons between different pharmacological treatments for the primary endpoint of all‐cause death. Each treatment (single drug or combination therapy) is represented by a node and is connected to the other treatments (either single drug class or a combination therapy), irrespective of the existence of head‐to‐head comparison. The thickness of the lines is proportional to the number of patients/years. Interventions with different molecules belonging to the same pharmacological class, for example, BB, were pooled together to form one node. ACEi, angiotensin converting enzyme inhibitors; ARB, angiotensin receptor blockers; ARNI, angiotensin receptor–neprilysin inhibitor; BB, beta blockers; DIGO, digoxin; IVA, ivabradine; MRA, mineralocorticoid receptor antagonists; OM, omecamtiv mecarbil; SGLT2i, sodium–glucose cotransporter 2 inhibitors; VERI, vericiguat.

Fig. 2. Results of the random‐effects network meta‐analysis for all‐cause death (a), cardiovascular death (b), heart failure hospitalization (c), and all‐cause hospitalization (d). The points and the bars represent the hazard ratios (HRs) and 95% credible intervals (CrI), respectively, for intervention versus placebo (i.e., none of the drugs evaluated in the randomized controlled trials). ACEi, angiotensin converting enzyme inhibitors; ARB, angiotensin receptor blockers; ARNI, angiotensin receptor–neprilysin inhibitor; BB, beta blockers; DIGO, digoxin; IVA, ivabradine; MRA, mineralocorticoid receptor antagonists; OM, omecamtiv mecarbil; SGLT2i, sodium–glucose cotransporter 2 inhibitors; VERI, vericiguat.

Fig. 3. Graphical representation of random‐effects Bayesian network meta‐analysis direct and indirect comparisons for all‐cause mortality. The hazard ratios (HRs) for the comparisons are color coded. Green indicates HR between 0.31 and 0.70, yellow HR between 0.71 and 0.99 (to the left of the grey cells) or between 1.01 and 1.30 (to the right of the grey cells), and red HR higher than 1.31. Within each color, shades become darker with every 0.10‐unit decrease or increase (e.g., HRs between 0.50 and 0.60 are darker green than those between 0.60 and 0.70, and HRs between 1.40 and 1.50 are darker red than those between 1.31 and 1.40). White indicates HR = 1.00, and the symbol “*” indicates statistical significance. ACEi, angiotensin converting enzyme inhibitors; ARB, angiotensin receptor blockers; ARNI, angiotensin receptor–neprilysin inhibitor; BB, beta blockers; DIGO, digoxin; IVA, ivabradine; MRA, mineralocorticoid receptor antagonists; OM, omecamtiv mecarbil; SGLT2i, sodium–glucose cotransporter 2 inhibitors; VERI, vericiguat.

Fig. 4. Graphical representation of random‐effects Bayesian network meta‐analysis direct and indirect comparisons for cardiovascular mortality (a) and heart failure hospitalization (b). For color coding, see legend for Fig. 3. ACEi, angiotensin converting enzyme inhibitors; ARB, angiotensin receptor blockers; ARNI, angiotensin receptor–neprilysin inhibitor; BB, beta blockers; DIGO, digoxin; IVA, ivabradine; MRA, mineralocorticoid receptor antagonists; OM, omecamtiv mecarbil; SGLT2i, sodium–glucose cotransporter 2 inhibitors; VERI, vericiguat.

Fig. 5. Risk reduction in all‐cause mortality (a), cardiovascular mortality (b), and heart failure hospitalization (c) after distinguishing subgroups of combination therapy with sodium–glucose cotransporter‐2 inhibitors according to concomitant use of angiotensin receptor–neprilysin inhibitor. For each outcome, the hazard ratios (HRs) with 95% credible intervals (CrI)—as calculated by random‐effects network meta‐analysis—are shown for interventions versus placebo (i.e., none of the drugs evaluated in the randomized controlled trials). ACEi, angiotensin converting enzyme inhibitors; ARB, angiotensin receptor blockers; ARNI, angiotensin receptor–neprilysin inhibitor; BB, beta blockers; DIGO, digoxin; IVA, ivabradine; MRA, mineralocorticoid receptor antagonists; OM, omecamtiv mecarbil; SGLT2i, sodium–glucose cotransporter 2 inhibitors; VERI, vericiguat.