<table><caption>Supplementary Table 9: Additive model assumptions test – summary for cardiovascular mortality or heart failure hospitalization</caption><thead><tr><th>Metric</th><th>Value</th></tr></thead><tbody><tr><td>Total Treatments</td><td>17</td></tr><tr><td>Single Treatments</td><td>1</td></tr><tr><td>Combination Treatments</td><td>16</td></tr><tr><td>Total Studies</td><td>20</td></tr><tr><td>Reference Treatment</td><td>ACEI + BB</td></tr><tr><td>Network Heterogeneity (τ²)</td><td>0</td></tr><tr><td>Network I² (%)</td><td>0.1 (0-0.5)</td></tr><tr><td>Combinations Tested for Additivity</td><td>13</td></tr></tbody></table>

INCONSISTENCY TEST RESULTS

<table><thead><tr><th>Test</th><th>Q</th><th></th><th></th></tr></thead><tbody><tr><td>Overall (standard) Inconsistency Q-statistic</td><td>12.284917</td><td>11</td><td>0.3426125</td></tr><tr><td>Additive model Inconsistency</td><td></td><td></td><td></td></tr><tr><td>Difference Inconsistency</td><td></td><td></td><td></td></tr></tbody></table>
<table><caption>Supplementary Table 10: Predicted versus observed effects for cardiovascular mortality or heart failure hospitalization</caption><thead><tr><th>Combination</th><th>Observed Effect</th><th>Components</th><th>Component Effects</th><th>Predicted Additive</th><th>Difference</th><th>SE Observed</th></tr></thead><tbody><tr><td>ACEI + BB</td><td>0</td><td>ACEI + BB</td><td>0.324, -0.324</td><td>0</td><td>0</td><td>0</td></tr><tr><td>ACEI + BB + MRA</td><td>-0.37</td><td>ACEI + BB + MRA</td><td>0.324, -0.324, -0.37</td><td>-0.37</td><td>0</td><td>0.074</td></tr><tr><td>ACEI + BB + MRA + IVA</td><td>-0.544</td><td>ACEI + BB + MRA + IVA</td><td>0.324, -0.324, -0.37, -0.173</td><td>-0.544</td><td>0</td><td>0.088</td></tr><tr><td>ACEI + BB + MRA + SGLT2</td><td>-0.628</td><td>ACEI + BB + MRA + SGLT2</td><td>0.324, -0.324, -0.37, -0.258</td><td>-0.628</td><td>0</td><td>0.088</td></tr><tr><td>ACEI + BB + MRA + Vericiguat</td><td>-0.444</td><td>ACEI + BB + MRA + Vericiguat</td><td>0.324, -0.324, -0.37, -0.073</td><td>-0.444</td><td>0</td><td>0.083</td></tr><tr><td>ARB + BB</td><td>-0.468</td><td>ARB + BB</td><td>-0.144, -0.324</td><td>-0.468</td><td>0</td><td>0.223</td></tr><tr><td>ARB + BB + MRA</td><td>-0.839</td><td>ARB + BB + MRA</td><td>-0.144, -0.324, -0.37</td><td>-0.839</td><td>0</td><td>0.235</td></tr><tr><td>ARNI + BB</td><td>-0.208</td><td>ARNI + BB</td><td>0.116, -0.324</td><td>-0.208</td><td>0</td><td>0.043</td></tr><tr><td>ARNI + BB + MRA</td><td>-0.578</td><td>ARNI + BB + MRA</td><td>0.116, -0.324, -0.37</td><td>-0.578</td><td>0</td><td>0.086</td></tr><tr><td>ARNI + BB + MRA + Omecamtiv</td><td>-0.626</td><td>ARNI + BB + MRA + Omecamtiv</td><td>0.116, -0.324, -0.37, -0.048</td><td>-0.626</td><td>0</td><td>0.093</td></tr><tr><td>ARNI + BB + MRA + SGLT2</td><td>-0.836</td><td>ARNI + BB + MRA + SGLT2</td><td>0.116, -0.324, -0.37, -0.258</td><td>-0.836</td><td>0</td><td>0.098</td></tr><tr><td>ARNI + BB + MRA + SGLT2 + Vericiguat</td><td>-0.909</td><td>ARNI + BB + MRA + SGLT2 + Vericiguat</td><td>0.116, -0.324, -0.37, -0.258, -0.073</td><td>-0.909</td><td>0</td><td>0.105</td></tr><tr><td>ARNI + BB + MRA + Vericiguat</td><td>-0.652</td><td>ARNI + BB + MRA + Vericiguat</td><td>0.116, -0.324, -0.37, -0.073</td><td>-0.652</td><td>0</td><td>0.093</td></tr></tbody></table>
<table><caption>Supplementary Table 11: Relative differences in all-cause death for different treatment combinations. The estimates presented are for the treatment combination in the column versus the treatment combination in the respective row.</caption><thead><tr><th></th><th>ARNI + BB + MRA</th><th>ARNI + BB + MRA + Omecamtiv</th><th>ARNI + BB + MRA + SGLT2</th><th>ARNI + BB + MRA + Vericiguat</th><th>ARNI + BB + MRA + SGLT2 + Vericiguat</th></tr></thead><tbody><tr><td>ACEI</td><td>0.5 (0.42-0.6); &lt;0.0001</td><td>0.51 (0.42-0.61); &lt;0.0001</td><td>0.44 (0.36-0.55); &lt;0.0001</td><td>0.44 (0.36-0.54); &lt;0.0001</td><td>0.39 (0.31-0.49); &lt;0.0001</td></tr><tr><td>ACEI + ARB + BB + Dig</td><td>0.69 (0.57-0.84); 1e-04</td><td>0.7 (0.57-0.86); 6e-04</td><td>0.61 (0.49-0.76); &lt;0.0001</td><td>0.61 (0.49-0.76); &lt;0.0001</td><td>0.54 (0.42-0.69); &lt;0.0001</td></tr><tr><td>ACEI + ARB + Dig</td><td>0.54 (0.44-0.66); &lt;0.0001</td><td>0.54 (0.43-0.67); &lt;0.0001</td><td>0.47 (0.38-0.6); &lt;0.0001</td><td>0.47 (0.38-0.6); &lt;0.0001</td><td>0.42 (0.32-0.54); &lt;0.0001</td></tr><tr><td>ACEI + BB</td><td>0.65 (0.56-0.76); &lt;0.0001</td><td>0.65 (0.55-0.78); &lt;0.0001</td><td>0.57 (0.47-0.69); &lt;0.0001</td><td>0.57 (0.47-0.69); &lt;0.0001</td><td>0.5 (0.4-0.63); &lt;0.0001</td></tr><tr><td>ACEI + BB + Dig</td><td>0.66 (0.55-0.78); &lt;0.0001</td><td>0.66 (0.54-0.8); &lt;0.0001</td><td>0.58 (0.47-0.71); &lt;0.0001</td><td>0.58 (0.47-0.71); &lt;0.0001</td><td>0.51 (0.4-0.64); &lt;0.0001</td></tr><tr><td>ACEI + BB + Dig + H-ISDN</td><td>0.96 (0.72-1.28); 0.7878</td><td>0.96 (0.71-1.3); 0.8087</td><td>0.85 (0.62-1.15); 0.2922</td><td>0.85 (0.62-1.15); 0.2882</td><td>0.75 (0.54-1.04); 0.0794</td></tr><tr><td>ACEI + BB + MRA</td><td>0.86 (0.78-0.95); 0.0022</td><td>0.86 (0.75-0.98); 0.0223</td><td>0.75 (0.65-0.88); 3e-04</td><td>0.76 (0.65-0.87); 1e-04</td><td>0.66 (0.55-0.8); &lt;0.0001</td></tr><tr><td>ACEI + BB + MRA + IVA</td><td>0.94 (0.81-1.1); 0.4488</td><td>0.94 (0.79-1.13); 0.5243</td><td>0.83 (0.68-1.01); 0.0577</td><td>0.83 (0.69-1); 0.0509</td><td>0.73 (0.59-0.91); 0.0052</td></tr><tr><td>ACEI + BB + MRA + Omecamtiv</td><td>0.86 (0.75-0.97); 0.0182</td><td>0.86 (0.78-0.95); 0.0022</td><td>0.75 (0.63-0.9); 0.0014</td><td>0.75 (0.64-0.89); 9e-04</td><td>0.66 (0.54-0.81); 1e-04</td></tr><tr><td>ACEI + BB + MRA + SGLT2</td><td>0.97 (0.84-1.13); 0.7341</td><td>0.98 (0.82-1.16); 0.788</td><td>0.86 (0.78-0.95); 0.0022</td><td>0.86 (0.71-1.03); 0.1053</td><td>0.76 (0.65-0.87); 1e-04</td></tr><tr><td>ACEI + BB + MRA + Vericiguat</td><td>0.97 (0.84-1.12); 0.7147</td><td>0.98 (0.83-1.15); 0.7746</td><td>0.86 (0.71-1.03); 0.1027</td><td>0.86 (0.78-0.95); 0.0022</td><td>0.75 (0.65-0.88); 3e-04</td></tr><tr><td>ACEI + Dig</td><td>0.51 (0.42-0.62); &lt;0.0001</td><td>0.51 (0.42-0.63); &lt;0.0001</td><td>0.45 (0.36-0.56); &lt;0.0001</td><td>0.45 (0.36-0.56); &lt;0.0001</td><td>0.4 (0.31-0.51); &lt;0.0001</td></tr><tr><td>ACEI + MRA + Dig</td><td>0.68 (0.58-0.78); &lt;0.0001</td><td>0.68 (0.57-0.8); &lt;0.0001</td><td>0.59 (0.49-0.72); &lt;0.0001</td><td>0.59 (0.5-0.71); &lt;0.0001</td><td>0.52 (0.42-0.65); &lt;0.0001</td></tr><tr><td>ARB</td><td>0.47 (0.39-0.58); &lt;0.0001</td><td>0.47 (0.38-0.59); &lt;0.0001</td><td>0.42 (0.33-0.52); &lt;0.0001</td><td>0.42 (0.33-0.52); &lt;0.0001</td><td>0.37 (0.29-0.47); &lt;0.0001</td></tr><tr><td>ARB + BB</td><td>0.61 (0.51-0.73); &lt;0.0001</td><td>0.61 (0.5-0.75); &lt;0.0001</td><td>0.54 (0.43-0.67); &lt;0.0001</td><td>0.54 (0.44-0.66); &lt;0.0001</td><td>0.47 (0.37-0.6); &lt;0.0001</td></tr><tr><td>ARB + BB + Dig</td><td>0.62 (0.51-0.75); &lt;0.0001</td><td>0.62 (0.5-0.77); &lt;0.0001</td><td>0.54 (0.43-0.68); &lt;0.0001</td><td>0.54 (0.43-0.68); &lt;0.0001</td><td>0.48 (0.37-0.62); &lt;0.0001</td></tr><tr><td>ARB + BB + MRA</td><td>0.81 (0.7-0.92); 0.0019</td><td>0.81 (0.69-0.95); 0.009</td><td>0.71 (0.59-0.85); 2e-04</td><td>0.71 (0.6-0.84); 1e-04</td><td>0.62 (0.51-0.77); &lt;0.0001</td></tr><tr><td>ARB + Dig</td><td>0.48 (0.39-0.59); &lt;0.0001</td><td>0.48 (0.38-0.6); &lt;0.0001</td><td>0.42 (0.33-0.54); &lt;0.0001</td><td>0.42 (0.33-0.54); &lt;0.0001</td><td>0.37 (0.29-0.48); &lt;0.0001</td></tr><tr><td>ARNI + BB</td><td>0.76 (0.67-0.85); &lt;0.0001</td><td>0.76 (0.66-0.88); 2e-04</td><td>0.67 (0.56-0.79); &lt;0.0001</td><td>0.67 (0.57-0.78); &lt;0.0001</td><td>0.59 (0.48-0.71); &lt;0.0001</td></tr><tr><td>ARNI + BB + MRA</td><td>1</td><td>1 (0.92-1.09); 0.9541</td><td>0.88 (0.78-0.99); 0.0315</td><td>0.88 (0.79-0.98); 0.0189</td><td>0.78 (0.66-0.91); 0.0015</td></tr><tr><td>ARNI + BB + MRA + Omecamtiv</td><td>1 (0.92-1.09); 0.9541</td><td>1</td><td>0.88 (0.76-1.01); 0.0764</td><td>0.88 (0.77-1.01); 0.0615</td><td>0.77 (0.65-0.92); 0.0048</td></tr><tr><td>ARNI + BB + MRA + SGLT2</td><td>1.14 (1.01-1.28); 0.0315</td><td>1.14 (0.99-1.32); 0.0764</td><td>1</td><td>1 (0.85-1.17); 0.9942</td><td>0.88 (0.79-0.98); 0.0189</td></tr><tr><td>ARNI + BB + MRA + SGLT2 + Vericiguat</td><td>1.29 (1.1-1.51); 0.0015</td><td>1.29 (1.08-1.55); 0.0048</td><td>1.14 (1.02-1.26); 0.0189</td><td>1.14 (1.01-1.28); 0.0315</td><td>1</td></tr><tr><td>ARNI + BB + MRA + Vericiguat</td><td>1.14 (1.02-1.26); 0.0189</td><td>1.14 (0.99-1.3); 0.0615</td><td>1 (0.85-1.17); 0.9942</td><td>1</td><td>0.88 (0.78-0.99); 0.0315</td></tr><tr><td>ARNI + BB + SGLT2</td><td>0.86 (0.73-1.02); 0.0745</td><td>0.86 (0.72-1.04); 0.1182</td><td>0.76 (0.67-0.85); &lt;0.0001</td><td>0.76 (0.62-0.92); 0.0057</td><td>0.67 (0.57-0.78); &lt;0.0001</td></tr><tr><td>BB</td><td>0.58 (0.49-0.69); &lt;0.0001</td><td>0.58 (0.48-0.7); &lt;0.0001</td><td>0.51 (0.41-0.63); &lt;0.0001</td><td>0.51 (0.42-0.62); &lt;0.0001</td><td>0.45 (0.35-0.57); &lt;0.0001</td></tr><tr><td>Dig</td><td>0.45 (0.37-0.56); &lt;0.0001</td><td>0.46 (0.36-0.57); &lt;0.0001</td><td>0.4 (0.32-0.51); &lt;0.0001</td><td>0.4 (0.32-0.51); &lt;0.0001</td><td>0.35 (0.27-0.46); &lt;0.0001</td></tr><tr><td>Dig + H-ISDN</td><td>0.66 (0.49-0.9); 0.0092</td><td>0.67 (0.48-0.92); 0.0126</td><td>0.59 (0.42-0.81); 0.0014</td><td>0.59 (0.42-0.81); 0.0012</td><td>0.52 (0.36-0.73); 2e-04</td></tr></tbody></table>
<table><caption>Supplementary Table 12: Relative differences in cardiovascular mortality and heart failure hospitalizations for different treatment combinations. The estimates presented are for the treatment combination in the column versus the treatment combination in the respective row.</caption><tr><td>PLBO</td><td>0.45 (0.37-0.54); &lt;0.0001</td><td>0.45 (0.37-0.55); &lt;0.0001</td><td>0.39 (0.32-0.49); &lt;0.0001</td><td>0.4 (0.32-0.49); &lt;0.0001</td><td>0.35 (0.27-0.45); &lt;0.0001</td></tr></table>

<table><thead><tr><th></th><th>ACEI + BB + MRA + SGLT2</th><th>ARB + BB + MRA</th><th>ARNI + BB + MRA + SGLT2</th><th>ARNI + BB + MRA + Vericiguat</th><th>ARNI + BB + MRA + SGLT2 + Vericiguat</th></tr></thead><tbody><tr><td>ACEI + ARB + BB + Dig</td><td>0.62 (0.5-0.76); &lt;0.0001</td><td>0.5 (0.31-0.81); 0.0048</td><td>0.5 (0.39-0.63); &lt;0.0001</td><td>0.6 (0.48-0.76); &lt;0.0001</td><td>0.46 (0.36-0.6); &lt;0.0001</td></tr><tr><td>ACEI + BB</td><td>0.53 (0.44-0.64); &lt;0.0001</td><td>0.43 (0.27-0.69); 5e-04</td><td>0.43 (0.35-0.53); &lt;0.0001</td><td>0.52 (0.42-0.64); &lt;0.0001</td><td>0.4 (0.32-0.51); &lt;0.0001</td></tr><tr><td>ACEI + BB + Dig</td><td>0.53 (0.44-0.64); &lt;0.0001</td><td>0.43 (0.27-0.69); 5e-04</td><td>0.43 (0.35-0.53); &lt;0.0001</td><td>0.52 (0.42-0.64); &lt;0.0001</td><td>0.4 (0.32-0.51); &lt;0.0001</td></tr><tr><td>ACEI + BB + MRA</td><td>0.77 (0.69-0.86); &lt;0.0001</td><td>0.62 (0.4-0.98); 0.0387</td><td>0.62 (0.54-0.73); &lt;0.0001</td><td>0.75 (0.66-0.87); 1e-04</td><td>0.58 (0.49-0.69); &lt;0.0001</td></tr><tr><td>ACEI + BB + MRA + IVA</td><td>0.92 (0.79-1.08); 0.303</td><td>0.74 (0.47-1.18); 0.2101</td><td>0.74 (0.62-0.9); 0.0024</td><td>0.9 (0.75-1.08); 0.2498</td><td>0.69 (0.56-0.86); 6e-04</td></tr><tr><td>ACEI + BB + MRA + SGLT2</td><td>1</td><td>0.81 (0.51-1.28); 0.3642</td><td>0.81 (0.73-0.9); 1e-04</td><td>0.98 (0.82-1.16); 0.7959</td><td>0.75 (0.66-0.87); 1e-04</td></tr><tr><td>ACEI + BB + MRA + Vericiguat</td><td>0.83 (0.72-0.95); 0.0073</td><td>0.67 (0.42-1.06); 0.0842</td><td>0.67 (0.56-0.8); &lt;0.0001</td><td>0.81 (0.73-0.9); 1e-04</td><td>0.62 (0.54-0.73); &lt;0.0001</td></tr><tr><td>ACEI + Dig</td><td>0.45 (0.35-0.57); &lt;0.0001</td><td>0.36 (0.22-0.59); 1e-04</td><td>0.36 (0.28-0.47); &lt;0.0001</td><td>0.44 (0.34-0.56); &lt;0.0001</td><td>0.34 (0.25-0.44); &lt;0.0001</td></tr><tr><td>ARB + BB</td><td>0.85 (0.52-1.39); 0.5199</td><td>0.69 (0.59-0.81); &lt;0.0001</td><td>0.69 (0.43-1.11); 0.1248</td><td>0.83 (0.52-1.33); 0.4468</td><td>0.64 (0.4-1.04); 0.0726</td></tr><tr><td>ARB + BB + MRA</td><td>1.24 (0.78-1.96); 0.3642</td><td>1</td><td>1 (0.64-1.57); 0.9958</td><td>1.21 (0.78-1.88); 0.4011</td><td>0.93 (0.59-1.47); 0.7665</td></tr><tr><td>ARNI + BB</td><td>0.66 (0.53-0.82); 1e-04</td><td>0.53 (0.33-0.84); 0.0073</td><td>0.53 (0.44-0.64); &lt;0.0001</td><td>0.64 (0.54-0.77); &lt;0.0001</td><td>0.5 (0.4-0.61); &lt;0.0001</td></tr><tr><td>ARNI + BB + MRA</td><td>0.95 (0.82-1.11); 0.5381</td><td>0.77 (0.5-1.19); 0.2406</td><td>0.77 (0.69-0.86); &lt;0.0001</td><td>0.93 (0.85-1.02); 0.1161</td><td>0.72 (0.63-0.83); &lt;0.0001</td></tr><tr><td>ARNI + BB + MRA + Omecamtiv</td><td>1 (0.84-1.2); 0.9957</td><td>0.81 (0.52-1.26); 0.3505</td><td>0.81 (0.7-0.94); 0.0046</td><td>0.98 (0.86-1.12); 0.7403</td><td>0.75 (0.64-0.89); 0.0012</td></tr><tr><td>ARNI + BB + MRA + SGLT2</td><td>1.24 (1.11-1.37); 1e-04</td><td>1 (0.64-1.56); 0.9958</td><td>1</td><td>1.21 (1.05-1.39); 0.0073</td><td>0.93 (0.85-1.02); 0.1161</td></tr><tr><td>ARNI + BB + MRA + SGLT2 + Vericiguat</td><td>1.33 (1.16-1.52); 1e-04</td><td>1.07 (0.68-1.69); 0.7665</td><td>1.07 (0.98-1.17); 0.1161</td><td>1.3 (1.16-1.44); &lt;0.0001</td><td>1</td></tr><tr><td>ARNI + BB + MRA + Vericiguat</td><td>1.02 (0.86-1.22); 0.7959</td><td>0.83 (0.53-1.29); 0.4011</td><td>0.83 (0.72-0.95); 0.0073</td><td>1</td><td>0.77 (0.69-0.86); &lt;0.0001</td></tr><tr><td>BB</td><td>0.74 (0.45-1.21); 0.2287</td><td>0.6 (0.49-0.72); &lt;0.0001</td><td>0.6 (0.37-0.97); 0.0369</td><td>0.72 (0.44-1.17); 0.1817</td><td>0.56 (0.34-0.91); 0.0197</td></tr></tbody></table>

Abbreviations: ACEI, ACE-inhibitor; ARB, angiotensin-receptor blocker; ARNI, angiotensin receptor neprilysin inhibitor; BB, beta-blocker; Dig, digoxin; H-ISDN, hydralazine-isosorbide dinitrate; MRA, mineralocorticoid receptor antagonist; PLBO, placebo; SGLT2i, sodium-glucose cotransporter 2 inhibitor.
<table><caption>Supplementary Table 13: Relative differences in cardiovascular mortality for different treatment combinations. The estimates presented are for the treatment combination in the column versus the treatment combination in the respective row.</caption><thead><tr><th></th><th>ARNI + BB + MRA</th><th>ARNI + BB + MRA +<br>Omecamtiv</th><th>ARNI + BB + MRA +<br>SGLT2</th><th>ARNI + BB +<br>MRA + Vericiguat</th><th>ARNI + BB + MRA +<br>SGLT2 + Vericiguat</th></tr></thead><tbody><tr><td>ACEI</td><td>0.47 (0.39-0.57); &lt;0.0001</td><td>0.44 (0.34-0.56); &lt;0.0001</td><td>0.41 (0.32-0.52); &lt;0.0001</td><td>0.41 (0.32-0.51); &lt;0.0001</td><td>0.35 (0.27-0.46); &lt;0.0001</td></tr><tr><td>ACEI + ARB + BB + Dig</td><td>0.68 (0.55-0.85); 5e-04</td><td>0.64 (0.49-0.83); 7e-04</td><td>0.59 (0.46-0.76); 1e-04</td><td>0.59 (0.46-0.76); &lt;0.0001</td><td>0.51 (0.39-0.68); &lt;0.0001</td></tr><tr><td>ACEI + ARB + Dig</td><td>0.53 (0.42-0.67); &lt;0.0001</td><td>0.49 (0.37-0.65); &lt;0.0001</td><td>0.46 (0.35-0.6); &lt;0.0001</td><td>0.46 (0.35-0.6); &lt;0.0001</td><td>0.4 (0.3-0.54); &lt;0.0001</td></tr><tr><td>ACEI + BB</td><td>0.6 (0.51-0.72); &lt;0.0001</td><td>0.56 (0.45-0.7); &lt;0.0001</td><td>0.53 (0.42-0.65); &lt;0.0001</td><td>0.52 (0.42-0.64); &lt;0.0001</td><td>0.46 (0.36-0.58); &lt;0.0001</td></tr><tr><td>ACEI + BB + Dig</td><td>0.6 (0.49-0.72); &lt;0.0001</td><td>0.56 (0.44-0.71); &lt;0.0001</td><td>0.52 (0.41-0.65); &lt;0.0001</td><td>0.52 (0.41-0.65); &lt;0.0001</td><td>0.45 (0.35-0.58); &lt;0.0001</td></tr><tr><td>ACEI + BB + Dig + H-ISDN</td><td>0.68 (0.43-1.07); 0.0966</td><td>0.64 (0.4-1.02); 0.0618</td><td>0.59 (0.37-0.95); 0.0298</td><td>0.59 (0.37-0.94); 0.0273</td><td>0.51 (0.32-0.84); 0.0073</td></tr><tr><td>ACEI + BB + MRA</td><td>0.82 (0.74-0.92); 4e-04</td><td>0.77 (0.64-0.92); 0.0041</td><td>0.71 (0.6-0.85); 1e-04</td><td>0.71 (0.6-0.84); &lt;0.0001</td><td>0.62 (0.5-0.76); &lt;0.0001</td></tr><tr><td>ACEI + BB + MRA + IVA</td><td>0.9 (0.76-1.06); 0.2192</td><td>0.84 (0.67-1.05); 0.1241</td><td>0.78 (0.63-0.97); 0.025</td><td>0.78 (0.64-0.96); 0.0182</td><td>0.68 (0.53-0.87); 0.0019</td></tr><tr><td>ACEI + BB + MRA +<br>Omecamtiv</td><td>0.88 (0.73-1.06); 0.1671</td><td>0.82 (0.74-0.92); 4e-04</td><td>0.77 (0.61-0.96); 0.0199</td><td>0.76 (0.61-0.95); 0.0147</td><td>0.66 (0.51-0.86); 0.0016</td></tr><tr><td>ACEI + BB + MRA + SGLT2</td><td>0.94 (0.79-1.12); 0.495</td><td>0.88 (0.7-1.1); 0.2613</td><td>0.82 (0.74-0.92); 4e-04</td><td>0.82 (0.66-1.01); 0.0573</td><td>0.71 (0.6-0.84); &lt;0.0001</td></tr><tr><td>ACEI + BB + MRA + Vericiguat</td><td>0.95 (0.8-1.11); 0.5072</td><td>0.88 (0.71-1.1); 0.2646</td><td>0.82 (0.67-1.02); 0.0696</td><td>0.82 (0.74-0.92); 4e-04</td><td>0.71 (0.6-0.85); 1e-04</td></tr><tr><td>ACEI + Dig</td><td>0.46 (0.37-0.57); &lt;0.0001</td><td>0.43 (0.33-0.56); &lt;0.0001</td><td>0.4 (0.31-0.52); &lt;0.0001</td><td>0.4 (0.31-0.51); &lt;0.0001</td><td>0.35 (0.27-0.46); &lt;0.0001</td></tr><tr><td>ACEI + MRA + Dig</td><td>0.63 (0.53-0.75); &lt;0.0001</td><td>0.59 (0.47-0.74); &lt;0.0001</td><td>0.55 (0.44-0.68); &lt;0.0001</td><td>0.55 (0.44-0.67); &lt;0.0001</td><td>0.48 (0.37-0.61); &lt;0.0001</td></tr><tr><td>ARB</td><td>0.45 (0.36-0.56); &lt;0.0001</td><td>0.42 (0.32-0.55); &lt;0.0001</td><td>0.39 (0.3-0.51); &lt;0.0001</td><td>0.39 (0.3-0.5); &lt;0.0001</td><td>0.34 (0.25-0.45); &lt;0.0001</td></tr><tr><td>ARB + BB</td><td>0.58 (0.47-0.71); &lt;0.0001</td><td>0.54 (0.42-0.69); &lt;0.0001</td><td>0.5 (0.39-0.64); &lt;0.0001</td><td>0.5 (0.39-0.63); &lt;0.0001</td><td>0.44 (0.33-0.57); &lt;0.0001</td></tr><tr><td>ARB + BB + MRA</td><td>0.78 (0.67-0.92); 0.0027</td><td>0.73 (0.59-0.91); 0.0046</td><td>0.68 (0.56-0.84); 3e-04</td><td>0.68 (0.56-0.83); 1e-04</td><td>0.59 (0.47-0.75); &lt;0.0001</td></tr><tr><td>ARB + Dig</td><td>0.44 (0.35-0.57); &lt;0.0001</td><td>0.41 (0.31-0.55); &lt;0.0001</td><td>0.39 (0.29-0.51); &lt;0.0001</td><td>0.38 (0.29-0.5); &lt;0.0001</td><td>0.34 (0.25-0.45); &lt;0.0001</td></tr><tr><td>ARNI + BB</td><td>0.74 (0.64-0.84); &lt;0.0001</td><td>0.69 (0.56-0.83); 2e-04</td><td>0.64 (0.53-0.77); &lt;0.0001</td><td>0.64 (0.53-0.76); &lt;0.0001</td><td>0.55 (0.44-0.69); &lt;0.0001</td></tr><tr><td>ARNI + BB + MRA</td><td>1</td><td>0.93 (0.81-1.08); 0.3519</td><td>0.87 (0.76-0.99); 0.039</td><td>0.87 (0.77-0.98); 0.0193</td><td>0.75 (0.63-0.9); 0.0019</td></tr><tr><td>ARNI + BB + MRA +<br>Omecamtiv</td><td>1.07 (0.93-1.24); 0.3519</td><td>1</td><td>0.93 (0.77-1.14); 0.4905</td><td>0.93 (0.77-1.12); 0.4444</td><td>0.81 (0.64-1.02); 0.0708</td></tr><tr><td>ARNI + BB + MRA + SGLT2</td><td>1.15 (1.01-1.31); 0.039</td><td>1.07 (0.88-1.3); 0.4905</td><td>1</td><td>1 (0.83-1.19); 0.9595</td><td>0.87 (0.77-0.98); 0.0193</td></tr><tr><td>ARNI + BB + MRA +<br>SGLT2 + Vericiguat</td><td>1.33 (1.11-1.58); 0.0019</td><td>1.24 (0.98-1.56); 0.0708</td><td>1.15 (1.02-1.3); 0.0193</td><td>1.15 (1.01-1.31); 0.039</td><td>1</td></tr><tr><td>ARNI + BB + MRA + Vericiguat</td><td>1.15 (1.02-1.3); 0.0193</td><td>1.08 (0.89-1.3); 0.4444</td><td>1 (0.84-1.2); 0.9595</td><td>1</td><td>0.87 (0.76-0.99); 0.039</td></tr><tr><td>ARNI + BB + SGLT2</td><td>0.84 (0.7-1.02); 0.0745</td><td>0.79 (0.62-1); 0.048</td><td>0.74 (0.64-0.84); &lt;0.0001</td><td>0.73 (0.59-0.91); 0.0057</td><td>0.64 (0.53-0.76); &lt;0.0001</td></tr><tr><td>BB</td><td>0.51 (0.42-0.61); &lt;0.0001</td><td>0.47 (0.37-0.6); &lt;0.0001</td><td>0.44 (0.35-0.55); &lt;0.0001</td><td>0.44 (0.35-0.55); &lt;0.0001</td><td>0.38 (0.29-0.5); &lt;0.0001</td></tr><tr><td>Dig</td><td>0.39 (0.31-0.49); &lt;0.0001</td><td>0.36 (0.28-0.48); &lt;0.0001</td><td>0.34 (0.26-0.44); &lt;0.0001</td><td>0.34 (0.26-0.44); &lt;0.0001</td><td>0.29 (0.22-0.39); &lt;0.0001</td></tr><tr><td>Dig + H-ISDN</td><td>0.44 (0.28-0.71); 6e-04</td><td>0.42 (0.26-0.68); 4e-04</td><td>0.39 (0.24-0.63); 1e-04</td><td>0.39 (0.24-0.62); 1e-04</td><td>0.34 (0.2-0.55); &lt;0.0001</td></tr></tbody></table>
<table><tr><td>PLBO</td><td>0.39 (0.32-0.49); &lt;0.0001</td><td>0.37 (0.28-0.48); &lt;0.0001</td><td>0.34 (0.27-0.44); &lt;0.0001</td><td>0.34 (0.27-0.44); &lt;0.0001</td><td>0.3 (0.22-0.39); &lt;0.0001</td></tr></table>

**Abbreviations:** ACEI, ACE-inhibitor; ARB, angiotensin-receptor blocker; ARNI, angiotensin receptor neprilysin inhibitor; BB, beta-blocker; Dig, digoxin; H-ISDN, hydralazine-isosorbide dinitrate; MRA, mineralocorticoid receptor antagonist; PLBO, placebo; SGLT2i, sodium-glucose cotransporter 2 inhibitor.
<table><caption>Supplementary Table 14: Number of life years saved in the combined cohort compared to no treatment, ASIAN-HF and BIOSTAT-CHF.</caption><thead><tr><th rowspan="3"></th><th colspan="9">Life-years gained compared to Placebo</th></tr><tr><th colspan="3">50 years</th><th colspan="3">60 years</th><th colspan="3">70 years</th></tr><tr><th>Mean</th><th>95%CI</th><th>Mean</th><th>95%CI</th><th>Mean</th><th>95%CI</th><th>Mean</th><th>95%CI</th><th>Mean</th><th>95%CI</th></tr></thead><tbody><tr><td>ARNi, BB, MRA, SGLT2, Vericiguat</td><td>9.18</td><td>5.96 12.39</td><td>7.57</td><td>4.72 10.42</td><td>6.04</td><td>3.65 8.43</td><td></td><td></td><td></td><td></td></tr><tr><td>ASIAN-HF</td><td>8.99</td><td>5.79 12.2</td><td>7.41</td><td>4.55 10.28</td><td>5.28</td><td>2.99 7.57</td><td></td><td></td><td></td><td></td></tr><tr><td>BIOSTAT-CHF</td><td>9.02</td><td>5.73 12.3</td><td>7.72</td><td>4.91 10.52</td><td>5.5</td><td>3.21 7.79</td><td></td><td></td><td></td><td></td></tr><tr><td>ARNi, BB, MRA, SGLT2</td><td>7.82</td><td>4.58 11.05</td><td>6.5</td><td>3.62 9.39</td><td>5.29</td><td>2.85 7.73</td><td></td><td></td><td></td><td></td></tr><tr><td>ASIAN-HF</td><td>7.64</td><td>4.42 10.86</td><td>6.35</td><td>3.45 9.25</td><td>4.57</td><td>2.24 6.9</td><td></td><td></td><td></td><td></td></tr><tr><td>BIOSTAT-CHF</td><td>7.72</td><td>4.39 11.04</td><td>6.67</td><td>3.82 9.52</td><td>4.83</td><td>2.49 7.16</td><td></td><td></td><td></td><td></td></tr><tr><td>ARNi, BB, MRA, Vericiguat</td><td>7.81</td><td>4.58 11.05</td><td>6.5</td><td>3.61 9.38</td><td>5.29</td><td>2.85 7.73</td><td></td><td></td><td></td><td></td></tr><tr><td>ASIAN-HF</td><td>7.63</td><td>4.41 10.86</td><td>6.35</td><td>3.44 9.25</td><td>4.57</td><td>2.24 6.9</td><td></td><td></td><td></td><td></td></tr><tr><td>BIOSTAT-CHF</td><td>7.71</td><td>4.39 11.03</td><td>6.66</td><td>3.81 9.51</td><td>4.82</td><td>2.49 7.16</td><td></td><td></td><td></td><td></td></tr><tr><td>ARNi, BB, MRA, Omecamtiv</td><td>6.47</td><td>3.24 9.7</td><td>5.42</td><td>2.52 8.33</td><td>4.5</td><td>2.02 6.98</td><td></td><td></td><td></td><td></td></tr><tr><td>ASIAN-HF</td><td>6.3</td><td>3.09 9.52</td><td>5.28</td><td>2.36 8.2</td><td>3.85</td><td>1.49 6.21</td><td></td><td></td><td></td><td></td></tr><tr><td>BIOSTAT-CHF</td><td>6.42</td><td>3.08 9.76</td><td>5.6</td><td>2.72 8.48</td><td>4.12</td><td>1.75 6.49</td><td></td><td></td><td></td><td></td></tr><tr><td>ARNi, BB, MRA</td><td>6.5</td><td>3.26 9.73</td><td>5.44</td><td>2.54 8.35</td><td>4.52</td><td>2.04 7</td><td></td><td></td><td></td><td></td></tr><tr><td>ASIAN-HF</td><td>6.33</td><td>3.11 9.55</td><td>5.3</td><td>2.38 8.22</td><td>3.86</td><td>1.5 6.22</td><td></td><td></td><td></td><td></td></tr><tr><td>BIOSTAT-CHF</td><td>6.44</td><td>3.1 9.78</td><td>5.62</td><td>2.74 8.5</td><td>4.13</td><td>1.76 6.51</td><td></td><td></td><td></td><td></td></tr><tr><td>ACEi, BB, MRA</td><td>4.98</td><td>1.79 8.18</td><td>4.21</td><td>1.31 7.11</td><td>3.58</td><td>1.07 6.09</td><td></td><td></td><td></td><td></td></tr><tr><td>ASIAN-HF</td><td>4.84</td><td>1.66 8.01</td><td>4.08</td><td>1.17 7</td><td>3.02</td><td>0.64 5.4</td><td></td><td></td><td></td><td></td></tr><tr><td>BIOSTAT-CHF</td><td>4.97</td><td>1.64 8.3</td><td>4.39</td><td>1.5 7.28</td><td>3.29</td><td>0.88 5.7</td><td></td><td></td><td></td><td></td></tr><tr><td>ACEi, BB</td><td>2.56</td><td>-0.48 5.59</td><td>2.18</td><td>-0.63 5</td><td>1.94</td><td>-0.57 4.45</td><td></td><td></td><td></td><td></td></tr><tr><td>ASIAN-HF</td><td>2.46</td><td>-0.55 5.48</td><td>2.1</td><td>-0.72 4.92</td><td>1.59</td><td>-0.76 3.94</td><td></td><td></td><td></td><td></td></tr><tr><td>BIOSTAT-CHF</td><td>2.58</td><td>-0.66 5.81</td><td>2.31</td><td>-0.52 5.15</td><td>1.8</td><td>-0.62 4.22</td><td></td><td></td><td></td><td></td></tr></tbody></table>
<table><caption>Supplementary Table 15: Number of life years saved in the combined cohort compared to no treatment, ASIAN-HF and BIOSTAT-CHF when adherence after 2 years is 80%.</caption><thead><tr><th rowspan="3"></th><th colspan="9">Life-years gained compared to Placebo</th></tr><tr><th colspan="3">50 years</th><th colspan="3">60 years</th><th colspan="3">70 years</th></tr><tr><th>Mean</th><th>95%CI</th><th></th><th>Mean</th><th>95%CI</th><th></th><th>Mean</th><th>95%CI</th><th></th></tr></thead><tbody><tr><td>ARNi, BB, MRA, SGLT2, Vericiguat</td><td>5.86</td><td>2.54</td><td>9.19</td><td>4.08</td><td>1.09</td><td>7.08</td><td>2.65</td><td>0.1</td><td>5.19</td></tr><tr><td>ASIAN-HF</td><td>4.87</td><td>1.53</td><td>8.2</td><td>2.54</td><td>-0.5</td><td>5.58</td><td>0.67</td><td>-1.79</td><td>3.13</td></tr><tr><td>BIOSTAT-CHF</td><td>6.65</td><td>3.24</td><td>10.06</td><td>4.63</td><td>1.67</td><td>7.6</td><td>2.17</td><td>-0.29</td><td>4.63</td></tr><tr><td>ARNi, BB, MRA, SGLT2</td><td>5</td><td>1.67</td><td>8.32</td><td>3.51</td><td>0.51</td><td>6.51</td><td>2.32</td><td>-0.24</td><td>4.88</td></tr><tr><td>ASIAN-HF</td><td>4.13</td><td>0.81</td><td>7.46</td><td>2.17</td><td>-0.87</td><td>5.21</td><td>0.58</td><td>-1.88</td><td>3.04</td></tr><tr><td>BIOSTAT-CHF</td><td>5.69</td><td>2.27</td><td>9.12</td><td>4</td><td>1.02</td><td>6.98</td><td>1.9</td><td>-0.57</td><td>4.37</td></tr><tr><td>ARNi, BB, MRA, Vericiguat</td><td>4.99</td><td>1.67</td><td>8.32</td><td>3.51</td><td>0.51</td><td>6.51</td><td>2.32</td><td>-0.24</td><td>4.88</td></tr><tr><td>ASIAN-HF</td><td>4.13</td><td>0.8</td><td>7.46</td><td>2.17</td><td>-0.87</td><td>5.21</td><td>0.58</td><td>-1.88</td><td>3.04</td></tr><tr><td>BIOSTAT-CHF</td><td>5.69</td><td>2.26</td><td>9.11</td><td>4</td><td>1.02</td><td>6.98</td><td>1.9</td><td>-0.57</td><td>4.37</td></tr><tr><td>ARNi, BB, MRA, Omecamtiv</td><td>4.14</td><td>0.83</td><td>7.45</td><td>2.93</td><td>-0.07</td><td>5.93</td><td>1.98</td><td>-0.59</td><td>4.55</td></tr><tr><td>ASIAN-HF</td><td>3.41</td><td>0.1</td><td>6.72</td><td>1.8</td><td>-1.23</td><td>4.83</td><td>0.49</td><td>-1.97</td><td>2.95</td></tr><tr><td>BIOSTAT-CHF</td><td>4.73</td><td>1.31</td><td>8.16</td><td>3.36</td><td>0.37</td><td>6.35</td><td>1.62</td><td>-0.86</td><td>4.11</td></tr><tr><td>ARNi, BB, MRA</td><td>4.16</td><td>0.85</td><td>7.47</td><td>2.94</td><td>-0.06</td><td>5.94</td><td>1.98</td><td>-0.59</td><td>4.55</td></tr><tr><td>ASIAN-HF</td><td>3.42</td><td>0.11</td><td>6.73</td><td>1.81</td><td>-1.22</td><td>4.84</td><td>0.49</td><td>-1.97</td><td>2.95</td></tr><tr><td>BIOSTAT-CHF</td><td>4.75</td><td>1.32</td><td>8.18</td><td>3.37</td><td>0.38</td><td>6.36</td><td>1.63</td><td>-0.85</td><td>4.11</td></tr><tr><td>ACEi, BB, MRA</td><td>3.2</td><td>-0.08</td><td>6.47</td><td>2.28</td><td>-0.71</td><td>5.27</td><td>1.58</td><td>-1</td><td>4.15</td></tr><tr><td>ASIAN-HF</td><td>2.61</td><td>-0.66</td><td>5.89</td><td>1.39</td><td>-1.63</td><td>4.41</td><td>0.39</td><td>-2.07</td><td>2.84</td></tr><tr><td>BIOSTAT-CHF</td><td>3.67</td><td>0.25</td><td>7.09</td><td>2.63</td><td>-0.36</td><td>5.62</td><td>1.3</td><td>-1.2</td><td>3.79</td></tr><tr><td>ACEi, BB</td><td>1.65</td><td>-1.52</td><td>4.82</td><td>1.19</td><td>-1.75</td><td>4.12</td><td>0.85</td><td>-1.72</td><td>3.43</td></tr><tr><td>ASIAN-HF</td><td>1.33</td><td>-1.86</td><td>4.51</td><td>0.71</td><td>-2.27</td><td>3.69</td><td>0.2</td><td>-2.25</td><td>2.65</td></tr><tr><td>BIOSTAT-CHF</td><td>1.9</td><td>-1.45</td><td>5.24</td><td>1.38</td><td>-1.57</td><td>4.34</td><td>0.71</td><td>-1.79</td><td>3.21</td></tr></tbody></table>
<figure><img src="image_156.png" /></figure>
<table><caption>Supplementary Table 16: Number needed to treat (NNT) for different treatment regimens to prevent one case of all-cause mortality.</caption><thead><tr><th>Treatment</th><th>NNT</th><th>NNT lower</th><th>NNT upper</th></tr></thead><tbody><tr><td>ACEI</td><td>36.72</td><td>36.25</td><td>37.18</td></tr><tr><td>ACEI + ARB + BB + Dig</td><td>11.06</td><td>10.93</td><td>11.20</td></tr><tr><td>ACEI + ARB + Dig</td><td>23.86</td><td>23.56</td><td>24.16</td></tr><tr><td>ACEI + BB</td><td>12.74</td><td>12.59</td><td>12.90</td></tr><tr><td>ACEI + BB + Dig</td><td>12.36</td><td>12.21</td><td>12.51</td></tr><tr><td>ACEI + BB + Dig + H-ISDN</td><td>7.20</td><td>7.12</td><td>7.28</td></tr><tr><td>ACEI + BB + MRA</td><td>8.10</td><td>8.01</td><td>8.19</td></tr><tr><td>ACEI + BB + MRA + IVA</td><td>7.34</td><td>7.26</td><td>7.42</td></tr><tr><td>ACEI + BB + MRA + Omecamtiv</td><td>8.12</td><td>8.03</td><td>8.21</td></tr><tr><td>ACEI + BB + MRA + SGLT2</td><td>7.11</td><td>7.04</td><td>7.19</td></tr><tr><td>ACEI + BB + MRA + Vericiguat</td><td>7.12</td><td>7.04</td><td>7.20</td></tr><tr><td>ACEI + Dig</td><td>33.10</td><td>32.68</td><td>33.51</td></tr><tr><td>ACEI + MRA + Dig</td><td>11.69</td><td>11.55</td><td>11.83</td></tr><tr><td>ARB</td><td>77.70</td><td>76.72</td><td>78.68</td></tr><tr><td>ARB + BB</td><td>14.99</td><td>14.80</td><td>15.17</td></tr><tr><td>ARB + BB + Dig</td><td>14.43</td><td>14.26</td><td>14.61</td></tr><tr><td>ARB + BB + MRA</td><td>8.75</td><td>8.65</td><td>8.85</td></tr><tr><td>ARB + Dig</td><td>62.54</td><td>61.75</td><td>63.32</td></tr><tr><td>ARNI + BB</td><td>9.55</td><td>9.44</td><td>9.66</td></tr><tr><td>ARNI + BB + MRA</td><td>6.95</td><td>6.88</td><td>7.03</td></tr><tr><td>ARNI + BB + MRA + Omecamtiv</td><td>6.97</td><td>6.89</td><td>7.04</td></tr><tr><td>ARNI + BB + MRA + SGLT2</td><td>6.30</td><td>6.24</td><td>6.37</td></tr><tr><td>ARNI + BB + MRA + SGLT2 + Vericiguat</td><td>5.82</td><td>5.77</td><td>5.89</td></tr><tr><td>ARNI + BB + MRA + Vericiguat</td><td>6.31</td><td>6.24</td><td>6.37</td></tr><tr><td>ARNI + BB + SGLT2</td><td>8.07</td><td>7.98</td><td>8.16</td></tr><tr><td>BB</td><td>17.81</td><td>17.59</td><td>18.03</td></tr><tr><td>Dig</td><td>308.56</td><td>304.65</td><td>312.45</td></tr><tr><td>Dig + H-ISDN</td><td>12.08</td><td>11.93</td><td>12.22</td></tr><tr><td>PLBO</td><td>ref</td><td>ref</td><td>ref</td></tr></tbody></table>
<figure><img src="image_157.png" /></figure>
Supplementary Figures

Supplementary Figure 1: Mean or median age per study with 95% confidence intervals.

<figure><img src="image_158.png" /></figure>
<figure><img src="image_159.png" /></figure>
<figure><img src="image_160.png" /><figcaption>Supplementary Figure 2: Mean or median left ventricular ejection fraction per study with 95% confidence intervals.</figcaption></figure>
<figure><img src="image_161.png" /></figure>
<figure><img src="image_162.png" /><figcaption>Supplementary Figure 3: Risk of Bias.</figcaption></figure>
Supplementary Figure 4: Funnel Plots for (A) all-cause mortality, (B) cardiovascular mortality, (C) cardiovascular mortality and heart failure hospitalization.

Journal Pre-proof
A

<figure><img src="image_163.png" /></figure>

C

<figure><img src="image_164.png" /></figure>

B

<figure><img src="image_165.png" /></figure>

<figure><img src="image_166.png" /></figure>
**Supplementary Figure 5: Network for all-cause mortality.** The size of the edges is determined by the amount of patient-years follow-up for that comparison. The size of the nodes is related to the number of studies including that specific combination of drugs. ACEI: angiotensin-converting enzyme inhibitor; ARB: angiotensin receptor blocker; ARNI: angiotensin receptor/neprilysin inhibitor; BB: beta-blocker; Dig: digoxin; HR: hazard ratio; H-ISDN: hydralazine-isosorbide dinitrate; IVA: ivabradine; MRA: mineralocorticoid receptor antagonist; PLBO: placebo; SGLT2: sodium glucose cotransporter-2 inhibitors.

<figure><img src="image_167.png" /></figure>
**Supplementary Figure 6. Network plot of available direct treatment comparisons for all-cause mortality.** Each node represents a treatment regimen. Edges connect treatments compared head-to-head in at least one included trial, with edge thickness proportional to the number of trials. Only direct evidence is displayed. ACEI: angiotensin-converting enzyme inhibitor; ARB: angiotensin receptor blocker; ARNI: angiotensin receptor/neprilysin inhibitor; BB: beta-blocker; Dig: digoxin; HR: hazard ratio; H-ISDN: hydralazine-isosorbide dinitrate; IVA: ivabradine; MRA: mineralocorticoid receptor antagonist; PLBO: placebo; SGLT2: sodium glucose cotransporter-2 inhibitors.

<figure><img src="image_168.png" /></figure>
**Supplementary Figure 7.** Network plot of available direct treatment comparisons for cardiovascular mortality or heart failure hospitalization. Each node represents a treatment regimen. Edges connect treatments compared head-to-head in at least one included trial, with edge thickness proportional to the number of trials. Only direct evidence is displayed. ACEI: angiotensin-converting enzyme inhibitor; ARB: angiotensin receptor blocker; ARNI: angiotensin receptor/neprilysin inhibitor; BB: beta-blocker; Dig: digoxin; HR: hazard ratio; H-ISDN: hydralazine-isosorbide dinitrate; IVA: ivabradine; MRA: mineralocorticoid receptor antagonist; PLBO: placebo; SGLT2: sodium glucose cotransporter-2 inhibitors

<figure><img src="image_169.png" /></figure>
**Supplementary Figure 8. Network plot of available direct treatment comparisons for cardiovascular mortality.** Each node represents a treatment regimen. Edges connect treatments compared head-to-head in at least one included trial, with edge thickness proportional to the number of trials. Only direct evidence is displayed. ACEI: angiotensin-converting enzyme inhibitor; ARB: angiotensin receptor blocker; ARNI: angiotensin receptor/neprilysin inhibitor; BB: beta-blocker; Dig: digoxin; HR: hazard ratio; H-ISDN: hydralazine-isosorbide dinitrate; IVA: ivabradine; MRA: mineralocorticoid receptor antagonist; PLBO: placebo; SGLT2: sodium glucose cotransporter-2 inhibitors

<figure><img src="image_170.png" /></figure>
Supplementary Figure 3. Era-stratified analyses for all-cause mortality. Pre-2000 era: placebo was used as the reference category. Heterogeneity: I2 = 2.90%, 95% CI 0 – 42.5%. Q p-value: 0.42, tau 0.043.

<figure><img src="image_171.png" /></figure>
Supplementary Figure 10. Era-stratified analyses for all-cause mortality. Era between 2000-2010.

The upper diagram is the first subnetwork (I2 0, 95% CI 0-56.6%, Qpvalue 0.67, tau 0), ACE inhibitors were used as the reference category. The lower diagram is the second subnetwork (I2 22.2%, 95% CI 0-61.2%, Qpvalue 0.23, tau 0.09), digoxine was used as the reference category.

<figure><img src="image_172.png" /></figure>

<figure><img src="image_173.png" /></figure>
**Supplementary Figure 11.** Era-stratified analyses for all-cause mortality. Post-2010 era. Treatment with ACE-inhibitors and beta-blockers was used as the reference category (I2 0%, 95% CI 0-52.3%, Qpvalue 0.98, tau 0). *quintuple therapy is dependent on one randomized controlled trial (VICTOR) and the estimates should be interpreted with caution.

<figure><img src="image_174.png" /></figure>
<table><caption>Supplementary Figure 12. Sensitivity analysis leave-one-out analysis excluding VIO ORI trial results for all-cause mortality.</caption><thead><tr><th>Treatment</th><th>All-cause mortality</th><th>HR</th><th>95%-CI</th></tr></thead><tbody><tr><td>ARNI + BB + MRA + SGLT2</td><td></td><td>0.39</td><td>[0.32; 0.49]</td></tr><tr><td>ARNI + BB + MRA + Vericiguat</td><td></td><td>0.42</td><td>[0.33; 0.54]</td></tr><tr><td>ARNI + BB + MRA</td><td></td><td>0.45</td><td>[0.37; 0.54]</td></tr><tr><td>ARNI + BB + MRA + Omecamtiv</td><td></td><td>0.45</td><td>[0.37; 0.55]</td></tr><tr><td>ACEI + BB + MRA + SGLT2</td><td></td><td>0.46</td><td>[0.38; 0.56]</td></tr><tr><td>ACEI + BB + Dig + H-ISDN</td><td></td><td>0.47</td><td>[0.36; 0.61]</td></tr><tr><td>ACEI + BB + MRA + IVA</td><td></td><td>0.48</td><td>[0.39; 0.58]</td></tr><tr><td>ACEI + BB + MRA + Vericiguat</td><td></td><td>0.49</td><td>[0.39; 0.62]</td></tr><tr><td>ARNI + BB + SGLT2</td><td></td><td>0.52</td><td>[0.43; 0.63]</td></tr><tr><td>ACEI + BB + MRA</td><td></td><td>0.52</td><td>[0.44; 0.62]</td></tr><tr><td>ACEI + BB + MRA + Omecamtiv</td><td></td><td>0.52</td><td>[0.44; 0.63]</td></tr><tr><td>ARB + BB + MRA</td><td></td><td>0.56</td><td>[0.47; 0.65]</td></tr><tr><td>ARNI + BB</td><td></td><td>0.59</td><td>[0.51; 0.69]</td></tr><tr><td>ACEI + ARB + BB + Dig</td><td></td><td>0.65</td><td>[0.55; 0.76]</td></tr><tr><td>ACEI + MRA + Dig</td><td></td><td>0.66</td><td>[0.56; 0.78]</td></tr><tr><td>Dig + H-ISDN</td><td></td><td>0.68</td><td>[0.53; 0.86]</td></tr><tr><td>ACEI + BB + Dig</td><td></td><td>0.68</td><td>[0.59; 0.78]</td></tr><tr><td>ACEI + BB</td><td></td><td>0.69</td><td>[0.62; 0.77]</td></tr><tr><td>ARB + BB + Dig</td><td></td><td>0.73</td><td>[0.63; 0.83]</td></tr><tr><td>ARB + BB</td><td></td><td>0.74</td><td>[0.66; 0.82]</td></tr><tr><td>BB</td><td></td><td>0.78</td><td>[0.72; 0.84]</td></tr><tr><td>ACEI + ARB + Dig</td><td></td><td>0.83</td><td>[0.72; 0.96]</td></tr><tr><td>ACEI + Dig</td><td></td><td>0.88</td><td>[0.78; 0.98]</td></tr><tr><td>ACEI</td><td></td><td>0.89</td><td>[0.82; 0.96]</td></tr><tr><td>ARB + Dig</td><td></td><td>0.94</td><td>[0.84; 1.04]</td></tr><tr><td>ARB</td><td></td><td>0.95</td><td>[0.88; 1.02]</td></tr><tr><td>Dig</td><td></td><td>0.99</td><td>[0.91; 1.07]</td></tr></tbody></table>
Supplementary Figure 10. Sensitivity analysis leave-one-out analysis excluding VIOKEK trial results for cardiovascular mortality or heart failure hospitalization.

<figure><img src="image_175.png" /></figure>
<table><caption>Supplementary Figure 14. Sensitivity analysis leave-one-out analysis excluding VIOKEK trial results for cardiovascular mortality.</caption><thead><tr><th>Treatment</th><th>CV mortality</th><th>IRR</th><th>95%-CI</th></tr></thead><tbody><tr><td>ARNI + BB + MRA + SGLT2</td><td></td><td>0.34</td><td>[0.27; 0.44]</td></tr><tr><td>ARNI + BB + MRA + Vericiguat</td><td></td><td>0.36</td><td>[0.27; 0.48]</td></tr><tr><td>ARNI + BB + MRA + Omecamtiv</td><td></td><td>0.37</td><td>[0.28; 0.48]</td></tr><tr><td>ARNI + BB + MRA</td><td></td><td>0.39</td><td>[0.32; 0.49]</td></tr><tr><td>ACEI + BB + MRA + SGLT2</td><td></td><td>0.42</td><td>[0.33; 0.52]</td></tr><tr><td>ACEI + BB + MRA + IVA</td><td></td><td>0.44</td><td>[0.35; 0.55]</td></tr><tr><td>ACEI + BB + MRA + Vericiguat</td><td></td><td>0.44</td><td>[0.34; 0.57]</td></tr><tr><td>ACEI + BB + MRA + Omecamtiv</td><td></td><td>0.45</td><td>[0.35; 0.57]</td></tr><tr><td>ARNI + BB + SGLT2</td><td></td><td>0.47</td><td>[0.38; 0.58]</td></tr><tr><td>ACEI + BB + MRA</td><td></td><td>0.48</td><td>[0.40; 0.58]</td></tr><tr><td>ARB + BB + MRA</td><td></td><td>0.50</td><td>[0.41; 0.61]</td></tr><tr><td>ARNI + BB</td><td></td><td>0.53</td><td>[0.45; 0.63]</td></tr><tr><td>ACEI + BB + Dig + H-ISDN</td><td></td><td>0.58</td><td>[0.37; 0.90]</td></tr><tr><td>ACEI + ARB + BB + Dig</td><td></td><td>0.58</td><td>[0.47; 0.70]</td></tr><tr><td>ACEI + MRA + Dig</td><td></td><td>0.62</td><td>[0.52; 0.75]</td></tr><tr><td>ACEI + BB</td><td></td><td>0.65</td><td>[0.57; 0.74]</td></tr><tr><td>ACEI + BB + Dig</td><td></td><td>0.66</td><td>[0.56; 0.77]</td></tr><tr><td>ARB + BB</td><td></td><td>0.68</td><td>[0.59; 0.78]</td></tr><tr><td>ACEI + ARB + Dig</td><td></td><td>0.74</td><td>[0.62; 0.88]</td></tr><tr><td>BB</td><td></td><td>0.78</td><td>[0.71; 0.86]</td></tr><tr><td>ACEI</td><td></td><td>0.84</td><td>[0.77; 0.91]</td></tr><tr><td>ACEI + Dig</td><td></td><td>0.85</td><td>[0.75; 0.96]</td></tr><tr><td>ARB</td><td></td><td>0.88</td><td>[0.79; 0.97]</td></tr><tr><td>Dig + H-ISDN</td><td></td><td>0.88</td><td>[0.58; 1.34]</td></tr><tr><td>ARB + Dig</td><td></td><td>0.89</td><td>[0.77; 1.01]</td></tr><tr><td>Dig</td><td></td><td>1.01</td><td>[0.93; 1.10]</td></tr></tbody></table>
<table><caption>Supplementary Figure 15. Sensitivity analysis with background therapy cut-off of 70%. Forest plot for treatment effects of treatment regimens for all-cause mortality.</caption><thead><tr><th>Treatment</th><th>All-cause mortality</th><th>HR</th><th>95%-CI</th></tr></thead><tbody><tr><td>ARNI + BB + MRA + SGLT2</td><td></td><td>0.38</td><td>[0.29; 0.48]</td></tr><tr><td>ARNI + BB + MRA + Vericiguat</td><td></td><td>0.40</td><td>[0.32; 0.49]</td></tr><tr><td>ACEI + BB + MRA + SGLT2</td><td></td><td>0.44</td><td>[0.35; 0.55]</td></tr><tr><td>ARNI + BB + MRA</td><td></td><td>0.45</td><td>[0.37; 0.54]</td></tr><tr><td>ARNI + BB + MRA + Omecamtiv</td><td></td><td>0.45</td><td>[0.37; 0.55]</td></tr><tr><td>ACEI + BB + H-ISDN</td><td></td><td>0.47</td><td>[0.37; 0.61]</td></tr><tr><td>ACEI + BB + MRA + IVA</td><td></td><td>0.48</td><td>[0.39; 0.58]</td></tr><tr><td>ARNI + BB + SGLT2</td><td></td><td>0.50</td><td>[0.40; 0.62]</td></tr><tr><td>ACEI + BB + MRA</td><td></td><td>0.52</td><td>[0.44; 0.62]</td></tr><tr><td>ARNI + BB</td><td></td><td>0.59</td><td>[0.51; 0.69]</td></tr><tr><td>ACEI + BB + Vericiguat</td><td></td><td>0.61</td><td>[0.52; 0.71]</td></tr><tr><td>ACEI + BB + IVA</td><td></td><td>0.63</td><td>[0.53; 0.74]</td></tr><tr><td>ACEI + ARB + BB</td><td></td><td>0.66</td><td>[0.57; 0.76]</td></tr><tr><td>ACEI + MRA + Dig</td><td></td><td>0.66</td><td>[0.56; 0.78]</td></tr><tr><td>ACEI + MRA</td><td></td><td>0.67</td><td>[0.58; 0.78]</td></tr><tr><td>Dig + H-ISDN</td><td></td><td>0.68</td><td>[0.53; 0.86]</td></tr><tr><td>ACEI + BB + Dig</td><td></td><td>0.68</td><td>[0.59; 0.78]</td></tr><tr><td>H-ISDN</td><td></td><td>0.68</td><td>[0.54; 0.86]</td></tr><tr><td>ACEI + BB</td><td></td><td>0.69</td><td>[0.62; 0.77]</td></tr><tr><td>ACEI + BB + Omecamtiv</td><td></td><td>0.69</td><td>[0.60; 0.80]</td></tr><tr><td>ARB + BB</td><td></td><td>0.74</td><td>[0.66; 0.82]</td></tr><tr><td>ARNI</td><td></td><td>0.76</td><td>[0.67; 0.87]</td></tr><tr><td>BB</td><td></td><td>0.78</td><td>[0.72; 0.84]</td></tr><tr><td>ACEI + ARB + Dig</td><td></td><td>0.83</td><td>[0.72; 0.96]</td></tr><tr><td>ACEI + ARB</td><td></td><td>0.84</td><td>[0.75; 0.95]</td></tr><tr><td>ACEI + Dig</td><td></td><td>0.88</td><td>[0.78; 0.98]</td></tr><tr><td>ACEI</td><td></td><td>0.89</td><td>[0.82; 0.96]</td></tr><tr><td>ARB + Dig</td><td></td><td>0.94</td><td>[0.84; 1.04]</td></tr><tr><td>ARB</td><td></td><td>0.95</td><td>[0.88; 1.02]</td></tr><tr><td>Dig</td><td></td><td>0.99</td><td>[0.91; 1.07]</td></tr></tbody></table>
Supplementary Figure 10. Sensitivity analysis with background therapy cut-off of 70%. Forest plot for treatment effects of treatment regimens for cardiovascular mortality or heart failure hospitalization. ACE-inhibitors were used as reference category.

<figure><img src="image_176.png" /></figure>
<figure><img src="image_177.png" /><figcaption>Supplementary Figure 17: Sensitivity analysis with background therapy cut-off of 70%. Forest plot for treatment effects of treatment regimens for cardiovascular mortality.</figcaption></figure>
<table><caption>Supplementary Figure 10: Sensitivity analysis with background therapy cut-off of 50%. Forest plot for treatment effects of treatment regimens for all-cause mortality.</caption><thead><tr><th>Treatment</th><th>All-cause mortality</th><th>HR</th><th>95%-CI</th></tr></thead><tbody><tr><td>ARNI + BB + MRA</td><td></td><td>0.47</td><td>[0.39; 0.56]</td></tr><tr><td>ARNI + BB + Vericiguat</td><td></td><td>0.47</td><td>[0.39; 0.57]</td></tr><tr><td>ACEI + BB + MRA + SGLT2</td><td></td><td>0.48</td><td>[0.40; 0.58]</td></tr><tr><td>ARNI + BB + SGLT2</td><td></td><td>0.52</td><td>[0.43; 0.63]</td></tr><tr><td>ACEI + BB + MRA</td><td></td><td>0.55</td><td>[0.47; 0.64]</td></tr><tr><td>BB + MRA + IVA</td><td></td><td>0.56</td><td>[0.47; 0.67]</td></tr><tr><td>ARNI + BB</td><td></td><td>0.59</td><td>[0.51; 0.69]</td></tr><tr><td>ARNI + BB + Omecamtiv</td><td></td><td>0.59</td><td>[0.50; 0.71]</td></tr><tr><td>BB + MRA</td><td></td><td>0.61</td><td>[0.54; 0.70]</td></tr><tr><td>BB + Vericiguat</td><td></td><td>0.62</td><td>[0.54; 0.71]</td></tr><tr><td>ACEI + ARB + BB</td><td></td><td>0.66</td><td>[0.57; 0.76]</td></tr><tr><td>Dig + H-ISDN</td><td></td><td>0.68</td><td>[0.53; 0.86]</td></tr><tr><td>ACEI + BB + Dig</td><td></td><td>0.68</td><td>[0.59; 0.78]</td></tr><tr><td>BB + SGLT2</td><td></td><td>0.68</td><td>[0.59; 0.79]</td></tr><tr><td>H-ISDN</td><td></td><td>0.68</td><td>[0.54; 0.86]</td></tr><tr><td>ACEI + BB</td><td></td><td>0.69</td><td>[0.62; 0.77]</td></tr><tr><td>ACEI + BB + Omecamtiv</td><td></td><td>0.69</td><td>[0.60; 0.80]</td></tr><tr><td>ACEI + MRA</td><td></td><td>0.70</td><td>[0.62; 0.80]</td></tr><tr><td>BB + IVA</td><td></td><td>0.71</td><td>[0.61; 0.82]</td></tr><tr><td>ARB + BB</td><td></td><td>0.74</td><td>[0.66; 0.82]</td></tr><tr><td>ARNI</td><td></td><td>0.76</td><td>[0.67; 0.87]</td></tr><tr><td>BB</td><td></td><td>0.78</td><td>[0.72; 0.84]</td></tr><tr><td>ACEI + SGLT2</td><td></td><td>0.78</td><td>[0.68; 0.90]</td></tr><tr><td>MRA</td><td></td><td>0.79</td><td>[0.71; 0.88]</td></tr><tr><td>ACEI + IVA</td><td></td><td>0.81</td><td>[0.70; 0.93]</td></tr><tr><td>ACEI + ARB + Dig</td><td></td><td>0.83</td><td>[0.72; 0.96]</td></tr><tr><td>ACEI + ARB</td><td></td><td>0.84</td><td>[0.75; 0.95]</td></tr><tr><td>ACEI + Dig</td><td></td><td>0.88</td><td>[0.78; 0.98]</td></tr><tr><td>ACEI</td><td></td><td>0.89</td><td>[0.82; 0.96]</td></tr><tr><td>ARB</td><td></td><td>0.95</td><td>[0.88; 1.02]</td></tr><tr><td>Dig</td><td></td><td>0.99</td><td>[0.91; 1.07]</td></tr></tbody></table>
Supplementary Figure 15. Sensitivity analysis with background therapy cut-off of 50%. Forest plot for treatment effects of treatment regimens for cardiovascular mortality or heart failure hospitalization. ACE-inhibitors were used as reference category.

<figure><img src="image_178.png" /></figure>
<table><caption>Supplementary Figure 20. Sensitivity analysis with background therapy cut-off of 50%. Forest plot for treatment effects of treatment regimens for cardiovascular mortality.</caption><thead><tr><th>Treatment</th><th>CV mortality</th><th>IRR</th><th>95%-CI</th></tr></thead><tbody><tr><td>ARNI + BB + Vericiguat</td><td></td><td>0.42</td><td>[0.34; 0.52]</td></tr><tr><td>ACEI + BB + MRA + SGLT2</td><td></td><td>0.44</td><td>[0.35; 0.54]</td></tr><tr><td>ARNI + BB + SGLT2</td><td></td><td>0.47</td><td>[0.38; 0.58]</td></tr><tr><td>ARNI + BB + Omecamtiv</td><td></td><td>0.50</td><td>[0.40; 0.62]</td></tr><tr><td>ACEI + BB + MRA</td><td></td><td>0.50</td><td>[0.42; 0.60]</td></tr><tr><td>ARNI + BB</td><td></td><td>0.53</td><td>[0.45; 0.63]</td></tr><tr><td>BB + MRA + IVA</td><td></td><td>0.55</td><td>[0.45; 0.67]</td></tr><tr><td>ARNI + SGLT2</td><td></td><td>0.60</td><td>[0.49; 0.72]</td></tr><tr><td>BB + MRA</td><td></td><td>0.60</td><td>[0.52; 0.70]</td></tr><tr><td>BB + Vericiguat</td><td></td><td>0.61</td><td>[0.52; 0.71]</td></tr><tr><td>ACEI + BB + Omecamtiv</td><td></td><td>0.61</td><td>[0.50; 0.74]</td></tr><tr><td>ACEI + MRA</td><td></td><td>0.65</td><td>[0.56; 0.75]</td></tr><tr><td>ACEI + BB</td><td></td><td>0.65</td><td>[0.57; 0.74]</td></tr><tr><td>ACEI + BB + Dig</td><td></td><td>0.66</td><td>[0.56; 0.77]</td></tr><tr><td>BB + SGLT2</td><td></td><td>0.68</td><td>[0.58; 0.80]</td></tr><tr><td>ARB + BB</td><td></td><td>0.68</td><td>[0.59; 0.78]</td></tr><tr><td>ARNI</td><td></td><td>0.69</td><td>[0.60; 0.79]</td></tr><tr><td>BB + IVA</td><td></td><td>0.71</td><td>[0.61; 0.83]</td></tr><tr><td>ACEI + ARB</td><td></td><td>0.73</td><td>[0.63; 0.85]</td></tr><tr><td>ACEI + IVA</td><td></td><td>0.76</td><td>[0.65; 0.89]</td></tr><tr><td>MRA</td><td></td><td>0.77</td><td>[0.69; 0.87]</td></tr><tr><td>BB</td><td></td><td>0.78</td><td>[0.71; 0.86]</td></tr><tr><td>ACEI</td><td></td><td>0.84</td><td>[0.77; 0.91]</td></tr><tr><td>ACEI + Dig</td><td></td><td>0.85</td><td>[0.75; 0.96]</td></tr><tr><td>H-ISDN</td><td></td><td>0.87</td><td>[0.58; 1.31]</td></tr><tr><td>ARB</td><td></td><td>0.88</td><td>[0.79; 0.97]</td></tr><tr><td>Dig</td><td></td><td>1.01</td><td>[0.93; 1.10]</td></tr></tbody></table>
<figure><img src="image_179.png" /><figcaption>Supplementary Figure 21. Forest plots displaying the estimated effect sizes for individual drugs after exclusion of the A-HeFT trial.</figcaption></figure>
# Protocol and Search Strategy

## Protocol

**Aim:** Evaluate the efficacy of heart failure pharmacotherapy using a network meta-analysis approach.

## Population

Patients with heart failure with reduced ejection fraction (LVEF<50%).

Participants given the study drug as outpatients or after stabilization following hospitalization for HF.

Entire studies exclusively enrolling a specific sub-population (e.g., patients post-myocardial infarction, or patients with diabetes) are excluded.

Studies treating patients exclusively in the acute phase of heart failure are excluded.

No limit on background therapy.

## Intervention

ARB

ACEi

ARNI

β-blockers

MRA

Isosorbide dinitrate and hydralazine

Ivabradine

SGLT2 inhibitors

Vericiguat

Omecamtiv-mecarbil

Digoxin

GLP1 receptor agonists

## Comparison

Control: Placebo

Interclass comparisons: any of the medications listed above. Intraclass comparisons are excluded.

## Outcome

Primary:

-All-cause mortality

Secondary:

-Cardiovascular death or hospitalization for HF.

-Cardiovascular death.

-Hospitalization for HF.

-Discontinuation of the study drug.

## Search strategy

The current study will update the findings from a previous network meta-analysis (Tromp et al, JACC-HF, 2021). A new search will be conducted for the period 2021 – 2025, complementing the previous period. In addition, GLP1 receptor agonists will be added to the current analysis.

Databases searched:

MEDLINE (via ovidsp.ovid.com), Embase (via ovidsp.ovid.com), and CENTRAL (via www.cochranelibrary.com)

From January 2021 and May 2025

The search will be carried out by BE. References are collected in Rayyan where duplicates will be handled.

## In- and exclusion criteria

### Inclusion

Adult populations (≥18 years)

Randomized clinical trials

HFrEF (left ventricular ejection fraction [LVEF] <50%)

Enrolled in the outpatient setting or after stabilization following hospitalization for HF

Drug classes currently recommended or proven effective in treating HFrEF

### Exclusion

Studies where the entire population had a concomitant diagnosis likely affecting outcome (e.g., LV dysfunction post myocardial infarction)
Studies treating patients in the acute phase of MI

Comparisons within the same drug class

**Screening:** References will be uploaded to Rayyan (https://rayyan.qcri.org/welcome). Title and abstracts will be screened for relevance by two authors picked from a screening team of four members (BE, DC, GT, TH, AK, HF) blinded to each other's choices with complete overlap of all studies. A specific reason will not be recorded. Articles inconsistently selected between the two reviewers, will be discussed and in- or excluded based on consensus.

**Review:** Articles remaining were reviewed by BE and DC in parallel and blinded. Articles not adhering to the inclusion and exclusion criteria were excluded. Articles inconsistently selected between the two reviewers, will be discussed and in- or excluded based on consensus.

Finally, additional systematic reviews and network meta-analysis relevant to the topic will be searched on MEDLINE. Any relevant articles will be hand screened for additional relevant trials.

## Data extraction

Two study authors (BE and DC) will extract the data in a parallel and independently on a dedicated standardized spread sheet in Microsoft Excel. The spreadsheets will be compared between the two reviewers to ensure validity of data extraction. The following information will be extracted:

- Trial information: authors, study acronym, year, journal of publication

- Characteristics of the trial: yes/no for double blind, multi center, multi country

- Per treatment arm: total number of participants, mean age with SD, mean LVEF with SD, number of men, number of patients with NYHA class I/II and III/IV, diabetes, ischemic heart failure, and diabetes mellitus, number of patients on background therapy.

- Per treatment arm outcomes mean or median follow-up time, absolute number of deaths, CV deaths, hospitalization for HF and composite of CV death and hospitalization for HF, number of participants discontinuing the drug.

## Statistical analyses

A frequentist random and fixed effects network and pair-wise meta-analysis will be performed using the netmeta package in R. Total event counts and numbers will be used to generate pooled risk ratios. Results will be presented as risk ratio with 95% CI. Studies with no events in either arm will be excluded. Studies with events in one arm, but no events in the other will have a continuity correction applied to the zero arm of 0.5. Heterogeneity will be assessed using the I² values, which represent the amount of inconsistency in our networks. Exploiting the fact that some treatments are combinations of common components, an additive component network meta-analysis model can be used to evaluate the influence of individual components. This model assumes that the effect of treatment combinations is the sum of the effects of its components. Calculating additive treatment effects from multiple randomized trials provides useful estimates of combination therapies. Treatments will be categorized by drug group combination using a patient threshold of 50%. if >50% of patients received concomitant pharmacotherapy of interest, the treatment is described as a combination therapy. In addition, we included the surface under the cumulative ranking curve (SUCRA) P-scores to provide a ranking of treatment combinations.

## Risk of bias assessment

We will use the Cochrane tool to assess risk of bias¹. This will be done independently by two investigators, discrepancies will be solved through discussion and mutual agreement. Risk of bias will be presented as a figure, summarizing the risk per component of bias. To further assess confidence of in the network meta-analysis, we implemented the Confidence in Network Meta-Analysis (CINEMA) framework to assess (i) within-study bias, (ii) reporting bias, (iii) indirectness, (iv) imprecision, (v) heterogeneity, and (vi) incoherence². To assess within study bias, we will use the Cochrane tool classifying as ‘low’, ‘medium’ and ‘high’ across 6-domains including (missing data, selective reporting, imbalanced dropout, similar groups at baseline, treatment allocation blinding, allocation concealment and randomization)¹. We will use the average of all 6 domains to assess overall within study bias – if more than 3 domains are considered high risk, the study was considered high risk, otherwise it is considered low risk. Reporting bias will be formally tested using the Egger test, which assesses the symmetry of funnel plots³. When this is non-significant, we consider risk of reporting bias as ‘low’. Indirectness, will be assessed based on published guidelines⁴. To assess heterogeneity, we will calculate I² values⁵. The used model will be determined by the degree
of heterogeneity, with random effects favored in the presence of heterogeneity (I > 50%), incongruence will be assessed using a global test based on a random-effects design-by-treatment interaction model.

## Sensitivity analyses

Given the low (<50%) use of ARNIs in real-world populations with HFrEF<sup>6,7</sup>, and recent clinical trials<sup>8</sup>; we will consider more recent clinical trials using two approaches; (1) against a background of ARNi, and (2) against a background of ACEi. Primary results will be presented against a background of ARNi, results against a background of ACEi will be presented as a sensitivity analyses.

<figure><img src="image_180.png" /></figure>
Search strategy

MEDLINE(R)/EMBASE search – Update 2021-2025

1. exp Heart Failure/

2. Cardiomyopathy, Dilated/

3. (heart failure or cardiac failure or cardiac insufficiency or cardiomyopathy$).tw.

4. ((cardi$ or myocard$) adj2 (failure$ or insufficien$)).tw.

5. OR/1-4

6. exp angiotensin receptor-neprilysin inhibitor/ OR ARNI

7. LCZ696 OR LCZ 696 OR LCZ-696 OR valsartan adj6 sacubitril OR valsartan adj6 sacubitril OR sacubitril OR sacubitril OR sacubitril adj6 valsartan OR sacubitril valsartan OR sacubitril-valsartan

8. exp dipeptidyl carboxypeptidase inhibitor/ OR exp Angiotensin-Converting Enzyme Inhibitors/

9. (angiotensin converting enzyme inhibitor OR ACEI OR ACEI OR antagonist$ OR inhibitor$ benazepril OR captopril OR enalapril OR fosinopril OR imidapril OR lisinopril OR moexipril OR perindopril OR quinapril OR ramipril OR trandolapril OR zofenopril OR alacepril OR cilazapril OR spirapril OR delapril).mp.

10. exp beta adrenergic receptor blocking agent/ OR exp Adrenergic beta-Antagonists/

11. (beta blocker$ OR BB OR acebutolol OR atenolol OR betaxolol OR bisoprolol OR carvedilol OR labetalol OR metoprolol OR nadolol OR nebivolol OR penbutolol OR pindolol OR propranolol OR sotalol OR timolol).mp.

12. exp aldosterone antagonist/

13. (aldosterone antagonist$ OR mineralocorticoid-receptor antagonist OR MRA OR eplerenone OR spironolactone OR finerenone OR non-steroidal MRA OR nonsteroidal MRA).mp.

14. exp angiotensin receptor antagonist/

15. (angiotensin receptor blocker$ OR angiotensin receptor antagonist$ OR ARB OR azilsartan OR candesartan OR eprosartan OR irbesartan OR losartan OR olmesartan OR telmisartan OR valsartan).mp.

16. sodium-glucose co-transporter 2 OR SGLT2 OR SGLT2 inhibitor* OR sodium glucose adj6 inhibitor* OR (SGLT2 inhibitor*) OR sodium-glucose adj6 inhibitor* OR Sodium-Glucose Transporter 2 OR sodium glucose-cotransporter 2 OR sodium-glucose co-transporter$ OR sodium glucose-cotransporter$

17. (dapagliflozin OR empagliflozin).mp.

18 exp ivabradine plus metoprolol/ or exp ivabradine/ or exp carvedilol plus ivabradine/

19 (Omecamtiv mecarbil OR CK-1827452 OR Omecamtiv OR mecarbil)

20 (Vericiguat OR guanylate cyclase stimulator OR guanylate cyclase stimulator)

21. (Hydralazine-Isosorbide Dinitrate OR Hydralazine-Isosorbide adj6 Dinitrate OR Hydralazine Isosorbide Dinitrate OR Hydralazine adj6 Isosorbide adj6 Dinitrate)

22. digoxin* OR lanoxin*

23. OR/6-22

24. "randomized controlled trial".pt.

25. (random$ or placebo$ or single blind$ or double blind$ or triple blind$).ti,ab.

26. (retraction of publication or retracted publication).pt.

27. OR/24-26

28. (animals not humans).sh.

29. ((comment or editorial or meta-analysis or practice-guideline or review or letter or journal correspondence) not "randomized controlled trial").pt.

30. (random sampl$ or random digit$ or random effect$ or random survey or random regression).ti,ab. not "randomized controlled trial".pt.

31. 28 OR 29 OR 30

32. 27 NOT 31

33. (random$ or placebo$ or single blind$ or double blind$ or triple blind$).ti,ab.

34. RETRACTED ARTICLE/

35. OR/33-34

36. (animal$ not human$).sh,hw.

37. (book or conference paper or editorial or letter or review).pt. not exp randomized controlled trial/

38. (random sampl$ or random digit$ or random effect$ or random survey or random regression).ti,ab. not exp randomized controlled trial/

39. OR/36-38

40. 35 NOT 39

41. 32 OR 40
42. 3 AND 22 AND 1

43. limit 42 to (human and yr="2021-Current" and (adult <18 to 64 years> or aged <65+ years>))

MEDLINE(R)/EMBASE search – GLP1

1. exp Heart Failure/

2. Cardiomyopathy, Dilated/

3. (heart failure or cardiac failure or cardiac insufficiency or cardiomyopath$).tw.

4. ((cardi$ or myocard$) adj2 (failure$ or insufficien$)).tw.

5. OR/1-4

6. (GLP-1 receptor agonist* or glucagon-like peptide-1 receptor agonist* or GLP1RA or GLP1a or liraglutide or semaglutide or dulaglutide or albiglutide or exenatide or lixisenatide or efpeglenatide or tirzepatide).tw.

7. "randomized controlled trial".pt.

8. (random$ or placebo$ or single blind$ or double blind$ or triple blind$).ti,ab.

9. (retraction of publication or retracted publication).pt.

10. OR/7-9

11. (animals not humans).sh.

12. ((comment or editorial or meta-analysis or practice-guideline or review or letter or journal correspondence) not "randomized controlled trial").pt.

13. (random sampl$ or random digit$ or random effect$ or random survey or random regression).ti,ab. not "randomized controlled trial".pt.

14. 11 OR 12 OR 13

15. 10 NOT 14

16. (random$ or placebo$ or single blind$ or double blind$ or triple blind$).ti,ab.

17. RETRACTED ARTICLE/

18. OR/16-17

19. (animal$ not human$).sh,hw.

20. (book or conference paper or editorial or letter or review).pt. not exp randomized controlled trial/

21. (random sampl$ or random digit$ or random effect$ or random survey or random regression).ti,ab. not exp randomized controlled trial/

22. OR/19-21

23. 18 NOT 22

24. 15 OR 23

25. 5 AND 6 AND 24

26. limit 25 to (human and yr="1987-Current" and (adult <18 to 64 years> or aged <65+ years>))

Cochrane Clinical Trial search – Update 2021-2025

#1 MeSH descriptor: [Heart Failure] explode all trees

#2 MeSH descriptor: [Cardiomyopathy, Dilated] explode all trees

#3 (heart failure or cardiac failure or cardiac insufficiency or cardiomyopath$):ti,ab,kw

#4 #1 or #2 or #3

#5 (LCZ696 or LCZ 696 or LCZ-696 or valsartan adj6 sacubitril or valsartan adj6 sacubitril or valsartan sacubitril or valsartan-sacubitril or sacubitril adj6 valsartan or sacubitril valsartan or sacubitril- valsartan):ti,ab,kw

#6 MeSH descriptor: [Angiotensin-Converting Enzyme Inhibitors] explode all trees 5189

#7 (angiotensin converting enzyme inhibitor or ACEI or ACEI or antagonist$ or inhibitor$ benazepril or captopril or enalapril or fosinopril or imidapril or lisinopril or moexipril or perindopril or quinapril or ramipril or trandolapril or zofenopril or alacepril or cilazapril or spirapril or delapril):ti,ab,kw

#8 MeSH descriptor: [Adrenergic beta-Antagonists] explode all trees

#9 (beta blocker$ or BB or acebutolol or atenolol or betaxolol or bisoprolol or carvedilol or labetalol or metoprolol or nadolol or nebivolol or penbutolol or pindolol or propranolol or sotalol or timolol):ti,ab,kw

#10 MeSH descriptor: [Mineralocorticoid Receptor Antagonists] explode all trees

#11 (aldosterone antagonist* or mineralocorticoid-receptor antagonist* or MRA or eplerenone or spironolactone or non-steroidal MRA or nonsteroidal MRA or finerenone):ti,ab

#12 MeSH descriptor: [Angiotensin Receptor Antagonists] explode all trees

#13 (angiotensin receptor blocker$ or angiotensin receptor antagonist$ or ARB or azilsartan or candesartan or eprosartan or irbesartan or losartan or olmesartan or telmisartan or valsartan):ti,ab,kw
#14 MeSH descriptor: [Sodium-Glucose Transporter 2 inhibitors] explode all trees

#15 (sodium-glucose co-transporter 2 or SGLT2 or SGLT2 inhibitor* or sodium glucose adj6 inhibitor* OR (SGLT2 inhibitor*) or sodium-glucose adj6 inhibitor* or Sodium-Glucose Transporter 2 or sodium glucose-cotransporter 2 or sodium-glucose co-transporter$ or sodium glucose-cotransporter$):ti,ab,kw

#16 (dapagliflozin or empagliflozin):ti,ab,kw

#17 MeSH descriptor: [Digoxin] explode all trees

#18 digoxin* or lanoxin*

#19 MeSH descriptor: [Ivabradine] explode all trees

#20 (ivabradine plus metoprolol or ivabradine or exp carvedilol plus ivabradine):ti,ab,kw

#21 (Omecamtiv mecarbil or CK-1827452 or Omecamtiv or mecarbil):ti,ab,kw

#22 (Vericiguat OR guanylate cyclase stimulator OR guanylate cyclase stimulator):ti,ab,kw

#23 (Hydralazine-Isosorbide Dinitrate OR Hydralazine-Isosorbide adj6 Dinitrate OR Hydralazine Isosorbide Dinitrate OR Hydralazine adj6 Isosorbide adj6 Dinitrate):ti,ab,kw

#24 #5 or #6 or #7 or #8 or #9 or #10 or #11 or #12 or #13 or #14 or #15 or #16 or #17 or #18 or #19 or #20 or #21 or #22 or #23

#25 #4 and #24

#26 human not animal

#27 #25 and #26

#28 #27 in trials with Cochrane Library publication date Between Jan 2021 and May 2025

## Cochrane Clinical Trial search – GLP1

#1 MeSH descriptor: [Heart Failure] explode all trees

#2 MeSH descriptor: [Cardiomyopathy, Dilated] explode all trees

#3 (heart failure or cardiac failure or cardiac insufficiency or cardiomyopath$):ti,ab,kw

#4 #1 or #2 or #3

#5 MeSH descriptor: [Glucagon-Like Peptide-1 Receptor Agonists] explode all trees

#6 ((GLP-1 receptor agonist*) OR (glucagon-like peptide-1 receptor agonist*) OR GLP1RA OR GLP1a OR liraglutide OR semaglutide OR dulaglutide OR albiglutide OR exenatide OR lixisenatide OR efpeglenatide OR tirzepatide)

#7 #6

#8 #4 and #7

#9 human not animal

#10 #8 and #9

#11 #10 in trials with Cochrane Library publication date Between Jan 1987 and May 2025
References

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2. Nikolakopoulou A, Higgins JPT, Papakonstantinou T, Chaimani A, Giovane C Del, Egger M, Salanti G. CINEMA: An approach for assessing confidence in the results of a network meta-analysis. *PLoS Med* 2020;17:e1003082.

3. Sterne JAC, Egger M, Smith GD. Systematic reviews in health care: Investigating and dealing with publication and other biases in meta-analysis. *British Medical Journal*.

4. Guyatt GH, Oxman AD, Kunz R, Woodcock J, Brozek J, Helfand M, Alonso-Coello P, Falck-Ytter Y, Jaeschke R, Vist G, Akl EA, Post PN, Norris S, Meerpohl J, Shukla VK, Nasser M, Schünemann HJ. GRADE guidelines: 8. Rating the quality of evidence - Indirectness. *J Clin Epidemiol* 2011;64:1303–1310.

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6. Greene SJ, Butler J, Albert NM, DeVore AD, Sharma PP, Duffy CI, Hill CL, McCague K, Mi X, Patterson JH, Spertus JA, Thomas L, Williams FB, Hernandez AF, Fonarow GC. Medical Therapy for Heart Failure With Reduced Ejection Fraction: The CHAMP-HF Registry. *J Am Coll Cardiol* 2018;72:351–366.

7. Komajda M, Anker SD, Cowie MR, Filippatos GS, Mengelle B, Ponikowski P, Tavazzi L. Physicians' adherence to guideline-recommended medications in heart failure with reduced ejection fraction: Data from the QUALIFY global survey. *Eur J Heart Fail* 2016;18:514–522.

8. McMurray JJV, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, Rouleau JL, Shi VC, Solomon SD, Swedberg K, Zile MR. Angiotensin-Neprilysin Inhibition versus Enalapril in Heart Failure. *New England Journal of Medicine* 2014;371:993–1004.