3.1 Sex differences in generalizability of HFrEF trials 93 With regard to medical management of HF, the uptake of MRA was low for both sexes in all groups, (47.1% and 41.9% in the RCTs, 38.4% and 39.8% in the RCTeligible, and 33.9% and 32.7% in RCT-ineligible, percentages for females and males, respectively). Overall, loop diuretics were prescribed more often in every female population compared to males, with highest difference in the RCT populations (78.9% in females vs 69.6% in males). Target dosing did not meaningfully differ between the sexes in any medication except for ACEI and ARB where less females received ≥50% - ≥100% of target dose for ACEI and ARB compared to males in the RCT-eligible (65.4% vs 71.6%) and RCT-ineligible groups (36.9% vs 46.4%), but not in the RCT group (54.7% vs. 56.8%) (Supplementary Table 3). Unadjusted clinical outcomes Cumulative incidence curves for unadjusted cumulative incidence rates for all-cause and cardiovascular mortality, and HF hospitalization rates are shown in Figure 2 and unadjusted rates are summarized in Table 2. Females showed a lower unadjusted one-year mortality rate in the RCT population compared to males (5.6% vs 6.9%, P<0.01), but higher unadjusted one-year mortality rates compared to males in both the RCT-eligible (14.0% vs 10.7%, p<0.0001) and RCT-ineligible groups (28.6% vs 24.6%, p<0.0001). Similar trends were also observed for cardiovascular mortality (see Table 2). Rate of first HF hospitalization was lowest in the RCTs for both females and males (8.4% and 7.8%, p>0.05), and highest in the registry groups, (RCTeligible: 23.2% and 24.8%, p<0.01; RCT-ineligible: 23.7% and 25.3%, P<.05 for females and males respectively) (Figure 2 and Table 2). Case-mix adjusted clinical outcomes Unadjusted SMRs (empty model) showed that females had 55% fewer deaths in the RCT group than expected (SMR 0.45; 95% CI 0.39 to 0.52), while males had 46% fewer deaths in the RCT group (SMR 0.54; 95% CI 0.51 to 0.58). Model 2, which adjusted for age between the younger RCT patients (mean age 63.5 years) and RCTeligible patients (mean age 71.one-years), showed that females still had 31% fewer observed deaths than expected (SMR 0.69; 95% CI 0.60 to 0.80), whereas in males there was 7% higher observed deaths in the trials than expected (SMR 1.07; 95% 1.00 to 1.15). For cardiovascular mortality, the difference after adjusting for age was more
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