Cardiorenal effects of dual blockade with Angiotensin-converting enzyme inhibitors and Angiotensin receptor blockers in people with CKD: analysis of routinely collected data with emulation of a reference trial (ONTARGET)

We aimed to explore whether the ONTARGET trial results, which led to an end of recommendations of dual angiotensin-converting enzyme inhibitor (ACEi) and angiotensin receptor blocker (ARB) use, extended to patients with chronic kidney disease (CKD) who were underrepresented in the trial. We selected people prescribed an ACEi and/or an ARB in the UK Clinical Practice Research Datalink Aurum during 1/1/2001-31/7/2019. We specified an operational definition of dual users and applied ONTARGET eligibility criteria. We used propensity-score--weighted Cox-proportional hazards models to compare dual therapy to ACEi for the primary composite trial outcome (cardiovascular death, myocardial infarction, stroke, or hospitalisation for heart failure), as well as a primary composite renal outcome ([≥]50% reduction in GFR or end-stage kidney disease), and other secondary outcomes, including hyperkalaemia. Conditional on successfully benchmarking results against the ONTARGET trial, we explored treatment effect heterogeneity by CKD at baseline. In the propensity-score--weighted trial-eligible analysis cohort (n=412 406), for dual therapy vs ACEi we observed hazard ratio (HR) 0.98 (95% CI: 0.93, 1.03), for the primary composite outcome, consistent with the trial results (ONTARGET HR 0.99, 95% CI: 0.92, 1.07). Dual therapy use was associated with an increased risk of the primary renal composite outcome, HR 1.25 (95% CI: 1.15, 1.36) vs ONTARGET HR 1.24 (1.01, 1.51) and hyperkalaemia, HR 1.15 (95% CI: 1.09, 1.22) in the trial eligible cohort, consistent with ONTARGET. The presence of CKD at baseline had minimal impact on results. Translational statementWe extended ONTARGET trial findings of the comparative effectiveness of dual ARB and ACEi therapy use compared to ACEi alone for a composite cardiovascular outcome to UK patients at high-risk of cardiovascular disease, including those with CKD. As in ONTARGET, we found an increased risk of a composite renal outcome ([≥]50% reduction in GFR or end-stage kidney disease) and an increased risk of hyperkalaemia among dual users compared to ACEi alone. Consistent results were observed among patients with CKD at baseline. This is evidence against the hypothesis that dual blockade provides cardiorenal benefits among high-risk cardiovascular patients with CKD.