(144) Treatment Effects of Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers in People Underrepresented from The ONTARGET Trial: Analysis of Routinely Collected Data Using Trial Replication Methods

Publication Number: 1189

Background: Evidence of the effectiveness of medications is not always generalisable due to trial criteria that restrict inclusion, often to younger patients with fewer comorbidities. Observational data can be used to confirm trial findings and investigate treatment effects in trial-underrepresented groups.

Objectives: Using routinely-collected data from the UK Clinical Practice Research Datalink (CPRD) GOLD, our objectives were to (1) replicate findings of the ONTARGET trial, which compared angiotensin receptor blockers (ARB) to angiotensin-converting enzyme inhibitors (ACEI) and (2) to explore effectiveness for patients with chronic kidney disease (CKD) (G3-5ND, i.e. glomerular filtration rate (GFR) < 60mL/min/1.73m2).

Methods: We applied the ONTARGET trial eligibility criteria in CPRD to select prevalent users of an ACEI/ARB between 1/1/2001-31/7/2019 to develop a trial-analogous cohort. We used propensity score weighting and adjustment of imbalanced variables to address confounding and compared treatment effects observed from a time-to-event analysis in our trial-analogous cohort with those obtained in the trial, for the trial primary composite outcome of cardiovascular related death, myocardial infarction, stroke and hospitalisation for heart failure. We used a pre-specified validation criteria of HR between 0.9-1.12 and CI containing 1.
We created an extended cohort, omitting the ONTARGET exclusion criteria of serum creatinine >265 umol/L, increasing patients with CKD, who were underrepresented in the trial. We assessed effect modification by CKD using a Wald test for the primary outcome. As in ONTARGET, components of the composite outcome were studied as secondary outcomes.

Results: In a propensity-score–weighted analysis of the trial-analogous CPRD cohort (ACEI: 96,602, ARB: 40,553), for ARB vs ACEI we observed a HR 0.97 (95% CI: 0.93, 1.01) for the trial primary outcome, which met our pre-specified criteria for similarity to the ONTARGET result HR 1.01 (95% CI: 0.94, 1.09).
In the extended cohort, 41767 (35%) of patients had CKD. For ARB vs ACEI, analysis of the primary outcome gave CKD: HR 1.01 (95% CI: 0.94, 1.08) and no CKD: HR 0.93 (95% CI: 0.88, 0.99). Analysis of secondary outcomes in those with CKD also showed non-inferiority of ARBs.

Conclusions: Analysis of observational data generated estimates of ARB vs ACEI effectiveness for reduction of cardiovascular events closely comparable with those of the ONTARGET trial. Our results support the findings of the trial when extended to the underrepresented group of those with CKD.