Dual ACE inhibitor plus ARB therapy worsens kidney status in CKD

Use of dual therapy with ACE inhibitors and ARBs tends to elevate the risk of renal outcomes in people with or without chronic kidney disease (CKD), reports a study presented at ERA 2024.

“Applying a reference trial emulation approach and successfully benchmarking findings against ONTARGET, where confounding was not present due to randomization, provides confidence in the validity of these results,” said lead author Dr Paris J Baptiste from the Department of Noncommunicable Disease Epidemiology, London School of Hygiene & Tropical Medicine, UK.

The ONTARGET trial established whether the ARB telmisartan is noninferior or superior to the ACE inhibitor ramipril in the reduction of cardiovascular (CV) events in patients with established CV disease or diabetes with target organ damage. [Vasc Health Risk Manag 2007;3:901-908]

Baptiste and colleagues used data from the UK Clinical Practice Research Datalink (CPRD) Aurum linked with Hospital Episode Statistics secondary data and applied the ONTARGET trial eligibility criteria to patients receiving ARB or ACE inhibitor between 1 January 2001 and 31 July 2019.

“As the number of patients receiving prescriptions for both medications on the same day was likely to be small in routine care, we used an operational definition to capture dual users,” Baptiste said.

The authors assessed the composite outcome of CV-related death, myocardial infarction, stroke, or hospitalization for heart failure and a composite renal outcome of ³50-percent reduction in glomerular filtration rate (GFR) or end-stage kidney disease (ESKD).

Using a Cox proportional hazards model, a propensity score-weighted time-to-event analysis was carried out to compare the outcomes between patients receiving dual therapy and those on ACE inhibitors alone. The authors also assessed treatment effect heterogeneity by CKD (defined as estimated [e]GFR <60ml/min/1.73m²) at baseline.

Renal events

The analysis included a total of 412,406 trial-eligible patients in CPRD. Thirty-seven percent of those with available eGFR data at baseline had CKD. [ERA 2024, abstract 530]

Dual therapy and ACE inhibitor monotherapy were both effective in reducing the risk of cardiovascular events (hazard ratio [HR], 0.98, 95 percent confidence interval [CI], 0.93‒1.03). This finding was consistent with that of the ONTARGET trial (HR, 0.99, 95 percent CI, 0.92‒1.07), with no evidence of heterogeneity by CKD (p=0.14 for interaction).

Dual therapy, however, seemed to increase the risk for the composite renal outcome relative to ACE inhibitor alone (HR, 1.24, 95 percent CI, 1.14‒1.35), with no evidence of heterogeneity by CKD (p=0.93).

Similar results were noted when analysing components of the composite renal outcome separately (≥50-percent reduction in GFR: HR, 1.22, 95 percent CI, 1.12‒1.33; ESKD: HR, 1.34, 95 percent CI, 1.24‒1.57) and in a post hoc sensitivity analysis by proteinuria status (no proteinuria: HR, 1.28, 95 percent CI, 1.03‒1.59; proteinuria: HR, 1.27, 95 percent CI, 1.08‒1.49).

“We found evidence that dual therapy use was associated with increased risk of renal outcomes in both those with and without CKD at baseline,” Baptiste said.

“Results from the ONTARGET trial, in conjunction with the ALTITUDE and VA-Nephron-D studies, led to an end of recommendations for dual ACE inhibitor and ARB therapy due to an increase in acute kidney injury,” Baptiste noted.