Background: Guidelines caution against co-prescribing angiotensin-converting enzyme (ACE) inhibitors/angiotensin II receptor blockers (ARBs) together with lithium, as this may increase lithium levels leading to toxicity. Several case reports and one nested case-control study have found a higher risk of lithium toxicity after ACE inhibitor/ARB co-prescriptions. However, the evidence remains inconclusive.
Objectives: To evaluate whether chronic lithium users newly prescribed ACE inhibitors/ARBs have a higher risk of hospitalization with lithium toxicity than patients newly prescribed beta-blockers.
Methods: Using linked healthcare data in Ontario, Canada, from April 1, 2002, to May 31, 2022, we conducted a population-based cohort study of adults aged ≥50 years taking lithium who were newly prescribed an ACE inhibitor/ARB versus a beta-blocker. The primary outcome was hospital admission with lithium toxicity. We used inverse probability of treatment weighting on the propensity score to balance comparison groups on baseline health. Weighted risk ratios (RR) and risk differences (RD) were obtained using modified Poisson regression and binomial regression, respectively. Several sensitivity analyses, including fine stratification weight and weight truncation, were conducted to assess the robustness of the results.
Results: Of 4027 patients taking lithium (median age, 65 years [IQR, 57-72 years]; 2270 women [56%]), 2138(53 %) started a new prescription with ACE inhibitors/ARBs, and 1889(47 %) started a new prescription with beta-blockers. Co-prescription of ACE inhibitors/ARBs vs beta-blockers with lithium was not associated with a higher 90-day risk of hospital admission with lithium toxicity: number of events (weighted), 46 patients of 2138 co-prescribed an ACE inhibitor/ARB [2.15%] vs 55 patients of 2108 co-prescribed a beta-blocker[2.61%]; [RR] 0.82 [95% CI, 0.51-1.31]; [RD], -0.47%[95% CI -1.61%-0.68%]. Results remain consistent when using fine stratification weight ([RR] 0.67 [95% CI, 0.37-1.30]; [RD], -1.08%[95% CI -2.84%-0.68%] ) and weight truncation ([RR] 0.82 [95% CI, 0.51-1.30]; [RD],-0.48% [95% CI -1.63%-0.66%].
Conclusions: Among adults taking lithium, concurrent use of ACE inhibitor/ARB versus beta-blocker was not associated with a greater 90-day risk of hospital admission with lithium toxicity. The results of this study suggest that the risk described in some previous studies may be overstated.
