Adverse Effects and Treatment Discontinuation of Blood Pressure–Lowering Drugs and Combinations

Importance: Adverse drug effects from blood pressure (BP)-lowering drugs contribute to significant undertreatment and poor overall BP control rates. Objective: To review adverse effects and discontinuation of BP-lowering drugs and their combinations from the 5 major classes in short-term clinical trials. Data Sources and Study Selection: Cochrane Central Register of Controlled Trials for randomized clinical trials, MEDLINE, and Epistemonikos were searched from the date of inception until December 31, 2024, for double-blind randomized clinical trials of angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers (ARBs), β-blockers, calcium channel blockers (CCBs), thiazide and thiazide-like diuretics, or their combinations, with follow-up durations between 4 and 26 weeks. Data Extraction and Synthesis: Data extraction was performed by 2 independent reviewers. Synthesis was performed using fixed-effect network meta-analyses according to drug class, summarized using odds ratios (ORs) and 95% credible intervals (CrIs) and surface under the cumulative ranking curves. Final statistical analysis was conducted in April 2026. Main Outcomes and Measures: Treatment discontinuation due to adverse events (AEs), defined as discontinuation of randomized treatment due to an AE. Secondary outcomes included headache, dizziness, edema, and cough. Results: A total of 716 trials were included, with mean (SD) follow-up of 8.6 (5) weeks, including 159 362 participants (mean SD age, 54.6 7 years; 44% female; mean baseline BP, 158/100 mm Hg). Compared with placebo, treatment discontinuation due to AEs was significantly increased by CCBs (OR, 1.43 95% CrI, 1.23-1.67; risk difference RD, 1.2% 95% CrI, 0.6%-2.0%), angiotensin-converting enzyme inhibitors plus CCBs (OR, 1.46 95% CrI, 1.13-1.87; RD, 1.1% 95% CrI, 0.2%-2.4%), and β-blockers plus thiazide diuretics (OR, 1.58 95% CrI, 1.04-2.47; RD, 1.7% 95% CrI, 0.1%-4.3%). All ARB-containing regimens had fewer treatment discontinuations due to AEs than placebo, and these differences were statistically significant for ARB monotherapy (OR, 0.73 95% CrI, 0.61-0.86; RD, -0.8% 95% CrI, -1.3% to -0.4%) and ARBs plus CCBs (OR, 0.61 95% CrI, 0.47-0.79; RD, -1.2% 95% CrI, -1.8% to -0.6%). In network meta-analyses, 5 combination and 2 monotherapy regimens had higher surface under the cumulative ranking curve values than placebo for treatment discontinuation due to AEs, suggesting overall symptomatic improvement compared with placebo. All regimens significantly increased dizziness, and all but CCBs significantly decreased headache compared with placebo. Conclusions and Relevance: This meta-analysis of short-term randomized clinical trials found that adverse drug effects that led to discontinuation of BP-lowering therapy varied by drug class and regimen, with several combination therapies being better tolerated than monotherapies. Some regimens were associated with fewer drug withdrawals than placebo, suggesting a net symptomatic improvement. These findings are based on trial-level results and rely on assumptions underlying the network meta-analysis; they may not apply to individual patients.