Short-Term Tolerability of Blood Pressure-Lowering Drugs and Combinations

Key Takeaways

• Angiotensin II receptor blocker–containing regimens ranked among the best tolerated, with angiotensin II receptor blocker plus calcium channel blocker at the top.
• Higher discontinuation due to adverse events was observed with calcium channel blockers, angiotensin-converting enzyme inhibitor plus calcium channel blocker combinations, and beta-blocker plus thiazide diuretic combinations versus placebo.
• Dizziness increased across regimens, headache decreased with all but calcium channel blockers, and the authors noted that trial-level rankings may not map cleanly to individual patients.

Across 716 short-term, double-blind randomized trials involving 159,362 participants, angiotensin II receptor blocker plus calcium channel blocker had fewer treatment discontinuations due to adverse events than placebo (OR 0.61, 95% CrI 0.47-0.79; RD −1.2%) in a JAMA network meta-analysis. It ranked as the best-tolerated regimen, and four of the five highest-ranked regimens included an angiotensin II receptor blocker. Some combination therapies were also better tolerated than monotherapy and/or placebo. The comparison focused on adverse events that led patients to stop randomized treatment during follow-up. The findings provide a short-term tolerability comparison across antihypertensive drug classes and combinations.

The analysis asked whether antihypertensive drug classes and combinations differed in adverse drug effects and treatment withdrawal in short-term, double-blind randomized clinical trials. Eligible studies included ACE inhibitors, angiotensin II receptor blockers, beta-blockers, calcium channel blockers, thiazide and thiazide-like diuretics, and combination regimens. Treatment discontinuation due to adverse events was the main outcome, and prespecified secondary symptoms included headache, dizziness, edema, and cough. Follow-up ranged from 4 to 26 weeks, averaging 8.6 weeks, in a population with mean age 54.6 years, 44% female, and baseline pressure 158/100 mm Hg. Searches of Cochrane Central, MEDLINE, and Epistemonikos, with extraction by 2 reviewers, supported a fixed-effect network meta-analysis of short-term tolerability.

Compared with placebo, discontinuation due to adverse events was higher with calcium channel blockers (OR 1.43, 95% CrI 1.23-1.67; RD 1.2%). It was also higher with angiotensin-converting enzyme inhibitor plus calcium channel blocker combinations (OR 1.46, 95% CrI 1.13-1.87; RD 1.1%) and beta-blocker plus thiazide diuretic combinations (OR 1.58, 95% CrI 1.04-2.47; RD 1.7%). All angiotensin II receptor blocker–containing regimens had fewer discontinuations than placebo, including monotherapy (OR 0.73, 95% CrI 0.61-0.86; RD −0.8%). Five combination regimens and two monotherapy regimens ranked above placebo by surface under the cumulative ranking curve values, and some combinations were better tolerated than monotherapy and/or placebo.

At the symptom level, all evaluated regimens significantly increased dizziness compared with placebo in these short-term trials. All regimens except calcium channel blockers also showed significantly lower headache rates than placebo. Headache, dizziness, edema, and cough were prespecified secondary outcomes, although comparative results for edema and cough were not detailed. The authors cautioned that these short-term, trial-level findings depend on network meta-analysis assumptions and may not translate cleanly to individual patients.