Do antihypertensive classes differ in adverse effect rates leading to discontinuation?

The development of adverse drug effects from blood pressure (BP)-lowering drugs contributes to significant undertreatment of hypertension, discontinuation of treatment and poor overall BP control. As most adverse effects manifest soon after starting treatment, high-quality data on short-term adverse effects and discontinuation of BP-lowering drugs is important.1To determine which antihypertensive classes are most commonly associated with discontinuation due to adverse effects, investigators conducted a network meta-analysis of double-blind randomized clinical trials to evaluate the short-term tolerability of antihypertensive drugs.1The study reviewed short-term clinical trials for adverse effects and discontinuation rates of BP-lowering drugs and their combinations from the five major antihypertensive classes. The study included double-blind randomized clinical trials of angiotensin-converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), β-blockers, calcium channel blockers (CCBs), thiazide and thiazide-like diuretics, or their combinations, with follow-up durations between four and 26 weeks.1Data synthesis was performed using fixed-effect network meta-analyses according to drug class, summarized using odds ratios (ORs) and 95% credible intervals (CrIs). The investigators also used surface under the cumulative ranking curves (SUCRA) to rank the overall probability that a drug class or combination ranked as the best among all included options. The primary outcome was treatment discontinuation due to adverse events. Secondary outcomes included the occurrence of headache, dizziness, edema and cough.1Key results:A total of 716 trials were included in the analysis, with mean follow-up of 8.6 weeks.The trials included 159,362 participants (mean age, 54.6 years; 44% female; mean baseline BP, 158/100 mmHg). Compared with placebo, treatment discontinuation due to adverse events 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%])ACEIs 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 adverse events 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 ranked order, the top five best-tolerated drug classes and combinations (in terms of lowest treatment discontinuation rates due to adverse events) in short-term trials were ARB plus CCB, ARB plus β-blocker, ARB monotherapy, CCB plus thiazide diuretic, and ARB plus thiazide diuretic.In network meta-analyses, five combination and two monotherapy regimens had higher SUCRA values than placebo for treatment discontinuation due to adverse events, suggesting overall symptomatic improvement compared with placebo. All regimens significantly increased dizziness, with greater risk with combination therapy than monotherapy.All BP-lowering drug classes significantly reduced headache compared with placebo, except for CCB monotherapy, ACEI plus CCB, and β-blocker plus CCB regimens. Trials that included a diuretic were generally ranked as having the lowest incidence of edema, while regimens that contained a CCB were generally ranked as having the highest incidence of edema.1The authors conclude that this meta-analysis of short-term randomized clinical trials found that adverse drug events leading 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. The authors caution that their findings are based on trial-level results and rely on assumptions underlying the network meta-analysis; they may not apply to individual patients.1An accompanying editorial highlights that nonadherence to antihypertensive medications is more common among people who report adverse effects. Prescribing medications with fewer adverse effects has the potential to improve antihypertensive medication adherence, thereby reducing cardiovascular event rates. The current study shows that compared with placebo, all medication regimens containing ARBs were less likely to be discontinued due to an adverse event; these associations were statistically significant for ARB monotherapy and for ARBs plus CCBs combined, suggesting that ARBs are significantly better tolerated than placebo. In contrast, compared with placebo, CCB monotherapy, CCBs plus ACEIs, and β-blockers plus thiazide diuretics were significantly more likely to be discontinued due to adverse events.2The editorial points out that these current study results can help inform clinicians when selecting antihypertensive therapies. However, the results should not be used to override the selection of specific antihypertensive medications for patients for whom the benefits are well established, such as ARBs or ACEIs for patients with diabetes and albuminuria or heart failure with reduced ejection fraction. In addition, the current study results should not prompt changes in therapies for patients taking stable antihypertensive regimens without adverse effects and good BP control.2Current clinical practice guidelines recommend thiazide diuretics, ACEIs, ARBs or CCBs as initial therapies for people with hypertension. Based on the current study results, when starting antihypertensive therapy in patients without a comorbid condition requiring an alternative medication, an ARB may reduce the likelihood that a patient will discontinue their antihypertensive medication. For patients prone to headaches or lower-extremity edema, thiazide diuretics, ACEIs or ARBs are preferred over CCBs. Healthcare professionals should routinely ask patients about adverse effects that may be associated with antihypertensive therapy, particularly because adverse effects can impair adherence, which in turn may reduce the ability of antihypertensive medications to prevent cardiovascular events.2 References:Wang N, Van Der Hoorn S, Pant R, et al. Adverse effects and treatment discontinuation of blood pressure–lowering drugs and combinations. A network meta-analysis. JAMA 2026. Published online May 28, 2026. (accessed May 28, 2026).McDermott MM, Persell SD. Minimizing adverse effects in hypertension treatment (editorial). JAMA 2026. Published online May 28, 2026. (accessed May 28, 2026).

Do antihypertensive classes differ in adverse effect rates leading to discontinuation?

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