BACKGROUND: We aimed to quantify the blood pressure-lowering efficacy of antihypertensive drugs and their combinations from the five major drug classes.

METHODS: We conducted a systematic review and meta-analysis of randomised, double-blind, placebo-controlled trials involving adult participants randomly assigned to receive angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, ß blockers, calcium channel blockers, or diuretics. Eligibility criteria included follow-up duration between 4 weeks and 26 weeks, antihypertensive drug treatment fixed in all participants for at least 4 weeks before follow-up blood pressure assessment; and availability of clinic blood pressure for the calculation of mean difference in systolic blood pressure between treatment groups. Crossover trials with less than 2 weeks' washout between the crossover periods were excluded. Eligible studies published between database inception and Dec 31, 2022 were identified from searches of the Cochrane Central Register of Controlled Trials, MEDLINE, and Epistemonikos; searches were updated to include studies published between Jan 1, 2023, and Feb 28, 2025. The primary outcome was placebo-corrected reduction in systolic blood pressure. Blood pressure-lowering efficacy was estimated using fixed-effects meta-analyses standardised to mean baseline blood pressure across included trials. Drug regimens were categorised into low, moderate, and high intensity, corresponding to systolic blood pressure-lowering efficacy of <10 mm Hg, 10-19 mm Hg, and =20 mm Hg, respectively, from a baseline of 154 mm Hg. A model was developed to calculate efficacy for any combination of antihypertensives and validated on external trials of dual and triple combination antihypertensives. The study protocol was registered on the International Platform of Registered Systematic Review and Meta-analysis Protocols (INPLASY202410036).

FINDINGS: We analysed 484 trials including 104 176 participants (mean age 54 years [SD 8], 57 422 [55%] men, 46 754 [45%] women, and mean baseline systolic blood pressure 154/100 mm Hg). Mean follow-up duration was 8·6 weeks (SD 5·2). On average, monotherapy at standard dose reduced systolic blood pressure by 8·7 mm Hg (95% CI 8·2-9·2), and each doubling in dose conferred an additional 1·5 mm Hg (1·2-1·7) reduction. Dual combinations at one standard dose conferred a 14·9 mm Hg (95% CI 13·1-16·8) reduction in systolic blood pressure, with each doubling of doses of both drugs conferring an additional reduction of 2·5 mm Hg (1·4-3·7). Each 10 mm Hg decrease in baseline systolic blood pressure reduced pressure-lowering efficacy by 1·3 mm Hg (1·0-1·5) for monotherapies, although differences between drug classes were observed. Among 57 monotherapies at standard dose, 45 (79%) were classified as low intensity. Of 189 different drug-dose dual combinations, 110 (58%) were classified as moderate intensity, and 21 (11%) as high intensity. There were considerable differences in dose-response and baseline blood pressure-response relationships between and within drug classes. The efficacy model showed a high correlation between predicted and observed systolic blood pressures when validated on external trials (r=0·76, p<0·0001).

INTERPRETATION: These analyses provide robust estimates of the expected blood pressure-lowering effect for any combination of antihypertensive drugs, allowing their efficacy to be classified into low, moderate, and high intensity.

FUNDING: National Health and Medical Research Council, Australia.

Cardiology rater

This study is a systematic review and meta-analysis of 484 double-blind, placebo-controlled randomized clinical trials assessing the blood pressure–lowering efficacy of antihypertensive drugs across major classes, doses, and baseline blood pressure levels. It demonstrates clinically meaningful differences in average reduction, dose–response relationships, and baseline effect modification between drug classes. The authors developed the first calculator that provides trial-based estimates of blood pressure reduction for any combination of antihypertensive drugs and proposed a new classification system for regimen intensity (low, moderate, high). These findings support a more precise evidence-based selection of antihypertensive therapies tailored to treatment goals.

Family Medicine (FM)/General Practice (GP) rater

This is a huge undertaking: almost 500 double-blind RCTs involving over 100,000 patients with hypertension. Measured by the reduction in systolic blood pressure, combination therapy does indeed appear to be more effective. Problems with the transferability of the study: 1. The patients were 54 years old on average – significantly younger than most of those treated in daily practice; 2. The reduction in systolic blood pressure is only a surrogate parameter per se – we do not know for sure whether this is also associated with clinically measurable endpoints; 3. Only studies lasting up to 26 weeks were included. We do not know what the effect would be after years of use; and 4. Perhaps the most important argument: antihypertensive drugs are not always well tolerated. If patients cannot tolerate a drug, several substances in a combination may be “burned” for further use.

Family Medicine (FM)/General Practice (GP) rater

This review offers strong evidence that adding a second or (when necessary) a third drug using low-to-standard doses to initial low-to-standard dose monotherapy will lower BP much more effectively than titration to ever higher doses. It also suggests that there is a maximum BP lowering that can be achieved with 3-drug treatment of HTN.

Internal Medicine rater

Nothing ground-breaking but a useful compendium of how much different classes of anti-hypertensives lower BP. I'll keep the article in my desk for reference.