Physicians' Academy for Cardiovascular Education

Thiazide or thiazide-like diuretics superior to ACEi as initial monotherapy in hypertension

Comprehensive comparative effectiveness and safety of first-line antihypertensive drug classes: a systematic, multinational, large-scale analysis

Literature - Suchard MA, Schuemie MJ, Krumholz HM et al. - The Lancet 2019, S0140-6736(19)32461-4

Introduction and methods

There is uncertainty on which specific first-line agent to use for initiation of therapy in hypertension. The 2017 American College of Cardiology/American Heart Association (ACC/AHA) Blood Pressure Treatment Guidelines recommend any thiazide or thiazide-like diuretics, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, or calcium channel blockers unless contraindicated. The 2018 European Society of Cardiology/European Society of Hypertension (ESC/ESH) Guidelines further include β blockers [2]. Thus far, real-world comparative effectiveness of common antihypertensive drugs with respect to clinical outcomes and safety trade-offs are unknown.

The open-science, large-scale evidence generation and evaluation across a network of databases for hypertension (LEGEND-HTN) study was conducted to compare common antihypertensive drugs by a systematic, large-scale analysis across nine observational databases from the Observational Health Data Science and Informatics (OHDSI) distributed data network [1], including data records of 4,893,591 patients. Results were reported of comparison of monotherapy drug classes from data sources through November, 2018, covering patient data from July, 1996, to March, 2018. Within each database source, a retrospective, comparative new-user cohort design was used [2,3]. Patients were considered new users if their first observed treatment for hypertension was monotherapy with any of the five drug classes: thiazide or thiazide-like diuretics, ACEi, ARBs, dihydropyridine calcium channel blockers, or non-dihydropyridine calcium channel blockers. There were 55 outcomes of interest, with three primary outcomes being acute MI, hospitalization for HF and stroke, and six secondary outcomes being CV event, ischemic stroke, hemorrhagic stroke, HF, sudden cardiac death and unstable angina. Safety outcomes consisted of 46 end points. In total, 22,000 HR were generated. The analysis addressed residual confounding, publication bias and p-hacking using large-scale propensity adjustment, a large set of control outcomes and full disclosure of hypotheses tested. Median follow-up was >2 years for most databases.

Main results


In this comprehensive framework for real-world evidence using data of millions of patients, most comparisons of effectiveness of initiating monotherapies for hypertension showed no differences between classes. The exceptions are that patients initiating thiazide or thiazide-like diuretic had a lower risk of acute MI, hospitalization for HF and stroke compared to ACEi and patients who initiated treatment with a non-dihydropyridine calcium channel blocker had a significantly higher risk of effectiveness outcomes compared with all other class choices.


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