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

  • More than half of comparisons showed no significant difference between classes.
  • Thiazide or thiazide-like diuretics were associated with a lower risk of acute MI (HR: 0.84, 95%CI: 0.75-0.95), HF (HR: 0.83, 95%CI:0.74-0.95) and stroke (HR: 0.83, 95%CI: 0.74-0.95) and lower risk of secondary endpoints ischemic stroke, hemorrhagic stroke and angina compared to ACEi.
  • Thiazide or thiazide-like diuretics also showed a significantly lower risk of acute MI, hospitalization for HF, and stroke compared to non-dihydropyridine calcium channel blockers.
  • Dihydropyridine calcium channel blockers were associated with a lower risk of acute MI, hospitalization for HF and stroke compared to non-dihydropyridine calcium channel blockers.
  • Non-dihydropyridine calcium channel blockers underperformed all other drug classes.
  • Thiazide or thiazide-like diuretics had a significantly higher risk of hypokalemia (HR: 2.8, 95%CI: 2.2-3.6 compared to ACEi, HR:2.9, 95%CI:2.9, 95%CI: 2.2-4.3 compared to ARBS, HR:1.9, 95%CI:1.6-2.4 compared to non-dihydropyridine calcium channel blockers). Thiazide or thiazide-like diuretics also showed a significantly higher risk of hyponatremia compared with other drug classes.
  • Angio-oedema and cough was significantly increased for ACEi (HR for thiazide or thiazide-like diuretic vs ACEi: 0.44, 95%CI: 0.35-0.57). Sixteen further safety outcomes occurred at a significantly higher rate in ACEi compared with thiazide or thiazide-like diuretic including mortality, gastrointestinal side-effects, and renal disorders.


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.


1. Hripcsak G, Duke JD, Shah NH, et al. Observational Health Data Sciences and Informatics (OHDSI): opportunities for observational researchers. Stud Health Technol Inform 2015; 216: 574–78.

2. Ryan PB, Schuemie MJ, Gruber S, Zorych I, Madigan D. Empirical performance of a new user cohort method: lessons for developing a risk identification and analysis system. Drug Saf 2013; 36 (suppl 1): S59–72.

3. Hernan MA, Robins JM. Using big data to emulate a target trial when a randomized trial is not available. Am J Epidemiol 2016; 183: 758–64

Find this article online at The Lancet

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