Comparison of First-Line Antihypertensive Drug Classes

Study Questions:

Is there a difference in outcome by primary antihypertensive agents among the first-line drug classes in the absence of comorbid indications?


LEGEND-HTN is one of the studies designed and implemented by an international group to provide a comprehensive framework for real-world evidence that enables comparative effectiveness and safety evaluation across many drugs and outcomes from observational data encompassing millions of patients, while minimizing inherent bias. They estimated the relative risks of three primary (acute myocardial infarction, hospitalization for heart failure, and stroke) and six secondary effectiveness and 46 safety outcomes comparing all first-line antihypertensive classes across a global network (thiazide or thiazide-like diuretics, angiotensin-converting enzyme [ACE] inhibitors, angiotensin-receptor blockers, dihydropyridine calcium channel blockers, and non-dihydropyridine calcium channel blockers). The framework 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.


Using 4.9 million patients, they generated 22,000 calibrated propensity-score-adjusted hazard ratios (HRs) comparing all classes and outcomes across databases. Most estimates revealed no effectiveness differences between classes; however, thiazide or thiazide-like diuretics showed better primary effectiveness than angiotensin-converting enzyme inhibitors: acute myocardial infarction (HR, 0.84, 95% confidence interval [CI], 0.75–0.95), hospitalization for heart failure (HR, 0.83; 95% CI, 0.74–0.95), and stroke (HR, 0.83, 95% CI, 0.74–0.95) risk while on initial treatment. Safety profiles also favored thiazide or thiazide-like diuretics over ACE inhibitors. The non-dihydropyridine calcium channel blockers were significantly inferior to the other four classes.


This comprehensive framework introduces a new way of doing observational health care science at scale. The approach supports equivalence between drug classes for initiating monotherapy for hypertension—in keeping with current guidelines, with the exception of thiazide or thiazide-like diuretics superiority to angiotensin-converting enzyme inhibitors and the inferiority of non-dihydropyridine calcium channel blockers.


Trialists and hypertension specialists might consider this ‘fake news,’ but the list of authors is very impressive. The method equates to 22,000 traditional observational studies, which could have had the bias of investigators for both results and publication (p-hacking). Nearly 50% were initiated on ACE inhibitors, about 18% on thiazide or thiazide-like diuretics, and less for the other drug classes. To what degree cardiovascular risk selection bias influenced the results could not be gleaned from the data presented.

Keywords: Angiotensin Receptor Antagonists, Angiotensin-Converting Enzyme Inhibitors, Antihypertensive Agents, Calcium Channel Blockers, Dihydropyridines, Diuretics, Heart Failure, Hypertension, Myocardial Infarction, Peptidyl-Dipeptidase A, Primary Prevention, Risk Factors, Stroke, Thiazides

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