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

Background: Uncertainty lingers about optimal monotherapy initiation for hypertension. Recent guidelines recommend starting any primary agent among five first-line drug classes, thiazide or thiazide-like diuretics (THZ), angiotensin converting-enzyme inhibitors (ACEi), angiotensin receptor blockers, dihydropyridine calcium channel blockers, and non-dihydropyridine calcium channel blockers (ndCCB), in the absence of comorbid indications. Randomized trials fail to further refine this choice. Methods: We develop 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. Using this framework, we conduct a systematic, large-scale study under a new-user cohort design to estimate the relative risks of 3 primary and 6 secondary effectiveness and 46 safety outcomes comparing all first-line classes across a global network of 6 administrative claims and 3 electronic health record databases. The framework addresses residual confounding, publication bias and p-hacking using large-scale propensity adjustment, a large set of control outcomes, and full disclosure of hypotheses tested. Findings: Using 4.9 million patients, we generate 22,000 calibrated, propensity-score adjusted hazard ratios (HRs) comparing all classes and outcomes across databases. Most estimates reveal no effectiveness differences between classes. THZ, however, demonstrate better primary effectiveness than ACEi: acute myocardial infarction (HR 0.84; 95% CI 0.75-0.95), hospitalization for heart failure (0.83; 0.74-0.95) and stroke (0.83; 0.74-0.95) risk while on initial treatment. Safety profiles also favor THZ over ACEi. The ndCCB drugs are significantly inferior to the other four classes. Interpretation: This comprehensive framework introduces a new way of conducting observational healthcare science at scale. The approach supports equivalence between drug classes for initiating monotherapy for hypertension-in keeping with current guidelines-with the exception of THZ superiority to ACEi and the inferiority of ndCCB.