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

Abstract

Background: Uncertainty remains about the optimal monotherapy for hypertension, with current guidelines recommending any primary agent among the first-line drug classes thiazide or thiazide-like diuretics, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, dihydropyridine calcium channel blockers, and non-dihydropyridine calcium channel blockers, in the absence of comorbid indications. Randomised trials have not further refined this choice.

Methods: We developed 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 minimising inherent bias. Using this framework, we did a systematic, large-scale study under a new-user cohort design to estimate the relative risks of three primary (acute myocardial infarction, hospitalisation for heart failure, and stroke) and six secondary effectiveness and 46 safety outcomes comparing all first-line classes across a global network of six administrative claims and three electronic health record databases. 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.

Findings: Using 4·9 million patients, we 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% CI 0·75-0·95), hospitalisation 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 favoured thiazide or thiazide-like diuretics over angiotensin-converting enzyme inhibitors. The non-dihydropyridine calcium channel blockers were significantly inferior to the other four classes.

Interpretation: 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.

Funding: US National Science Foundation, US National Institutes of Health, Janssen Research & Development, IQVIA, South Korean Ministry of Health & Welfare, Australian National Health and Medical Research Council.

Figure 1:

Comparative effectiveness of THZ, ACEi, ARB, dCCB and ndCCB drug classes. Points report HR estimates and lines mark their 95% CIs. HRs < 1 favor target (row) over comparator (column). (a) Meta-analytic risk estimates across all nine effectiveness outcomes with primary outcomes in red and secondary outcomes in blue. (b) Cardiovascular (CV) event risk estimates by data source and meta-analysis. Colors identify databases; the top block are administrative claims databases, the middle block are EHRs and black highlights a meta-analysis across all other sources. Not all databases contain sufficient new-users for study inclusion. CV event is a composite outcome of acute MI, hospitalization for HF, stroke and sudden cardiac death.

Figure 2:

Meta-analytic safety profiles comparing THZ to ACEi, ARB, dCCB and ndCCB new-users across 46 outcomes listed on product labels. Points and lines identify HR estimates with their 95% CIs, respectively. Outcomes in grey signify that the CI covers HR =1 (null hypothesis of no differential risk).

Figure 3:

Effectiveness estimates comparing THZ to ACEi, ARB, dCCB and ndCCB new-users using propensity scores with and without baseline blood pressure (BP) adjustment in the PanTher database. Points and lines identify HR estimates with their 95% CIs, respectively. Black circles demarcate estimates based on large-scale propensity scores built without BP measurements and grey squares identify estimates additionally including baseline measurements from the electronic health record.