Elsevier

The Lancet

Volume 394, Issue 10211, 16–22 November 2019, Pages 1816-1826
The Lancet

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

https://doi.org/10.1016/S0140-6736(19)32317-7Get rights and content

Summary

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.

Introduction

Patients and physicians have a wide range of pharmacological options to treat hypertension but little guidance on which specific first-line agent to initiate. The 2017 American College of Cardiology/American Heart Association (ACC/AHA) Blood Pressure Treatment Guidelines1 endorse any thiazide or thiazide-like diuretics, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, or calcium channel blockers unless contraindicated. Similar non-specificity emerges from the 2018 European Society of Cardiology/European Society of Hypertension (ESC/ESH) Guidelines, with the further inclusion of β blockers.2

These recommendations derive largely from earlier randomised clinical trials (RCTs) that provided direct comparisons between a few agents, not drug classes, and often did not restrict to therapy initiation. For example, the largest head-to-head RCT of antihypertensives, the ALLHAT trial,3 enrolled patients from February, 1994, to January, 1998, more than two decades ago, evaluated three representative agents and a majority of participants had been previously treated. Moreover, most studies considered in the 2017 ACC/AHA Guidelines systematic review4 were done before 2000.

The 2017 Cochrane Review5 of first-line therapy for hypertension, an update from 2009, found no new RCTs to include. Their review concludes that “first-line low-dose thiazides reduced all morbidity and mortality outcomes in adult patients with moderate to severe primary hypertension. First-line angiotensin-converting enzyme inhibitors and calcium channel blockers may be similarly effective, but the evidence was of lower quality”. Thus, there remains uncertainty and, unfortunately, we do not have contemporary knowledge of the real-world comparative effectiveness of common antihypertensive drugs with respect to outcomes—and the safety trade-offs among these options.

Research in context

Evidence before this study

2017 American College of Cardiology/American Heart Association Blood Pressure Treatment Guidelines recommend initiating monotherapy for hypertension with any primary agent among five first-line drug classes based on a systematic review of randomised trials. Similar non-specificity emerges from the 2018 European Society of Cardiology/European Society of Hypertension Guidelines. The largest such trial, ALLHAT, enrolled patients more than two decades ago, only evaluated three representative agents, and a majority of participants had been previously treated for hypertension. We lack contemporary knowledge of the real-world comparative effectiveness of common antihypertensive drugs with respect to outcomes and the safety trade-offs among these class options for treatment initiation.

Added value of this study

Our study uses state-of-the-art methods to control for residual confounding, publication bias, and p-hacking in real-world evidence studies, and shows generally comparable effectiveness between drug classes across nine international health databases. However, effectiveness and safety benefits suggest initiating with a thiazide or thiazide-like diuretic over an angiotensin converting-enzyme inhibitor, the most common initiating monotherapy across databases. Non-dihydropyridine calcium channel blockers are also inferior to thiazide or thiazide-like diuretics, angiotensin converting-enzyme inhibitors, angiotensin receptor blockers, and dihydropyridine calcium channel blockers.

Implications of all the available evidence

Initiating with a thiazide instead of an angiotensin converting-enzyme inhibitor carries potential to avoid many major cardiovascular events and warrants further study.

Accordingly, we developed the open-science, large-scale evidence generation and evaluation across a network of databases for hypertension (LEGEND-HTN) study to compare common antihypertensive drug treatments by a systematic, large-scale analysis across nine observational databases from the Observational Health Data Science and Informatics (OHDSI) distributed data network.6 This novel approach used massive data across several countries and synthesised tens of thousands of comparisons with analytic techniques to minimise residual confounding. In contrast to a single comparison approach, LEGEND-HTN provides a comprehensive view of the findings and their consistency across populations, drugs, and outcomes, and by design avoids the harms of publication bias or overemphasising a single observational analysis subject to p-hacking. We report results comparing monotherapy drug classes from participating data sources through November, 2018, covering patients from July, 1996, to March, 2018.

Section snippets

Study design

LEGEND-HTN systematically executed a large-scale comparative effectiveness and safety study across six administrative claims and three electronic health record databases standardised to OHDSI's Observational Medical Outcomes Partnership common data model version 5 that maps international coding systems into standard vocabulary concepts. The claims databases were IBM MarketScan Commercial Claims and Encounters (US employer-based private payer; patient aged 65 years or older), Optum ClinFormatics

Results

LEGEND-HTN included longitudinal claims and electronic health record data from 4 893 591 patients, 48% of whom initiated an angiotensin-converting enzyme inhibitor, 17% a thiazide or thiazide-like diuretic, 16% a dihydropyridine calcium channel blocker, 15% an angiotensin receptor blocker, and 3% a non-dihydropyridine calcium channel blocker (table 1). The IBM MarketScan Commercial Claims and Encounters, Optum Pan-Therapeutic, and Optum ClinFormatics databases contributed the most patients to

Discussion

LEGEND-HTN is, to our knowledge, the largest and most comprehensive study to provide evidence about the comparative effectiveness and safety of first-line antihypertensives, representing 4·9 million patients initiating monotherapy across nine databases from four countries, examining all pairwise comparisons between the five first-line drug classes against a panel of 55 health outcomes. This equates to 22 000 traditional observational studies, many of which researchers could have hand-picked,

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