Real-world Evidence to Inform Decisions for Hypertension Treatment Escalation

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Project Summary Over 100 million US adults have hypertension, a leading cause of mortality and morbidity, and 70% of them cannot achieve adequate blood pressure control with monotherapy alone. Although recent clinical practice guidelines suggest initiating therapy with two drugs, more than 50% of people currently treated for hypertension start with a single medication. For these patients, clinical guidelines propose adding a second antihypertensive drug for treatment escalation. The absence of head-to-head comparison in randomized controlled trials (RCTs) has limited the ability of clinical guidelines to provide evidence-based recommendations about which drug to add next for which patients. Our long-term goal is to produce real-world evidence to inform decisions about RCTs for hypertension treatment escalation and to provide the highest quality non-randomized evidence to support guideline recommendations. The overall objective in this application is to determine the comparative effectiveness and safety of the second antihypertensive agents added to monotherapy in patients with hypertension. The central hypothesis is that there is heterogeneity in the effectiveness and safety of the second antihypertensive agents, and the optimal choice depends on patient characteristics and the initial therapy. Our preliminary data demonstrate a large variation in the choice of the second agents added to monotherapy, providing ample opportunity to leverage practice variation to test our hypothesis. We will first determine the comparative effectiveness of the second antihypertensive agents added to monotherapy on major cardiovascular outcomes, such as myocardial infarction, stroke, and hospitalization for heart failure (Aim 1). We will then determine the comparative risk of the second antihypertensive agents on potential drug-related adverse events, such as acute renal failure, angioedema, gastrointestinal bleeding, and hyperkalemia (Aim 2). Finally, we will assess heterogeneity in effectiveness and safety among key patient subgroups defined by age, sex, race, and comorbidity (Aim 3). We have assembled experts in observational methods for causal inference, pharmacoepidemiology, clinical informatics, hypertension management, and implementation science, and will use real-world data from over 100 million US adults in five electronic health record (EHR) databases (i.e., Optum, Department of Veterans Affairs, Columbia, Yale, and Sentara Healthcare EHR databases). We will employ state- of-the-art observational research methods, including an active comparator new-user design, large-scale propensity score modeling, negative control outcome experiments, and empirical calibration, to emulate RCTs and to compare drug combinations. The proposed research is innovative because it will be the first study that applies massive real-world datasets and state-of-the-art observational research methods to comprehensively investigate the effectiveness and safety of the second antihypertensive agents added to monotherapy. The proposed research is significant because it provides critical evidence to inform decisions about RCTs for hypertension treatment escalation and to support guideline recommendations.