Incremental effects of antihypertensive drugs: instrumental variable analysis

Abstract

Objectives: To assess the incremental effects of adding extra antihypertensive drugs from a new class to a patient's regimen.

Design: Instrumental variable analysis of data from SPRINT (Systolic Blood Pressure Intervention Trial). To account for confounding by indication-when treatments seem less effective if they are administered to sicker patients-randomization status was used as the instrumental variable. Patients' randomization status was either intensive (systolic blood pressure target <120 mm Hg) or standard (systolic blood pressure target <140 mm Hg) treatment. Results from instrumental variable models were compared with those from standard multivariable models.

Setting: Secondary data analysis of a randomized clinical trial conducted at 102 sites in 2010-15.

Participants: 9092 SPRINT participants with hypertension and increased cardiovascular risk but no history of diabetes or stroke.

Main outcomes measures: Systolic blood pressure, major cardiovascular events, and serious adverse events.

Results: In standard multivariable models not adjusted for confounding by indication, addition of an antihypertensive drug from a new class was associated with modestly lower systolic blood pressure (-1.3 mm Hg, 95% confidence interval -1.6 to -1.0) and no change in major cardiovascular events (absolute risk of events per 1000 patient years, 0.5, 95% confidence interval -1.5 to 2.3). In instrumental variable models, the addition of an antihypertensive drug from a new class led to clinically important reductions in systolic blood pressure (-14.4 mm Hg, -15.6 to -13.3) and fewer major cardiovascular events (absolute risk -6.2, -10.9 to -1.3). Incremental reductions in systolic blood pressure remained large and similar in magnitude for patients already taking drugs from zero, one, two, or three or more drug classes. This finding was consistent across all subgroups of patients. The addition of another antihypertensive drug class was not associated with adverse events in either standard or instrumental variable models.

Conclusions: After adjustment for confounding by indication, the addition of a new antihypertensive drug class led to large reductions in systolic blood pressure and major cardiovascular events among patients at high risk for cardiovascular events but without diabetes. Effects on systolic blood pressure persisted across all levels of baseline drug use and all subgroups of patients.

Fig 1

Incremental effects of antihypertensive drug classes on systolic blood pressure. Diamonds represent point estimates from pooled models. Squares represent point estimates from models stratified by baseline number of drug classes. Systolic blood pressure was each patient’s final recorded measurement. Antihypertensive drug classes are measured at baseline and at latest visit for which there was also recorded measurement of blood pressure. Multivariable adjusted models estimated with ordinary least squares regression. Instrumental variable models were estimated with two stage ordinary least squares regression

Fig 2

Incremental effects of antihypertensive drug classes on major cardiovascular events. Diamonds represent point estimates from pooled models. Squares represent point estimates from models stratified by baseline number of drug classes. Major cardiovascular events defined as composite including myocardial infarction, acute coronary syndrome not resulting in myocardial infarction, stroke, acute decompensated heart failure, or death from cardiovascular causes. Antihypertensive drug classes measured at baseline and at each patient’s final visit. To minimize reverse causality, last recorded value of drug classes before incidence of event was used for patients who experienced a major cardiovascular event. For standard multivariable models, additive hazards models estimated to account for right censored nature of survival outcomes. For instrumental variable models, recently validated two stage approach was implemented, substituting predicted number of drug classes from first stage (function of randomization status and covariates) into additive hazards model

Fig 3

Incremental effects of antihypertensive drug classes on serious adverse events. Diamonds represent point estimates from pooled models. Squares represent point estimates from models stratified by baseline number of drug classes. Serious adverse events defined as composite including emergency department evaluations for hypotension, syncope, bradycardia, electrolyte imbalance, injurious fall, or admissions for acute kidney injury or acute renal failure. Antihypertensive drug classes measured at baseline and at each patient’s final visit. To minimize reverse causality, last recorded value of drug classes before incidence of event was used for those patient who experienced serious adverse event. For standard multivariable models, additive hazards models were estimated to account for right censored nature of survival outcomes. For instrumental variable models, recently validated two stage approach was implmented, substituting predicted number of drug classes from first stage (function of randomization status and covariates) into additive hazards model