Longer-Term All-Cause and Cardiovascular Mortality With Intensive Blood Pressure Control: A Secondary Analysis of a Randomized Clinical Trial

Abstract

Importance: The Systolic Blood Pressure Intervention Trial (SPRINT) showed that intensive blood pressure control reduced cardiovascular morbidity and mortality. However, the legacy effect of intensive treatment is unknown.

Objective: To evaluate the long-term effects of randomization to intensive treatment with the incidence of cardiovascular and all-cause mortality approximately 4.5 years after the trial ended.

Design, setting, and participants: In this secondary analysis of a multicenter randomized clinical trial, randomization began on November 8, 2010, the trial intervention ended on August 20, 2015, and trial close-out visits occurred through July 2016. Patients 50 years and older with hypertension and increased cardiovascular risk but without diabetes or history of stroke were included from 102 clinic sites in the US and Puerto Rico. Analyses were conducted between October 2021 and February 2022.

Interventions: Randomization to systolic blood pressure (SBP) goal of less than 120 mm Hg (intensive treatment group; n = 4678) vs less than 140 mm Hg (standard treatment group; n = 4683).

Main outcomes and measures: Extended observational follow-up for mortality via the US National Death Index from 2016 through 2020. In a subset of 2944 trial participants, outpatient SBP from electronic health records during and after the trial were examined.

Results: Among 9361 randomized participants, the mean (SD) age was 67.9 (9.4) years, and 3332 (35.6%) were women. Over a median (IQR) intervention period of 3.3 (2.9-3.9) years, intensive treatment was beneficial for both cardiovascular mortality (hazard ratio [HR], 0.66; 95% CI, 0.49-0.89) and all-cause mortality (HR, 0.83; 95% CI, 0.68-1.01). However, at the median (IQR) total follow-up of 8.8 (8.3-9.3) years, there was no longer evidence of benefit for cardiovascular mortality (HR, 1.02; 95% CI, 0.84-1.24) or all-cause mortality (HR, 1.08; 95% CI, 0.94-1.23). In a subgroup of participants, the estimated mean outpatient SBP among participants randomized to intensive treatment increased from 132.8 mm Hg (95% CI, 132.0-133.7) at 5 years to 140.4 mm Hg (95% CI, 137.8-143.0) at 10 years following randomization.

Conclusions and relevance: The beneficial effect of intensive treatment on cardiovascular and all-cause mortality did not persist after the trial. Given increasing outpatient SBP levels in participants randomized to intensive treatment following the trial, these results highlight the importance of consistent long-term management of hypertension.

Trial registration: ClinicalTrials.gov Identifier: NCT01206062.

Figure 1.. Participant Flow in the Systolic Blood Pressure Intervention Trial

Figure 2.. Cardiovascular Disease (CVD) vs Non-CVD Mortality by Treatment Group

A, Cumulative incidence of CVD and non-CVD mortality by treatment group. B, Time-dependent hazard ratio (HR) for cardiovascular mortality estimated from a competing-risks regression model comparing intensive treatment with standard treatment. The trial phase and observational phase do not overlap for individual participants, but due to participants being randomized over time, there is an overlap in the trial and observational phase for the trial population when time is measured relative to the date of randomization. Trial phase encompasses follow-up through the end of study closeout visits (eFigure 1 in Supplement 2).

Figure 3.. Cardiovascular Disease (CVD) Mortality by Treatment Group According to Subgroups

Sociodemographic data were collected at baseline, with race and ethnicity collected via self-report using fixed categories to satisfy the National Institutes of Health Policy and Guidelines on the Inclusion of Women and Minorities as Subjects in Clinical Research. In the Systolic Blood Pressure Intervention Trial, the subgroups of Black and non-Black were prespecified. Chronic kidney disease was defined as an estimated glomerular filtration rate less than 60 mL/min/1.73 m² based on the 2021 Chronic Kidney Disease–Epidemiology Collaboration creatinine equation. Cognitive function groups based on age-specific and education-specific normative 10th percentile from the Irish Longitudinal Study of Ageing, after adding 3 points to the scores of non-White participants. Frailty status based on a 36-item Frailty Index, for which scores range from 0 to 1, with higher values indicating greater frailty. Trial phase encompasses follow-up through the end of study closeout visits (eFigure 1 in Supplement 2).

Figure 4.. Mean Systolic Blood Pressures by Treatment Group Comparing Trial Measurements With Outpatient Readings Extracted From the Electronic Health Record (EHR)

Estimates based on a linear mixed model with random intercepts for participant and clinic site, with years since randomization modeled using B-splines. Shaded areas denote pointwise 95% CIs. The trial phase and observational phase do not overlap for individual participants, but due to participants being randomized over time, there is an overlap in the trial and observational phase for the trial population when time is measured relative to the date of randomization. Trial phase encompasses follow-up through the end of study closeout visits (eFigure 1 in Supplement 2).