Patient Selection for Intensive Blood Pressure Management Based on Benefit and Adverse Events

Abstract

Background: Intensive systolic blood pressure (SBP) treatment prevents cardiovascular disease (CVD) events in patients with high CVD risk on average, though benefits likely vary among patients.

Objectives: The aim of this study was to predict the magnitude of benefit (reduced CVD and all-cause mortality risk) along with adverse event (AE) risk from intensive versus standard SBP treatment.

Methods: This was a secondary analysis of SPRINT (Systolic Blood Pressure Intervention Trial). Separate benefit outcomes were the first occurrence of: 1) a CVD composite of acute myocardial infarction or other acute coronary syndrome, stroke, heart failure, or CVD death; and 2) all-cause mortality. Treatment-related AEs of interest included hypotension, syncope, bradycardia, electrolyte abnormalities, injurious falls, and acute kidney injury. Modified elastic net Cox regression was used to predict absolute risk for each outcome and absolute risk differences on the basis of 36 baseline variables available at the point of care with intensive versus standard treatment.

Results: Among 8,828 SPRINT participants (mean age 67.9 years, 35% women), 600 CVD composite events, 363 all-cause deaths, and 481 treatment-related AEs occurred over a median follow-up period of 3.26 years. Individual participant risks were predicted for the CVD composite (C index = 0.71), all-cause mortality (C index = 0.75), and treatment-related AEs (C index = 0.69). Higher baseline CVD risk was associated with greater benefit (i.e., larger absolute CVD risk reduction). Predicted CVD benefit and predicted increased treatment-related AE risk were correlated (Spearman correlation coefficient = -0.72), and 95% of participants who fell into the highest tertile of predicted benefit also had high or moderate predicted increases in treatment-related AE risk. Few were predicted as high benefit with low AE risk (1.8%) or low benefit with high AE risk (1.5%). Similar results were obtained for all-cause mortality.

Conclusions: SPRINT participants with higher baseline predicted CVD risk gained greater absolute benefit from intensive treatment. Participants with high predicted benefit were also most likely to experience treatment-related AEs, but AEs were generally mild and transient. Patients should be prioritized for intensive SBP treatment on the basis of higher predicted benefit. (Systolic Blood Pressure Intervention Trial [SPRINT]; NCT01206062).

Keywords: blood pressure; cardiovascular disease; clinical decision making; hypertension; predictive modeling; prevention.

Conflict of interest statement

Funding Support and Author Disclosures This study was directly supported by grant R01HL139837 from the National Heart, Lung, and Blood Institute (NHLBI). Dr. Bress is also supported by NHLBI grant K01HL133468. Dr. Moran is also supported by NHLBI grant R01 HL 130500-01A1. SPRINT is funded with federal funds from the National Institutes of Health, including the NHLBI, the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute on Aging, and the National Institute of Neurological Disorders and Stroke, under contracts HHSN268200900040C, HHSN268200900046C, HHSN268200900047C, HHSN268200900048C, and HHSN268200900049C and interagency agreement A-HL-13-002-001. SPRINT was also supported in part with resources and use of facilities through the U.S. Department of Veterans Affairs. The SPRINT investigators acknowledge the contribution of study medications (azilsartan and azilsartan combined with chlorthalidone) from Takeda Pharmaceuticals International. All components of the SPRINT study protocol were designed and implemented by the investigators. The investigative team collected, analyzed, and interpreted the data. All aspects of manuscript writing, and revision were carried out by the coauthors. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health, the Department of Veterans Affairs, or the U.S. government. For a full list of contributors to SPRINT, see the Supplemental Appendix. The authors also acknowledge support from the following Clinical and Translational Science Awards funded by the National Center for Advancing Translational Sciences: Case Western Reserve University: UL1TR000439; The Ohio State University: UL1RR025755; University of Pennsylvania: UL1RR024134 and UL1TR000003; Boston University: UL1RR025771; Stanford University: UL1TR000093; Tufts University: UL1RR025752, UL1TR000073, and UL1TR001064; University of Illinois: UL1TR000050; University of Pittsburgh: UL1TR000005; University of Texas Southwestern Medical Center: 9U54TR000017-06; University of Utah: UL1TR000105-05; Vanderbilt University: UL1 TR000445; George Washington University: UL1TR000075; University of California, Davis: UL1 TR000002; University of Florida: UL1 TR000064; University of Michigan: UL1TR000433; Tulane University: P30GM103337 Centers of Biomedical Research Excellence Award (National Institute of General Medical Sciences). Drs. Bress and Derington have received research support to their institution from Amgen and Amarin (not related to the current project). Dr. Weintraub has received research support from Amarin; and is a consultant for Amarin and AstraZeneca. Dr. Cushman has received research support to his institution from Eli Lilly. Dr. Yeh is a consultant for AstraZeneca; and has received research grants from AstraZeneca. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Figures

FIGURE 1. Cumulative Incidence of the Benefit Outcomes and Risk for Adverse Events for Intensive Versus Standard Systolic Blood Pressure Treatment Within Tertiles of Predicted Benefit and Risk for Adverse Events

Shown are the cumulative hazards for the primary outcome (a composite of myocardial infarction, acute coronary syndrome, stroke, heart failure, or death due to cardiovascular causes) (A), all-cause mortality (B), and treatment-related adverse events (C) for intensive versus standard systolic blood pressure treatment within strata of predicted benefit and tertiles of risk for adverse events. CVD = cardiovascular disease.

FIGURE 2. Calibration Plots Showing the Observed Absolute Risks Within Deciles of Predicted Risk at 3.26-Year Follow-Up for the CVD Composite, All-Cause Mortality, and Adverse Events

Calibration plots showing the relationship between elastic net Cox model–predicted Kaplan-Meier event probabilities for the cardiovascular disease (CVD) composite (A), all-cause mortality (B), and adverse events (C) versus mean observed Kaplan-Meier event probabilities for each decile of risk in SPRINT (Systolic Blood Pressure Intervention Trial) at 3.26 years. The solid black diagonal lines show a perfect expected risk versus observed risk slope of 1. Calibration assesses how well elastic net Cox model–predicted CVD event rates correspond to observed rates. A formal test of calibration was performed using the modified Hosmer-Lemeshow chi-square statistic and the Greenwood-Nam-D’Agostino (GND) test.

FIGURE 3. Risk Magnification Plot Showing the Predicted Magnitude of Benefit (Reduced CVD Risk and All-Cause Mortality) and Risk for Treatment-Related Adverse Events With Intensive Versus Standard Treatment Across a Range of Predicted Baseline Risk for Each Benefit Outcome and Risk for Adverse Events

The solid red line represents direct risk magnification, where the absolute risk reduction is directly proportional to the baseline risk assuming a constant relative treatment effect. The solid black line represents the relationship between average elastic net Cox model–predicted absolute risk difference for each outcome across the full range of baseline risk. The dashed black line and shaded gray areas represent the 95% confidence bands for the predicted risk difference. The histogram represents the distribution of baseline risk for each outcome in the SPRINT population used in the present analysis. The black circles represent the average observed risk difference for each outcome within quartiles of the Cox model–predicted absolute risk difference. In contrast to the traditional C statistic, which assess a prediction model’s ability to predict outcome risk, C for benefit assesses a prediction model’s ability to predict treatment benefit by assessing the probability that among 2 randomly chosen and matched SPRINT participants on the basis of predicted benefit but with unequal observed benefit, the pair with greater observed benefit also has a higher predicted benefit (24). The bars represent 95% confidence limits of the observed risk differences. Abbreviations as in Figure 2.

CENTRAL ILLUSTRATION. Cardiovascular Disease Benefit and Adverse Event Risk of Intensive Versus Standard Systolic Blood Pressure Treatment

(A) Risk magnification plot showing the predicted magnitude of benefit (reduced risk for cardiovascular disease [CVD] composite outcome) with intensive versus standard systolic blood pressure (BP) treatment across a range of predicted baseline risk for the CVD composite outcome. The dashed black line and shaded gray areas represent the 95% confidence bands for the predicted risk difference. The bars represent 95% confidence limits of the observed risk differences. The histogram represents the distribution of baseline risk for each outcome in the SPRINT (Systolic Blood Pressure Intervention Trial) population used in the present analysis. (B) Distribution of SPRINT participants by tertile of the predicted magnitude of benefit (reduced risk for CVD composite outcome) and predicted increased risk for treatment-related adverse events with intensive versus standard systolic BP treatment.

FIGURE 4. Distribution of SPRINT Participants by Tertile of Predicted Magnitude of Benefit (Reduced CVD Risk and All-Cause Mortality) and Predicted Increased Risk of Treatment-Related Adverse Events With Intensive Versus Standard Systolic Blood Pressure Treatment

(A) Three-dimensional histogram showing the number of SPRINT participants within each cross-classification of tertiles of the elastic net Cox model–predicted Kaplan-Meier absolute risk differences for the CVD composite and adverse events at 3.26 years. (B) Three-dimensional histogram showing the number of SPRINT participants within each cross-classification of tertiles of the elastic net Cox model–predicted Kaplan-Meier absolute risk differences for all-cause mortality and treatment-related adverse events at 3.26 years. Abbreviations as in Figure 2.