Association of Intensive vs Standard Blood Pressure Control With Cerebral White Matter Lesions

Abstract

Importance: The effect of intensive blood pressure lowering on brain health remains uncertain.

Objective: To evaluate the association of intensive blood pressure treatment with cerebral white matter lesion and brain volumes.

Design, setting, and participants: A substudy of a multicenter randomized clinical trial of hypertensive adults 50 years or older without a history of diabetes or stroke at 27 sites in the United States. Randomization began on November 8, 2010. The overall trial was stopped early because of benefit for its primary outcome (a composite of cardiovascular events) and all-cause mortality on August 20, 2015. Brain magnetic resonance imaging (MRI) was performed on a subset of participants at baseline (n = 670) and at 4 years of follow-up (n = 449); final follow-up date was July 1, 2016.

Interventions: Participants were randomized to a systolic blood pressure (SBP) goal of either less than 120 mm Hg (intensive treatment, n = 355) or less than 140 mm Hg (standard treatment, n = 315).

Main outcomes and measures: The primary outcome was change in total white matter lesion volume from baseline. Change in total brain volume was a secondary outcome.

Results: Among 670 recruited patients who had baseline MRI (mean age, 67.3 [SD, 8.2] years; 40.4% women), 449 (67.0%) completed the follow-up MRI at a median of 3.97 years after randomization, after a median intervention period of 3.40 years. In the intensive treatment group, based on a robust linear mixed model, mean white matter lesion volume increased from 4.57 to 5.49 cm3 (difference, 0.92 cm3 [95% CI, 0.69 to 1.14]) vs an increase from 4.40 to 5.85 cm3 (difference, 1.45 cm3 [95% CI, 1.21 to 1.70]) in the standard treatment group (between-group difference in change, -0.54 cm3 [95% CI, -0.87 to -0.20]). Mean total brain volume decreased from 1134.5 to 1104.0 cm3 (difference, -30.6 cm3 [95% CI, -32.3 to -28.8]) in the intensive treatment group vs a decrease from 1134.0 to 1107.1 cm3 (difference, -26.9 cm3 [95% CI, 24.8 to 28.8]) in the standard treatment group (between-group difference in change, -3.7 cm3 [95% CI, -6.3 to -1.1]).

Conclusions and relevance: Among hypertensive adults, targeting an SBP of less than 120 mm Hg, compared with less than 140 mm Hg, was significantly associated with a smaller increase in cerebral white matter lesion volume and a greater decrease in total brain volume, although the differences were small.

Trial registration: ClinicalTrials.gov Identifier: NCT01206062.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Nasrallah reported receiving grants from the National Institutes of Health (NIH). Dr Pajewski reported receiving grants from NIH. Dr Auchus reported receiving grants from NIH/National Heart, Lung, and Blood Institute (NHLBI) (contract HHSN268200900047C, subaward 000336417-041). Dr Chelune reported receiving grants from University of Utah. Dr Cheung reported receiving grants from University of Utah and Veterans Affairs Salt Lake City Healthcare System. Dr Cushman reported receiving grants from NHLBI; personal fees from Sanofi; and nonfinancial support from Novartis. Dr Crowe reported receiving grants from NIH. Dr Davatzikos reported receiving grants from NIH. Dr Doshi reported receiving grants from NIH. Dr Erus reported receiving grants from the National Institute on Aging. Ms Gaussoin reported receiving other from NIH/NHLBI. Dr Johnson reported receiving grants from NHLBI. Dr Kimmel reported receiving royalties from Elsevier. Dr Lewis reported receiving grants from NIH. Dr Oparil reported receiving grants and nonfinancial support from NIH/NHLBI; personal fees from Actelion Clinical Research, Novo Nordisk, 98point6, George Clinical Pty Ltd/Actelion/Idorsia Pharmaceuticals, Pfizer, and ROX Medical; grants from George Clinical Pty Ltd/Actelion/Idorsia Pharmaceuticals, ROX Medical, Bayer, Idorsia Pharmaceuticals, and Novartis; and serving as editor in chief of Current Hypertension Reports. Dr Rahman reported receiving grants from NIH, Bayer, and Duke Clinical Research Institute. Dr Reboussin reported receiving grants from NIH. Dr Rocco reported receiving grants from NIH, Bayer, Boehringer Ingelheim, and GlaxoSmithKline and receiving personal fees from Abbvie, George Clinical, Beacon Bioscience, and Baxter. Dr Sachs reported receiving grants from NIH/NHLBI (contract HHSN268200900047C). Dr Sink reported receiving grants from NIH and through her institution from Biogen and vTv Therapeutics and that she was a full-time faculty member at Wake Forest School of Medicine during the conduct of SPRINT but is now a full-time employee of Genentech, a member of the Roche Group (Genentech had no involvement in SPRINT). Dr Still reported receiving grants from Case Western Reserve University. Dr Supiano reported receiving grants from NIH. Dr Wadley reported receiving grants from NIH. Ms Walker reported receiving grants from NIH. Dr Weiner reported receiving grants from University of Utah and receiving personal fees from Janssen Biopharmaceuticals. Dr Wilson reported receiving grants from Wake Forest University. Ms Woolard reported receiving grants from NIH/NHLBI (contract HHSN268200900047C). Dr J. Wright reported receiving grants from NIH. Dr C. Wright reported receiving grants from NIH. Dr Bryan reported receiving grants from NIH, having equity in GalileoCDS Inc, and having a licensed and issued patent for a System and Method for Medical Image Analysis and Probabilistic Diagnosis. No other authors reported disclosures.

Figures

Figure 1.. Eligibility, Randomization, and Follow-up for Participants in the MRI Substudy

MRI indicates magnetic resonance imaging; SBP, systolic blood pressure; SPRINT, Systolic Blood Pressure Intervention Trial; WML, white matter lesion. aOther reasons for unwillingness to participate include participant could not lie flat for extended period (n = 7), participant reported metal in body before formal screening (n = 8), participant concerns about stent or other cardiac device (n = 8), concerns about body size (n = 2), other reasons (n = 7), and unknown reason (n = 22). bOther reasons for ineligibility include participant concerns about stent or other cardiac device (n = 8), use of pain pump (n = 2), prolonged hospitalization (n = 2), participant declined consent (n = 2), participant too large for MRI scanner (n = 1), and other reasons (n = 7).

Figure 2.. Change in Transformed White Matter Lesion Volume According to Subgroups

Estimates denote the estimated change for transformed white matter lesion (WML) volume at 1452 days (3.98 years) among participants with WML measurement at baseline and follow-up, based on a linear mixed model, adjusting for intracranial volume and days since randomization, with random effects for participant and magnetic resonance imaging facility. Negative values denote decreases from baseline; positive values, increases from baseline. Differences represent intensive treatment group minus standard treatment group. WML volumes were transformed using inverse hyperbolic sine transformation, f(x) = log(x + (x2 + 1)0.5). BP indicates blood pressure; CVD, cardiovascular disease; SE, standard error.

Figure 3.. Change in Total Brain Volume According to Subgroups

Estimates denote the estimated change in total brain volume at 1452 days (3.98 years) among participants with WML measurement at baseline and follow-up, based on a linear mixed model, adjusting for intracranial volume and days since randomization, with random effects for participant and magnetic resonance imaging facility. Differences represent intensive treatment group minus standard treatment group. BP indicates blood pressure; CVD, cardiovascular disease; SE, standard error.