Effect of Standard vs Intensive Blood Pressure Control on the Risk of Recurrent Stroke: A Randomized Clinical Trial and Meta-analysis

Abstract

Importance: The Systolic Blood Pressure Intervention Trial (SPRINT) demonstrated that a systolic blood pressure (BP) target less than 120 mm Hg was superior to less than 140 mm Hg for preventing vascular events. This trial excluded patients with prior stroke; therefore, the ideal BP target for secondary stroke prevention remains unknown.

Objective: To assess whether intensive BP control would achieve fewer recurrent strokes vs standard BP control.

Design, setting, and participants: Randomized clinical trial (RCT) of standard vs intensive BP control in an intent-to-treat population of patients who had a history of stroke. Patients were enrolled between October 20, 2010, and December 7, 2016. For an updated meta-analysis, PubMed and the Cochrane Central Library database were searched through September 30, 2018, using the Medical Subject Headings and relevant search terms for cerebrovascular disease and for intensive BP lowering. This was a multicenter trial that included 140 hospitals in Japan; 1514 patients who had a history of stroke within the previous 3 years were approached, but 234 refused to give informed consent.

Interventions: In total, 1280 patients were randomized 1:1 to BP control to less than 140/90 mm Hg (standard treatment) (n = 640) or to less than 120/80 mm Hg (intensive treatment) (n = 640). However, 17 patients never received intervention; therefore, 1263 patients assigned to standard treatment (n = 630) or intensive treatment (n = 633) were analyzed.

Main outcomes and measures: The primary outcome was stroke recurrence.

Results: The trial was stopped early. Among 1263 analyzed patients (mean [SD] age, 67.2 [8.8] years; 69.4% male), 1257 of 1263 (99.5%) completed a mean (SD) of 3.9 (1.5) years of follow-up. The mean BP at baseline was 145.4/83.6 mm Hg. Throughout the overall follow-up period, the mean BP was 133.2/77.7 (95% CI, 132.5-133.8/77.1-78.4) mm Hg in the standard group and 126.7/77.4 (95% CI, 125.9-127.2/73.8-75.0) mm Hg in the intensive group. Ninety-one first recurrent strokes occurred. Nonsignificant rate reductions were seen for recurrent stroke in the intensive group compared with the standard group (hazard ratio [HR], 0.73; 95% CI, 0.49-1.11; P = .15). When this finding was pooled in 3 previous relevant RCTs in a meta-analysis, the risk ratio favored intensive BP control (relative risk, 0.78; 95% CI, 0.64-0.96; P = .02; absolute risk difference, -1.5%; 95% CI, -2.6% to -0.4%; number needed to treat, 67; 95% CI, 39-250).

Conclusions and relevance: Intensive BP lowering tended to reduce stroke recurrence. The updated meta-analysis supports a target BP less than 130/80 mm Hg in secondary stroke prevention.

Trial registration: ClinicalTrials.gov identifier: NCT01198496.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Kitagawa reported receiving grants and personal fees from Daiichi Sankyo, Bayer Inc, Takeda Pharmaceutical, Nippon Boehringer Ingelheim, Kyowa Hakko Kirin, Sumitomo Dainippon Pharma, Astellas Pharma, and Sanofi. Dr Arima reported receiving personal fees from Bayer, Daiichi Sankyo, Fukuda Denshi, Kyowa Kirin, and Takeda. Dr Minematsu reported receiving personal fees from Bayer Yakuhin, Otsuka Pharmaceutical, Boehringer Ingelheim, AstraZeneca, Pfizer, Mitsubishi Tanabe Pharma Cooperation, Japan Stryker, Kowa, Nihon Medi-Physics Co, BMS, Sawai Pharmaceutical Co, Sumitomo Dainippon Pharma Co Ltd, Daiichi Sankyo, Asteras Pharma, and Nippon Chemiphar and reported receiving other financial support from AstraZeneca, CSL Behring, Medico’s Hirata, and Bayer Yakuhin. Dr Ueda reported receiving grants from Kowa Soyaku, Bayer, Bristol-Myers Squibb, Pfizer, Daiichi Sankyo, and Takeda Yakuhin and reported receiving personal fees from Ezai, Novartis, MSD, and Boelinger Ingelheim. Dr Rakugi reported receiving grants and/or personal fees from MSD, Astellas Pharma, Daiichi Sankyo, Dainippon Sumitomo Pharma, Bayer Yakuhin, Kyowa Hakko Kirin, Mochida Pharmaceutical, Nippon Boehringer Ingelheim, Takeda Pharmaceutical, Mitsubishi Tanabe Pharma, Novartis Pharma, Otsuka Pharmaceutical, Pfizer Japan, Shionogi & Co, and Teijin Pharma. Dr Ohya reported receiving grants and/or personal fees from Takeda Pharma, Daiichi Sankyo, Novartis Pharma, Asterasu, Dainippon Sumitomo, MSD, Bayer, Pfizer, and Boehringer Ingelheim. Dr Umemura reported receiving grants from Dainippon Sumitomo, Asteras, Pfizer, Nippon Boehringer Ingelheim, Daiichi Sankyo, and Takeda and reported receiving personal fees from Nippon Boehringer Ingelheim and Takeda. Dr Matsumoto reported receiving personal fees from Kowa Pharmaceutical Co Ltd, Takeda Pharmaceutical Co Ltd, Bayer Yakuhin, Ltd, Sanofi KK, Daiichi Sankyo, Otsuka Pharmaceutical Co Ltd, Astellas Pharma Inc, AstraZeneca KK, Mochida Pharmaceutical Co, Ltd, Sumitomo Dainippon Pharma Co Ltd, Amgen Astellas BioPharma KK, Esai Co, Ltd, and Pfizer Japan Inc. Dr Shimamoto reported receiving personal fees from Takeda, Sumitomo Dainippon Pharma Co Ltd, MSD, Astellas Pharma, Boehringer Ingelheim, and Bayer Yakuhin. Dr Ito reported receiving grants and/or personal fees from MSD, Daiichi Sankyo, Takeda, Astellas, and Boehringer Ingelheim. Dr Shimada reported receiving personal fees from Dainippon Sumitomo Ltd, and Daiichi Sankyo. No other disclosures were reported.

Figures

Figure 1.. Flow of Participants Included in the RESPECT Study

RESPECT indicates Recurrent Stroke Prevention Clinical Outcome.

Figure 2.. Cumulative Incidence of Stroke by Randomized Groups

Stroke is a composite of ischemic stroke and intracerebral hemorrhage.

Figure 3.. Effects of Intensive Blood Pressure Lowering on Recurrent Stroke in a Meta-analysis of Randomized Clinical Trials

Boxes and horizontal lines represent relative risks and 95% CIs for each trial. The size of boxes is proportional to the inverse variance. Diamonds show the 95% CIs for pooled estimates of effect and are centered on the pooled relative risk. PAST-BP indicates Prevention After Stroke–Blood Pressure; PODCAST, Prevention of Decline in Cognition After Stroke Trial; RESPECT, Recurrent Stroke Prevention Clinical Outcome; and SPS3, Secondary Prevention of Small Subcortical Strokes.