The prematurely stopped and underpowered trial failed to meet its primary endpoint but was consistent with prior positive trials.
Controlling blood pressure to below 120/80 mm Hg in patients who have had a stroke may help prevent another event, a Japanese trial suggests.
Through an average follow-up of nearly 4 years, recurrent stroke was numerically but not significantly lower when the more-intensive goal was used instead of a less stringent one of less than 140/90 mm Hg, researchers led by Kazuo Kitagawa, MD, PhD (Tokyo Women’s Medical University, Japan), report in a study published online July 29, 2019, in JAMA Neurology.
The initial trial was designed to enroll 5,000 patients who had had a stroke within the past 3 years (but not the last month); however, that goal was lowered to 2,000 based on recruitment difficulties and an interim look at trial data. After continued slow enrollment and a loss of study funding, the trial was stopped after only 1,280 patients were randomized, leaving it underpowered to detect a difference between groups.
In a meta-analysis combining their results with three previous RCTs aiming for systolic BPs of less than 125 or 130 mm Hg, the combined data set showed an advantage for more intensive treatment (RR 0.78; 95% CI 0.64-0.96), with an absolute risk difference of 1.5% and a number needed to treat of 67. The apparent benefit was seen primarily in prevention of hemorrhagic stroke.
Those findings, Kitagawa et al say, “support that the use of a BP target less than 130/80 mm Hg is likely to be beneficial in patients with a history of stroke.”
Commenting for TCTMD, Larry Goldstein, MD (University of Kentucky, Lexington), said it is unfortunate that the trial was stopped early far short of its planned enrollment goal. That, combined with lower-than-expected event rates, made it “terribly underpowered” to assess the effect of intensive BP-lowering on recurrent stroke risk, he told TCTMD.
Nonetheless, though the difference in recurrent stroke fell short of statistical significance, it is consistent with the findings of prior studies and “not too dissimilar” from what was seen in the PROGRESS trial. Published in 2001, PROGRESS showed that lowering BP by an average of 9/4 mm Hg with a perindopril-based regimen significantly reduced recurrent stroke risk in patients with a prior stroke/TIA, regardless of hypertension history.
“Putting all of the studies together, it seems that treating blood pressure in patients who have had a stroke, almost regardless of whether they’re hypertensive or not hypertensive at baseline, seems to carry some benefit,” Goldstein said. He noted that guidelines already recommend reducing BP to lower recurrent stroke risk, saying, “I don’t know that this result is going to change the recommendation in any substantial way. It’s just consistent with the messages that have been available.”
Zeroing In On a BP Goal
In addition to PROGRESS, other trials—such as SPS3—have indicated that lowering BP after a stroke can prevent recurrent events, especially hemorrhagic strokes. Though somewhat controversial, the SPRINT trial demonstrated that intensive BP lowering to less than 120 mm Hg systolic versus a standard goal of less than 140 mm Hg improved outcomes in high-risk, nondiabetic patients, but the study excluded those with a history of stroke.
“Blood pressure-lowering has been strongly recommended for secondary prevention of chronic management after stroke since the results of the PROGRESS [trial] were published, but the optimum BP level and significance of intensive BP-lowering needed to be examined,” Kitagawa et al say.
The RESPECT trial, conducted at 140 hospitals in Japan, was designed to do that. Patients were randomized to a lower BP goal of less than 120/80 mm Hg or to a higher goal of less than 140/90 mm Hg. Patients with diabetes, chronic kidney disease, or a history of MI included in the latter group used a target of less than 130/80 mm Hg.
Analyses excluded 17 patients who did not receive any treatment.
The mean age of the patients was 67.2 years, and 69.4% were men. All patients had a history of hypertension, with an average BP at baseline of 145.4/83.6 mm Hg. The qualifying stroke was ischemic in 85% of participants.
During follow-up, the investigators achieved an average BP separation of 6.5/3.3 mm Hg between the intensive and standard arms using stepwise therapy that included a combination of losartan or another angiotensin II receptor blocker (ARB) and hydrochlorothiazide, amlodipine besylate, and spironolactone.
Recurrent stroke, the primary endpoint, was not significantly lower with more-intensive therapy (annualized rate 1.65% vs 2.26%; HR 0.73; 95% CI 0.49-1.11). Of all secondary endpoints, there was a significant difference between the trial arms for only one; intracerebral hemorrhage occurred at a lower rate in the intensive group (annualized 0.04% vs 0.46%; HR 0.09; 95% CI 0.01-0.70).
Adverse events, including those related to hypotension (syncope and dizziness), occurred at similar rates in the two groups.
Support for Lower BP Goals in Guidelines
In an accompanying editorial, Craig Anderson, MD, PhD (George Institute for Global Health, University of New South Wales, Sydney, Australia), says the RESPECT results are an important contribution considering the exclusion of patients with prior stroke from SPRINT, “not only in providing further support for the benefits of more-intensive BP-lowering for secondary stroke prevention but also in defining some of the complexities to achieving this goal in both research and practice.”
Despite the challenges faced by the Kitagawa et al, he says, RESPECT “provides support for the recent move of many hypertension guidelines across the world to recommend lower BP targets in high-risk patient populations (ie, BP levels < 130/85 mm Hg).”
Citing the burden of disease attributed to high BP, Anderson says “any recommendations for the initiation, intensification, and control of BP-lowering treatment for high-risk patients has substantial clinical and public health importance. The use of digital health solutions and simple, low-cost, fixed-dose combinations of BP-lowering agents to improve the uptake, adherence, and control of BP could have substantial public health gain in many populations, particularly those of low-income to middle-income countries, where most of the stroke and CV disease burden exists.”
Goldstein said that the type of antihypertensive agent might make a difference as well. He pointed to a growing amount of data suggesting that agents associated with less variability in BP may have an additional benefit beyond just lowering BP, noting that beta-blockers have been tied to a greater degree of variability compared with calcium channel blockers, ACE inhibitors, and ARBs.
- Kitagawa K, Yamamoto Y, Arima H, et al. Effect of standard vs intensive blood pressure control on the risk of recurrent stroke: a randomized clinical trial and meta-analysis. JAMA Neurol. 2019;Epub ahead of print.
- Anderson CS. Challenges to realizing benefits from more intensive blood pressure control for preventing recurrent stroke. JAMA Neurol. 2019;Epub ahead of print.
- RESPECT was funded by Merck, Bristol-Myers Squibb, Towa Pharmaceutical Co., Ltd., and Omron Corporation.
- Kitagawa reports receiving grants and personal fees from Daiichi Sankyo, Bayer, Takeda Pharmaceutical, Nippon Boehringer Ingelheim, Kyowa Hakko Kirin, Sumitomo Dainippon Pharma, Astellas Pharma, and Sanofi.
- Anderson reports receiving grants from the National Health and Medical Research Council of Australia and Takeda China paid to his institution; honoraria for advisory board activities from Boehringer Ingelheim and Amgen; and speaker fees from Takeda.