SPRINT MIND: What Have We Learned?

Aggressively lowering blood pressure in hypertensive older adults did not significantly reduce dementia risk, SPRINT MIND investigators reported.

Specifically, treating hypertensive older adults to a systolic blood pressure goal of <120 mm Hg, compared with treating them to a goal of <140 mm Hg, reduced the risk of probable dementia by 17%, a statistically non-significant difference (HR 0.83, 95% CI 0.67-1.04), according to Jeff Williamson, MD, MHS, of the Wake Forest School of Medicine in Winston-Salem, North Carolina, and colleagues.

But intensive blood pressure control showed statistically significant benefits in secondary outcomes, including a 19% lower rate in mild cognitive impairment (HR 0.81, 95% CI 0.69-0.95), they wrote in JAMA.

“How does one interpret a secondary endpoint in a trial that fails to win on the primary endpoint? With great circumspection,” observed Sanjay Kaul, MD, of Cedars-Sinai Medical Center in Los Angeles.

“Hence the caveat from the investigators: ‘There was no adjustment of the significance threshold for the secondary or other endpoints; because of the potential for type I error, the findings from these analyses should be considered exploratory,'” Kaul told MedPage Today.

SPRINT MIND was a substudy of the NIH-funded Systolic Blood Pressure Intervention Trial (SPRINT), which aimed to determine whether aggressively lowering blood pressure could protect the heart, kidney, and brain over 5 years. The success of the heart disease portion — which raised questions about trial design and how results should be applied — led to the trial’s early termination at 3.3 years.

This made the study too short to definitively answer the dementia question, Williamson said. As a result, the Alzheimer’s Association announced Monday that it is funding Williamson’s group for SPRINT MIND 2.0, a 2-year extension.

“The primary outcome was negative in the SPRINT MIND trial, but we’re very encouraged by the positive trend,” Maria Carrillo, PhD, the Alzheimer’s Association chief science officer, told MedPage Today. “And we are incredibly compelled by the secondary outcome of mild cognitive impairment being reduced by 19%. We think that with an extended time frame and an additional opportunity for follow-up, we may very well see that dementia outcome is positive.”

“Because dementia is a much more slowly progressive disease from no impairment to impairment, our hope is that with 2 more years of follow-up, SPRINT MIND will accrue the number of new cases of dementia that we originally planned for so that we can definitively answer this question,” Williamson added.

But even if the dementia results are positive, how that will translate into clinical practice is up for debate. “The relation of blood pressure — and in particular level and change in blood pressure — to brain function is complex,” noted Zoe Arvanitakis, MD, of Rush University Medical Center in Chicago.

While SPRINT MIND adds important information to this puzzle, more research needs to be done across a range of blood pressures, in a range of ages, using different outcomes beyond diagnostic dementia classification, Arvanitakis told MedPage Today.

A recent study of nearly 1,300 older people at autopsy showed that faster declining systolic blood pressure was associated with an increased number of brain infarcts and more severe cerebral vessel pathologies, she noted, and much research is needed to “better understand the potential benefits of intensive blood pressure treatment, as well as the potential risks.”

Like any other clinical trial, the results of SPRINT MIND should be interpreted in the context of the population it studied, added Behnam Sabayan, MD, PhD, of Northwestern University in Chicago.

“SPRINT excluded individuals who had diabetes, history of stroke, and those who are residing in nursing homes,” Sabayan told MedPage Today. “This means that frail individuals with highest burden of cerebrovascular pathologies were not necessarily a part of this study, and intensive blood pressure reduction in those subjects should be exercised with caution since it can put them at risk for brain hypoperfusion, falls, kidney impairment and might introduce further risk for subsequent strokes.”

SPRINT studied 9,361 individuals ages ≥50 who had baseline blood pressure — treated or untreated — from 130 to 180. All participants also had at least one additional cardiovascular risk factor, but not diabetes, and the average age in the study was 67.9. About 30% of the cohort was African American and 10% Hispanic.

Participants received anti-hypertensive medications to help achieve their assigned blood pressure target, mostly generic drugs. The trial was not designed to test a specific drug: “SPRINT used a quasi-pragmatic approach with suggestions for treatment choice, but practitioners approached systolic blood pressure control individually and most participants were taking multiple drugs,” wrote Kristine Yaffe, MD, of the University of California San Francisco, in an accompanying editorial.

And “although the study population in the SPRINT trial was quite diverse, there was limited power to address differential effect of treatment by race,” Yaffe added. “A recent study reported that older black adults may show greater effects of systolic blood pressure control on cognitive outcomes. This finding requires further investigation.”

The mild cognitive impairment finding in SPRINT MIND also needs a more careful look, Kaul suggested. “In a sensitivity analysis that accounts for multiple imputation for missing data for time to first mild cognitive impairment, the difference was not significant,” he said.

“And even if we were to take the results at face value, it is unproven whether lowering the risk of mild cognitive impairment will translate into reduced risk of progression to dementia or Alzheimer’s disease,” Kaul added.