Target Audience and Goal Statement:
Cardiologists, vascular medicine specialists, neurologists, geriatricians, internists, and family medicine physicians
The goal of the study was to determine whether reducing systolic blood pressure (BP) in older adults, ages 50 and up, who have hypertension but without diabetes or stroke, could reduce risk of dementia and/or mild cognitive impairment (MCI).
Questions Addressed:
- Does reducing systolic BP in adults older than age 50 reduce the risk of dementia and/or mild cognitive impairment and if so, by how much?
- Is the reduction of BP in this patient population safe?
- Are there any differences between subgroups in the effects of BP reduction on incident dementia and/or MCI?
Study Synopsis and Perspective:
Aggressively reducing blood pressure in hypertensive older adults reduced dementia risk by 17%, which was not statistically significant, and it reduced MCI by 19%, which was statistically significant, according to the SPRINT MIND study, reported in JAMA.
The SPRINT MIND study, a randomized trial conducted at 102 U.S. and Puerto Rico sites, compared the effects of treating hypertensive adults, ages 50 and up, to reach a systolic blood pressure (SBP) goal of <120 mm Hg, with treating them to a goal of <140 mm Hg. The primary outcome measure was incidence of probable dementia. Although this was reduced by 17% among patients with the lower target, it was not statistically significant (HR 0.83, 95% CI 0.67-1.04) and thus the primary endpoint was missed, according to author Jeff Williamson, MD, MHS, of the Wake Forest School of Medicine in Winston-Salem, North Carolina, and colleagues.
But attaining intensive blood pressure control did show statistically significant benefits in secondary outcomes, including a 19% lower rate for MCI (HR 0.81, 95% CI 0.69-0.95).
The mean SBP at baseline was 139.7 mm Hg, and the median Montreal Cognitive Assessment (MoCA) score was 23 (interquartile range, 20-26). Before the decision to terminate the trial, the mean SBP in the intensive treatment group was 121.6 mm Hg and 134.8 mm Hg in the standard treatment group, for a mean between-group difference of 13.3 mm Hg.
In the study, researchers included 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 no history of stroke; the average age in the study was 67.9. About 30% of the cohort was African American and 10% Hispanic. The median follow-up time was 5.11 years.
During this follow-up time, adjudicated probable dementia occurred in 149 participants in the intensive treatment group vs 176 in the standard treatment group (7.2 vs 8.6 cases per 1,000 person-years). Intensive BP control significantly reduced the risk of MCI (14.6 vs 18.3 cases per 1,000 person-years), as well as the combined incidence of MCI or probable dementia (20.2 vs 24.1 cases per 1,000 person-years; HR 0.85; 95% CI 0.74-0.97).
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,” noted Kristine Yaffe, MD, of the University of California San Francisco, in an accompanying editorial.
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. Initial apparent success of the heart disease portion — although questions were later raised about the trial’s design and conduct 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 in late January 2019 that it is funding Williamson’s group for SPRINT MIND 2.0, a 2-year extension.”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.
“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.”
The authors noted that the incidence of probable dementia “was likely underestimated in both treatment groups because of incomplete ascertainment.”
They also observed that there has been controversy surrounding the benefits and risks associated with lowering SBP to below 150 mm Hg, such as the possibility of hypotension and cerebral hypoperfusion resulting in negative effects on the brain. The authors stress that their trial “demonstrates no such negative effect; specifically, these results importantly show that intensive BP control did not result in harm to cognition after a median intervention period of 3.34 years and an overall median follow-up of 5.11 years.” To the contrary, they view this trial as evidence, the first in any study, of benefit for reducing SBP in the reduction of MCI occurrence, a known risk factor for dementia.
Study limitations include early termination of the study which reflects a probable loss of power to detect an effect on dementia beyond that point. As well, patients with common comorbidities including type 2 diabetes, previous stroke, advanced kidney disease, or heart failure were excluded. The study did not adjudicate baseline cognitive status, and there was no way to determine the relative effect of specific anti-hypertensive medications on MCI or dementia.
There was also limited power to detect differences among race/ethnic groups; a recent study mentioned by Yaffe reported that older black adults may show greater effects of SBP control on cognitive outcomes. “This finding requires further investigation,” she observed.
Source References: JAMA 2019; DOI:10.1001/jama.2018.21442
Editorial: JAMA 2019; DOI:10.1001/jama.2019.0008
Study Highlights: Explanation of Findings
The study found that aggressively reducing blood pressure in hypertensive older adults reduced dementia risk by 17%, which was not statistically significant, and it reduced MCI by 19%, which was statistically significant. Many observational studies have linked hypertension to dementia, Yaffe pointed out in her editorial.
“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, who was not involved in the research.
“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.
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.”
The MCI 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.
Primary Source
JAMA
Secondary Source
JAMA
Additional Source
MedPage Today
Source Reference: George J “SPRINT MIND: What Have We Learned?” 2019.
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