ARTICLE IN BRIEF:
A large randomized, controlled trial suggests that intensive blood pressure control can reduce the risk of mild cognitive impairment, though not dementia. Independent experts debated the clinical implications of the findings.
A debate among neurologists over the findings of a huge, multi-site, randomized clinical trial testing the effects of intensive control of systolic blood pressure on cognitive outcomes seemed to come down to the age-old question: Is the glass half empty or half full?
On the half-empty side, the so-called SPRINT MIND—for Systolic Blood Pressure Intervention Trial-Memory and Cognition in Decreased Hypertension—failed to reach statistical significance on its primary cognitive outcome of a reduction in the occurrence of dementia. Moreover, the trial did not explicitly screen out mild cognitive impairment (MCI) at baseline, and did not include the sort of very old, frail or medically complex patients for whom the risks of intensive blood pressure control may be highest.
On the half-full side, however, the trial did significantly reduce the risk of MCI (14.6 versus 18.3 cases per 1,000 person-years) and the combined rate of MCI or probable dementia (20.2 versus 24.1 cases per 1,000 person-years). What's more, the trend for dementia alone was in the right direction and only just missed statistical significance: (7.2 versus 8.6 cases per 1,000 person-years).
For all the uncertainty, neurologists praised the study for providing what appears to be the first evidence ever from a randomized controlled trial that an intervention can reduce the risk of cognitive decline, even as they emphasized that the results need to be interpreted with caution.
An editorial accompanying the paper in the Journal of the American Medical Association (JAMA) stated: “The SPRINT MIND study may not be the final approach for prevention of AD or other cognitive impairment, but it represents a major leap forward in what has emerged as a marathon journey.”
In hopes of clarifying the results, the Alzheimer's Association announced that it is providing $800,000 in “seed” money for the investigators to add two additional years of follow-up to the original study. The goal, the organization stated in a released statement, is “to allow for a more definitive statement on reducing dementia risk.”
SPRINT was designed to test the effect of more intensive BP control on cardiovascular, renal, and cognitive outcomes. Participants were aged 50 years or older and had a systolic blood pressure (SBP) between 130-180 mmHg at the screening visit. Individuals living in a nursing home, having a diagnosis of dementia (based on medical record review), or being treated with medications primarily used for dementia therapy were excluded. The study excluded persons with treated diabetes and prevalent stroke due to other trials addressing this hypothesis in these populations
The cognitive portion of the SPRINT study, referred to as MIND, examined outcomes in 4,683 participants randomized to receive blood-pressure treatment with a goal of less than 140 mmHg, compared with 4,678 randomized to intensive treatment with a goal of less than 120 mmHg.
The trial was originally designed to last for five years, but was stopped early, after a median intervention period of 3.34 years, when it became clear that there was a significant benefit for the intensive treatment group on cardiovascular events and all-cause mortality.
After the trial ended, however (on August 20, 2015), follow-up of cognitive outcomes continued for nearly another three years (until July 22, 2018).
In an interview with Neurology Today, the first author of the SPRINT-MIND paper, Jeff D. Williamson, MD, said he believes that the only reason the findings on dementia failed to reach significance was because the study had been curtailed early, and so had too few cases to achieve significance.
“The accrued cases of dementia were only about half of the accrued cases of MCI, even though the magnitude of the benefit was almost the same,” said Dr. Williamson, professor of medicine and chief of the section on gerontology and geriatric medicine at Wake Forest University. With the additional funding from the Alzheimer's Association for initiating one more follow-up assessment, he said, “I hope that this last remaining question about dementia can be answered in the affirmative.”
In the meanwhile, he said, physicians should consider aiming for an SBP of 130 mmHg in their patients.
“If the patient has a BP over 130, their physician should talk to them about getting it into the 120s,” Dr. Williamson said. “In my own practice as a primary-care geriatrician, I'm doing that. I have some patients who go from 140 to the low 120s. I think neurologists should do the same.”
But the author of an editorial accompanying the paper in JAMA said she did not agree with Dr. Williamson's view that physicians should now be setting an SBP target of 120 mmHg.
“There are some people who you might target for 120, depending on what else is going on, how old they are, how they do in terms of side effects. But I don't think we know yet who this really works for,” said Kristine Yaffe, MD, professor of psychiatry, neurology and epidemiology, and the Roy and Marie Scola Endowed Chair of Psychiatry, at the University of California, San Francisco.
“We don't know enough about the side effects, which blood pressure medications work best, which ages it works best for.”
Even so, Dr. Yaffe emphasized that she found the results of the SPRINT-MIND trial exciting and promising.
“They had to end the trial early, but they still found a significant reduction in MCI and MCI-dementia combined, and they just barely missed a significant reduction in dementia cases,” she said. “That is remarkable to me. That's why I think it's a big, important study. It's the first time anyone has been able to show that anything reduces the risk of MCI.”
Three neurologists familiar with the paper were generally more cautious in interpreting the results.
“I think we need to be conservative,” said Zoe Arvanitakis, MD, FAAN, a professor of neurology at the Rush Alzheimer's Disease Center. “These are the first results showing that there might be a benefit on a secondary endpoint. We need to keep in mind that the primary outcome was negative. At the end of the day, the study did not show a significant reduction in clinical dementia. So a recommendation that patients lower their blood pressure below 120 in hopes of lowering their risk of dementia cannot be made at this time.”
In August of 2018, Dr. Arvanitakis was the first author of a paper published in Neurology showing that a faster decline in late-life SBP is associated with increased neuropathology, specifically the neuropathology commonly associated with dementia, such as brain infarcts, among 1,300 older persons who came to autopsy.
Similar findings were reported in another observational study published in Neurology in December of 2017. The first author of that paper, Emer R. McGrath, MD, PhD, attending neurologist at Brigham and Women's Hospital and an instructor in neurology at Harvard Medical School, said in an email to Neurology Today that the findings from the SPRINT-MIND paper, while promising, are not definitive.
“The reduction in risk of MCI with intensive blood pressure lowering is certainly a promising exploratory finding,” Dr. McGrath said.
But, she added, “individuals in nursing homes, those with ongoing symptomatic heart failure, concern for orthostatic hypotension, and those with prior stroke were excluded, limiting applicability of findings to patients who are sicker and frailer.”
Furthermore, Dr. McGrath said the method used to obtain blood pressure readings—taking an average of three automated readings after the patient is sitting quietly for five minutes in the absence of staff in the room—is itself associated with lower blood pressure readings compared with those obtained in typical clinical practice, she said, adding: “Applying a target of less than 120 mmHg SBP in routine practice could result in over-treatment and a higher risk of adverse events if the same blood pressure measurement procedures are not followed.”
David S. Knopman, MD, FAAN, a clinical neurologist and professor of neurology at Mayo Clinic in Rochester, MN, said he is “overall quite enthusiastic” about the study's findings, even while noting that there are “some problems from a statistical design perspective.”
Because dementia was the pre-specified primary outcome, he said, “confidence in the findings on the secondary outcomes is weakened. If this were a drug, it wouldn't pass FDA muster.”
Another aspect of the study design that troubled him, Dr. Knopman said, was that it did not screen for MCI at the outset. “I wonder how many of the cases of MCI that appeared to develop over the course of the study were actually already prevalent,” he said.
He also expressed concern about the risk of orthostatic hypotension in older patients treated intensively to a target of 120 mmHg. “As neurologists, we often see people in their 80s who come in with syncope,” Dr. Knopman said. “We look at their medication list and they're on three hypertensives. Their sitting blood pressure is 100, but when they stand up, it's 60. That's a problem.”
As the immediate past chair of the Medical-Scientific Advisory Council of the Alzheimer's Association, Dr. Knopman was involved in making the decision to fund an additional two-year follow-up of the SPRINT-MIND study.
And for all his concerns, he said that previously published findings showing that intensive BP control reduces the risk of cardiovascular events, kidney disease and all-cause mortality already provide sufficient evidence to convince physicians to seek a target of 120 mmHg in otherwise healthy middle-aged adults.
“From a purely conceptual point of view,” Dr. Knopman said, “this clinical trial supported the general belief that cerebrovascular pathobiology as operationalized by manipulating systolic blood pressure has a causal relationship to later life cognitive impairment. Patients already had a reason to lower their blood pressure, because of the reduction in cardiovascular and kidney disease. Based on the totality of the evidence, even apart from the dementia and MCI findings, why wouldn't you do it?”
Drs. Williamson, McGrath, Knopman, and Arvanitakis had no disclosures. Dr. Yaffe has received honoraria for serving on data safety monitoring board for trials from Eli Lily and Takeda and has been reimbursed for travel-related expenses from the National Institutes of Health, American Federation of Aging, German government, and Alzheimer's Association.