Conference Coverage

Mild cognitive impairment risk slashed by 19% in SPRINT MIND


AT AAIC 2018

– Lowering systolic blood pressure to a target of 120 mm Hg or lower in people with cardiovascular risk factors reduced the risk of mild cognitive impairment by 19% and probable all-cause dementia by 17% relative to those who achieved a less intensive target of less than 140 mm Hg

Dr. Jeff D. Williamson

Drug class didn’t matter. Cheap generics were just as effective as expensive name brands. It equally benefited men and women, whites, blacks, and Hispanics. And keeping systolic blood pressure at 120 mm Hg or lower prevented MCI just as well in those older than 75 as it did for younger subjects.

The stunning announcement came during a press briefing at the Alzheimer’s Association International Conference, as Jeff D. Williamson, MD, unveiled the results of the 4-year SPRINT MIND study. Strict blood pressure control for 3.2 years, with a systolic target of 120 mm Hg or lower, reduced the incidence of mild cognitive impairment by a magnitude of benefit that no amyloid-targeting investigational drug has ever approached.

“I think we can say this is the first disease-modifying strategy to reduce the risk of MCI,” Dr. Williamson said during at the briefing. And although the primary endpoint – the 17% relative risk reduction for probable all-cause dementia – didn’t meet statistical significance, “It’s comforting to see that the benefit went in the same direction and was of the same magnitude. Three years of treatment and 3.2 years of follow-up absolutely reduced the risk.”

Brain imaging underscored the clinical importance of this finding and showed its physiologic pathway. People in the strict BP arm had 18% fewer white matter hyperintensities after 4 years of follow-up.

The news is an incredible step forward for the field that has stumbled repeatedly, clinicians agreed. Generic antihypertensives can be very inexpensive. They are almost globally available, and confer a host of other benefits, not only on cardiovascular health but on kidney health as well, said Dr. Williamson, chief of geriatric medicine at Wake Forest University, Winston-Salem, N.C.

“Hypertension is a highly prevalent condition, with 60%-70% having it. The 19% overall risk reduction for MCI will have a huge impact,” he said.

Maria Carrillo, PhD, chief scientific officer of the Alzheimer’s Association, was somewhat more guarded, but still very enthusiastic.

“I think the most we can say right now is we are able to reduce risk,” she said in an interview. “But the reality is that reducing the risk of MCI by 19% will have a huge impact on dementia overall. And slowing down the disease progress is a disease modification, versus developing symptoms. So, if that is the definition we are using, the I would say yes, it is disease modifying,” for dementias arising from cerebrovascular pathology.

SPRINT MIND was a substudy of the Hypertension Systolic Blood Pressure Intervention Trial (SPRINT). It compared two strategies for managing hypertension in older adults. The intensive strategy had a target of less than 120 mm Hg, and standard care, a target of less than 140 mm Hg. SPRINT showed that more intensive blood pressure control produced a 30% reduction in the composite primary composite endpoint of cardiovascular events, stroke, and cardiovascular death. The intensive arm was so successful that SPRINT helped inform the 2017 American Heart Association and American College of Cardiology high blood pressure clinical guidelines.

The SPRINT MIND substudy looked at whether intensive management had any effect on probable all-cause dementia or MCI, as well as imaging evidence of changes in white matter lesions and brain volume.

It comprised 9,361 SPRINT subjects who were 50 years or older (mean 68; 28% at least 75) and had at least one cardiovascular risk factor. Nearly a third (30%) were black, and 10% Hispanic. The primary outcome was incident probable dementia. Secondary outcomes were MCI and a composite of MCI and/or probable dementia.

In SPRINT, physicians could choose any appropriate antihypertensive regimen, but they were encouraged to use drugs with the strongest evidence of cardiovascular benefit: thiazide-type diuretics encouraged as first-line, and then loop diuretics and beta-adrenergic blockers. About 90% of the drugs used during the study were generics.

Subjects were seen monthly for the first 3 months, during which medications were adjusted to achieve the target, and then every 3 months after that. Medications could be adjusted monthly to keep on target.

At 1 year, the mean systolic blood pressure was 121.4 mm Hg in the intensive-treatment group and 136.2 mm Hg in the standard treatment group. Treatment was stopped in August 2015 due to the observed cardiovascular disease benefit, after a median follow up of 3.26 years, but cognitive assessment continued until the end of June (N Engl J Med. 2015 Nov 26; 373:2103-16).

The SPRINT MIND study did not meet its primary endpoint. Adjudicated cases of probable all-cause dementia developed in 175 of the standard care group and 147 of the intensive treatment group; the 17% risk reduction was not statistically significant (P = .10).

However, it did hit both secondary endpoints. Adjudicated cases of MCI developed in 348 of the standard treatment groups and 285 of the intensive treatment group: a statistically significant 19% risk reduction (P = .01). The combined secondary endpoint of MCI and probable dementia was a significant 15% risk reduction (P = .02), with 463 cases in the standard care group and 398 in the intensive care group.

The imaging study comprised 454 subjects who had brain MRI at baseline and 4 years after randomization. There was no change in total brain volume, said Ilya Nasrallah, MD, of the University of Pennsylvania. But those in the intensively managed group had 18% lower white matter lesion load than those in the standard care group (P = .004).

White matter lesions often point to small vessel disease, which is conclusively linked to vascular dementia, and may also linked to Alzheimer’s disease. Most AD patients, in fact, have a mixed dementia that often includes a vascular component, Dr. Carillo said.

SPRINT MIND didn’t follow subjects past 4 years, and didn’t include any follow-up for amyloid or Alzheimer’s diagnosis. But preventing MCI is no trivial thing, according to David Knopman, MD, who moderated the session.

“There’s nothing that is benign about MCI,” said Dr. Knopman of the Mayo Clinic, Rochester, Minn. “it’s the first sign of overt cognitive dysfunction, and although the rate at which MCI progress to dementia is slow, the appearance of it is just as important as the appearance of more severe dementia. To be able to see an effect in 3.2 years is quite remarkable. I think is going to change clinical practice for people in primary care and the benefits at the population level are going to be substantial.”

Dr. Williamson drove this point home in a later interview, suggesting that physicians may want to think about how the SPRINT MIND results might apply to even younger patients with hypertension, and even if they don’t have other cardiovascular risk factors.

“I can’t say as a scientist that we have evidence to do that, yet. But as a physician, and for my own self and my own patients, I will adhere to the guidelines we have and keep blood pressure at less than 130 mm Hg, and certainly start treating people in their 50s, and probably in their 40s.”

***This article was updated 7/31/18.

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SOURCE: Williamson et al. AAIC 2018 DT-0202 Nasrallah et al. AAIC 2018 DT-03-03

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