Is 120 the new 140…for systolic blood pressure, that is? The penultimate day of the Alzheimer's Association International Conference 2018, which ran July 20–26 in Chicago, brought some good news on prevention. Researchers reported data from the SPRINT MIND trial, which tested if reducing systolic blood pressure in older adults to below 120 mmHg staved off cognitive decline. It seems the strategy paid off. Over about three years, on average, 19 percent fewer cases of mild cognitive impairment emerged in the treatment group than in people on standard hypertension therapy, which typically aims for 140 mmHg or less. "This is the first time that a randomized-controlled trial has shown that we can reduce the occurrence of MCI with blood pressure lowering," said Jeff Williamson, Wake Forest School of Medicine, Winston-Salem, North Carolina, a leader of the study.
“This is important work, especially considering the lifestyle- or health-promoting aspects,” said Lon Schneider, University of Southern California, Los Angeles. “It could have profound effects on population incidence and prevention.” Charles DeCarli, University of California, Davis, also praised the trial. “This was a well-designed study with a relatively young age group, ethnic and racial heterogeneity, evidence that blood pressure could be lowered, and which found a moderately large effect, better than with any symptomatic treatment, that’s for certain,” he told Alzforum. “Given that 30–50 percent of the population has hypertension at age 65, this is a big deal.”
The treatment regimen did not reduce dementia incidence, which was the primary outcome measure for SPRINT MIND. Still, clinicians at AAIC did not quibble with that. Schneider, DeCarli, and many others agreed that the trial was probably too short to see an effect on dementia. That stems in part from it being a victim of its own success. The NIH ended the parent Systolic Blood Pressure Intervention Trial (SPRINT) early because reductions in cardiovascular events, including heart attacks, stroke, and all-cause mortality, were so profound. Like SPRINT, the Memory and Cognition in Decreased Hypertension (MIND) sub-study should have run for five years.
As Williamson explained at AAIC, the early termination complicated SPRINT MIND. The trial began recruiting in November 2010, with the last volunteer selected in March 2013. In August 2015 the NIH stopped the trial, unblinding and releasing the data. Concomitantly, investigators stopped dispensing blood pressure medicine to the participants but did continue to offer health advice. This closeout period lasted about a year. About a year after that, investigators restarted follow-up visits to assess longer-term outcomes. Much of the data has yet to be analyzed. The data Williamson presented reflected a mean of 3.26 years of intervention.
SPRINT recruited 9,361 adults at 102 centers throughout the mainland U.S. and Puerto Rico. The average age was 67.9. About 35 percent were women, 30 percent African-American, and 10 percent Hispanic. They had to be older than 50, have a systolic blood pressure (SBP) of 130–180 mmHg, plus one other risk factor for cardiovascular disease. People were excluded if they had prior stroke, diabetes, kidney disease, or dementia.
Investigators randomized 4,683 people to standard care, while 4,678 received intensive management to bring their SBP down to the 120 mmHg goal. At the beginning of the trial, both groups had an average SBP of 140 mmHg. Blood pressure measurements were taken monthly for the first three months, and every three months thereafter. The trial dispensed generic blood pressure medicines that were adjusted at each visit, if necessary, to keep SBP as low as 130 mmHg for the standard care arm, and to 120 mmHg for the intensive treatment.
The pressure lowering worked. Over the first three months, those in the intensive treatment arm saw their SBP fall to almost 120 mmHg. It held fairly steady during the intervention period at about 122 mmHg on average, while those on standard treatment had an average SBP of 135 mmHg. As Williamson and colleagues previously reported, the intervention reduced risk of cardiovascular events, including heart attack, other acute coronary syndromes, stroke, heart failure, and death from cardiovascular disease, by a whopping 27 percent compared to standard care (SPRINT Research Group et al., 2015).
What about cognition? Over the 3.26 years, 175 people in the standard care group and 147 in the intensive treatment group were diagnosed with dementia. That difference was not significant, said Williamson. The difference in MCI incidence was. In standard and intensive arms, respectively, 348 and 285 people were diagnosed with MCI, a 19 percent difference. Incidence of combined probable dementia or MCI was 15 percent lower in the intensive treatment group as well, and that was also significant. These are people who were deemed to have MCI first, and then on a subsequent visit diagnosed with dementia. In SPRINT, MCI was determined by a panel of adjudicators who reviewed data from a SPRINT MIND screening battery, a SPRINT MIND extended cognitive battery, a proxy report to assesses functional decline (a dementia questionnaire), and history of depression and related medications. Adjudicators were trained at the beginning of the trial and recertified yearly. All assessments were recorded and some were sampled later for quality control.
David Knopman, Mayo Clinic, Rochester, Minnesota, chaired a press briefing on the trial but was not involved in the study. He told Alzforum that he considers the methodology for cognitive diagnosis state-of-the-art. “This is the standard way to assign cognitive diagnoses in studies of the scale of SPRINT, where it is simply impossible to have a clinician sit down with each participant and their informant face-to-face,” he told Alzforum.
Rebecca Gottesman from Johns Hopkins University, Baltimore, said the findings were incredibly exciting. “We’ve been looking at this question in various ways, mostly finding that high blood pressure is a risk factor for cognitive decline and dementia, but we have not been able to make the leap that more aggressive lowering of blood pressure would reduce MCI and dementia,” she told Alzforum. “Showing reduced MCI, and MCI/dementia, especially after such a short follow-up, is tremendously important.”
Will this trial prompt a change in clinical practice? Clinicians were not sure. Since the SPRINT trial data came out, a combined American College of Cardiology and American Heart Association panel issued new clinical practice guidelines for managing high blood pressure in adults. The new normal is now 120/80 mmHg or less. Readings between 120/80 mmHg and 129/80 mmHg are deemed elevated, and anything higher than 130/80 mmHg is hypertension (Whelton et al., 2018). In effect, the threshold for hypertension was lowered by 10 mmHg (for a synopsis and a viewpoint see Cifu et al., 2017, and Whelton and Carey, 2017). Because of the new guidelines, the SPRINT MIND findings may not have any radical impact on formal recommendations for treatment, said Knopman. “However, they give primary care physicians more ammunition to recommend aggressive treatment,” he said. Gottesman noted that the cognitive outcomes from SPRINT were not known when the new guidelines were set. “These new [cognition] findings should make an even more compelling case,” she said. “It remains to be seen whether the [cognition data] will motivate people to get their blood pressure under control more than fear of cardiovascular disease would. People are very scared of dementia,” she said.
Despite the enthusiasm, the data may not be generally applicable. Researchers have questioned if people in SPRINT are at higher risk than general population. Julie Schneider, Rush University Medical Center, Chicago, who agreed the findings were good news, added similar words of caution. “We cannot generalize to all persons as these volunteers were selected based on a known history of hypertension treatment, elevated blood pressure, and at least one [cardiovascular] risk factor.” Indeed, researchers led by Paul Munter from the University of Alabama at Birmingham reported that only 16.7 percent of adults in the U.S. who have been treated with hypertension would meet the inclusion criteria. This broke down to 9, 19, and 34 percent of those aged 50–59, 60–74, and 75 or older, respectively (Bress et al., 2016).
Others were concerned about lowering blood pressure in people in their 70s and beyond. Jonathan Schott, University College London, told Alzforum that older adults tend to have stiffer arteries and need a higher blood pressure to maintain perfusion to the brain. Schneider and colleagues recently associated steeper declines in SBP with more brain infarcts in octogenarians (Arvanitakis et al., 2018). “We need more information in these older age groups, especially in those who are accustomed to higher blood pressure and may have pre-existing vessel disease,” first author Zoe Arvanitakis, also from Rush, wrote to Alzforum.
For his part, Schneider advised that any change to blood pressure management be done slowly and cautiously. On a positive note, Williamson and the SPRINT investigators have reported a sub-study of noncognitive outcomes in those aged 75 and older. In short, they seem to tolerate the lower blood pressure, with few reports of falls, hypotension, fainting, or other serious adverse events, while enjoying the same cardiovascular benefits as the younger volunteers (Williamson et al., 2016).
What about Alzheimer’s disease? There’s no evidence from SPRINT that lowering blood pressure has any effect on the main AD pathologies—plaques and tangles. That fits with the current literature. “While there is some limited evidence that hypertension might have an association with tauopathy, the overwhelming evidence to me is that hypertension is a disease/process that impacts later-life cognitive impairment through a cerebrovascular mechanism,” noted Knopman.
Evidence for this emerged in a subgroup of SPRINT patients. Ilya Nasrallah and colleagues at the University of Pennsylvania, Philadelphia, measured changes in brain volume and white-matter lesions using sequential MRI scans. At AAIC, Nasrallah reported no difference in whole-brain volumes between 203 people on standard care and 251 who received the intensive SBP lowering regimen. The latter did have fewer white-matter lesions, however. While the average number of lesions per person grew as the trial progressed, those in the intensive-treatment arm had 18 percent fewer over an average of 47 months follow-up.
Schneider thought the speed of the cognitive and structural brain changes indicate the two may be linked. “The quickness suggests that the hypertension itself contributed to the dementia. Putting that together with the MRI study, then maintaining lower blood pressure reduces white-matter lesions substantially, and flipping that around, those lesions contribute to the expression of cognitive impairment,” he suggested. DeCarli ties this in with AD. “I argue that [controlling hypertension] does not protect from AD, but if you get AD and have brain injury from cardiovascular disease, then you will do more poorly,” he said. “You could hypothesize that if you have AD pathology you would not suffer so drastically if the rest of your body is doing well.”
Where does this go from here? Since mid-life hypertension consistently emerges as a risk factor for late-life dementia, some have suggested a new trial in younger patients. To DeCarli’s mind, that should be the next step. Mortality, cardiovascular disease, dementia—all could benefit from low blood pressure in 50-year-olds, and they can tolerate 120/70 better than 60-year-olds.—Tom Fagan
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