No, A Big NIH Trial Did Not Show That Lowering Blood Pressure Will Prevent Dementia

It’s “breakthrough” time again. News reports out of the Alzheimer’s Association International Conference (AAIC) this week have been relentlessly upbeat and positive about findings from the NIH’s SPRINT MIND study. The message: aggressive blood pressure control can help protect the brain. But unless you look very carefully at the news reports and “expert” statements you won’t know that SPRINT MIND was a negative trial that missed its primary endpoint or that the results have not yet been peer reviewed.

Preliminary results from the SPRINT MIND trial were presented in Chicago on Wednesday at the AAIC. SPRINT MIND is a substudy of the main SPRINT trial, which found that intensive blood pressure control (systolic BP target of 120 mm Hg or lower) reduced the rate of major cardiovascular events and death compared to less intensive blood pressure control (systolic BP target of 140 mm Hg or lower).

The title of the AAIC press release set the tone for the coverage: “Study Shows Intensive Blood Pressure Control Reduces Risk of Mild Cognitive Impairment (MCI) and the Combined Risk of MCI and Dementia.”

The chief science officer of the AAIC leaves little doubt that the results have important and immediate relevance to clinical practice today: “To reduce new cases of MCI and dementia globally we must do everything we can — as professionals and individuals — to reduce blood pressure to the levels indicated in this study, which we know is beneficial to cardiovascular risk.”

The NIH press release is a bit more careful, noting that the results are “preliminary” and have not yet been peer reviewed (though Francis Collins, the NIH director, tweeted that the trial was “big news”).

News reports have been uniformly upbeat. The headlines tell the story:

•  Time: “There May Finally Be Something You Can Do to Lower Your Risk of Dementia”
• Washington Post: “A healthier heart may mean a healthier mind, new study shows”
• Medscape: “Aggressive Blood Pressure Lowering Cuts MCI Risk”
• Forbes: “Blood Pressure Drugs May Prevent Memory Problems, Study Says”
• NBC News: “Tight blood pressure control reduces Alzheimer’s dementia risk, study finds”
• USA Today: “Aggressively lowering blood pressure could reduce risk of developing dementia, study finds”

A Negative Trial

Buried underneath the avalanche of hype was the single most important fact anyone needs to know about SPRINT MIND: the trial missed its primary endpoint, which was the incidence of all-cause dementia. Even the abstract glosses over the failed primary endpoint, reporting first the secondary (but significant) endpoint of mild cognitive impairment (MCI):

There was a significantly lower rate of adjudicated incident MCI (HR = 0.81, 95% CI: 0.70 to 0.95, p=0.01) and a non-significant reduction in probable dementia (HR = 0.83, 95% CI: 0.67 to 1.04, p=0.10). The combined outcome of MCI plus probable all cause dementia was significantly lower (HR = 0.85, 95% CI: 0.74 to 0.97, p=0.02) in the intensive versus standard treatment group.

MCI, of course, is not something anyone wants to get, but it is not the same as dementia, and it is unclear whether the difference found in the trial, even if true, would have a clinically significant impact on dementia.

Sanjay Kaul (Cedars Sinai) expressed concern about the effort to gloss over the missed primary endpoint. “How does one interpret the results of a trial that fails to win on the primary endpoint (incident probable dementia), but yields a significant treatment effect on a secondary endpoint (mild cognitive impairment)? With great circumspection. Why? Because the possibility that the positive effect on the secondary outcome represents a false-positive (spurious) finding has not been ruled out.”

Kaul pointed out another important missing element in both the abstract and in the press coverage of the trial. The investigators report a 19% reduction in relative risk of the secondary endpoint (MCI). This sounds impressive, but lost in the coverage is the much smaller absolute reduction in risk. Kaul calculates that the absolute risk reduction was only 0.6% for the primary endpoint and only 1.34% for the secondary MCI endpoint. Here are Kaul’s calculations for the primary endpoint (PEP) and the secondary endpoint (SEP):

• PEP (incident probable dementia): 147/4678 (3.14%) vs 175/4683 (3.74%); ARD = 0.6%; RR 0.84, 95% CI 0.68-1.04, p = 0.11
• SEP (MCI): 285/4678 (6.09%) vs 348/4683 (7.43%); ARD = 1.34%; RR 0.82, 95% CI 0.70-0.95, p = 0.009
• Combined MCI or dementia endpoint: 398/4678 (8.51%) vs 463/4683 (9.89%); ARD = 1.38%; RR 0.86, 95% CI 0.76-0.98, p = 0.02

Kaul said that these results do “not represent a robust effect. However, this has to be interpreted in the context of lack of treatment effect on this outcome with currently available interventions and the relatively short duration of treatment exposure. So, promising data, but not the whole enchilada, as spun by trial investigators.”

As Kaul suggests, the results certainly don’t mean that aggressive blood pressure won’t help protect the brain, but that for now the evidence is inconclusive. And almost no one commenting on the study bothered to point out that there are potential harmful effects from over aggressive blood pressure reduction including, most importantly, an increased risk of falling.

Now it is important to remember that dementia is an enormous, and rapidly growing, public health problem. The desperate need for real progress undoubtedly fuels some of the hype we’ve seen. But it is precisely due to its desperate nature that we need to be extra careful that we don’t grasp at the first straw we find.

It is also important to remember that this is not SPRINT’s first rodeo. The results of the main trial were first announced in 2015. As I reported at the time, the SPRINT investigators sought to interpret and spin the meaning of the trial before the actual results and details were publicly available. Since then the trial has sparked an enormous amount of controversy. Although it is widely acknowledged to be an important trial, it is fair to say that it has not achieved the acclaim and acceptance that its investigators first claimed. Perhaps it’s time for the NIH to stop prematurely proclaiming victory. Instead the NIH should present data from its trials and let the scientific and medical community decide for themselves how the data should be interpreted.

Previous SPRINT Coverage:

• Slow Down. Don’t Sprint To More Aggressive BP Treatment
• SPRINT Will Change But Not Revolutionize Blood Pressure Treatment
• Heart Failure Experts SPRINT To An Early Finish
• A Premature SPRINT To The Finish Line
• NIH Trial, Stopped Early, Supports More Intensive Blood Pressure Targets
• Cardiologists: Thumbs Down To SPRINT
• SPRINT: More Controversy And Confusion About ‘Landmark’ Trial
• New Questions Raised About SPRINT
• Can SPRINT Be Used To Inform Hypertension Treatment?
• Principal Investigator Defends SPRINT Against Critics
• The Survey Says: BP Measurement In SPRINT Was All Over The Place