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The theory that certain antihypertensives can be tied to less dementia was supported by a secondary analysis of the hypertension trial SPRINT.

Between study participants with high blood pressure (BP) who only used medications that stimulate type 2 and 4 angiotensin II receptors and those who only used receptor-inhibiting drugs, the former tended to have a lower risk of cognitive impairment nearly 5 years later:

• Amnestic mild cognitive impairment or probable dementia: 45 vs 59 cases per 1,000 person-years (HR 0.76, 95% CI 0.66-0.87)

• Amnestic MCI alone: 40 vs 54 cases per 1,000 person-years (HR 0.74, 95% CI 0.64-0.87)

• Probable dementia alone: 8 vs 10 cases per 1,000 person-years (HR 0.80, 95% CI 0.57-1.14)

"On a population level, shifting antihypertensive prescribing from inhibiting to stimulating regimens, while adhering to current hypertension guideline recommendations, could be a promising strategy to reduce the burden of dementia," according to study authors led by Zachary Marcum, PharmD, PhD, of the University of Washington in Seattle, writing in .

"This strategy would mean shifting the treatment paradigm from ACE [angiotensin-converting enzyme] inhibitors to angiotensin II receptor type 1 blockers and reducing the amount of inappropriate β-blocker use in the absence of coronary heart disease or heart failure with reduced ejection fraction," the researchers continued.

Dementia is a growing public health problem with no good preventive measures to date.

"For now, we cannot recommend in the clinical setting that antihypertensives be prescribed for mild cognitive impairment or dementia. Yet, this study lays a solid foundation for future research on specific types of antihypertensives for the prevention of cognitive decline in aging," according to memory specialist Zoe Arvanitakis, MD, MS, of Rush University Medical Center in Chicago.

"While the results are based on secondary analyses from data collected for another research question, the findings that a certain group of BP medications are associated with a lower risk of developing cognitive impairment are very exciting," she commented.

SPRINT included over 9,000 people ages 50 and older at higher risk of cardiovascular disease. Participants were randomized to an intensive treatment strategy (targeting systolic BP <120 mm Hg) or a standard treatment strategy (targeting systolic BP <140 mm Hg).

It was on the basis of this trial that American guidelines started recommending 130/80 mm Hg as the new BP target for most people in 2017.

For the present analysis, Marcum's group analyzed the 8,685 people on BP-lowering medications at 6 months (mean age 67.7 years, 64.3% men). This cohort was split into three:

• 30.4% were users of only antihypertensives that stimulate type 2 and 4 angiotensin II receptors (e.g., angiotensin II receptor type 1 blockers, dihydropyridine calcium channel blockers, and thiazide diuretics)

• 17.7% were users of only inhibitors of type 2 and 4 angiotensin II receptors (e.g., ACE inhibitors, β-blockers, and nondihydropyridine calcium channel blockers)

• 51.9% were users of both types of BP-lowering medication

Dementia screening was conducted at 24 and 48 months after randomization, as well as at the closeout visit and an extended follow-up visit.

The investigators said the cognitive findings were consistent when incorporating the competing risk of death and were independent of systolic BP, cardiovascular risk factors, sociodemographic characteristics, and baseline cognitive function.

Yet negative control analyses suggested the presence of unmeasured confounding.

It was already known that before weighted propensity score matching, people only on stimulating antihypertensives were more likely to be women, Black participants, and randomized to intensive treatment; and less likely to have a history of cardiovascular disease, coronary revascularization, atrial fibrillation, and statin use, compared with users of inhibiting regimens.

"Both underadjustment caused by unmeasured confounding and overadjustment caused by inclusion of covariates measured after treatment initiation, which may be intermediate on the causal pathway between treatment and outcome, are possible," Marcum's group acknowledged.

For now, more research is merited, even in persons with no high BP. The next step may include randomized trials specifically testing whether antihypertensives prevent mild cognitive impairment or dementia, according to Arvanitakis.

"A clinical trial to test the hypothesis assessed in our study for primary prevention would take years to complete. Alternatively, observational studies in larger samples, using a new-user design, with validated cognitive outcomes could provide a useful replication," the researchers suggested.

They also cautioned that SPRINT had excluded people with diabetes, advanced kidney disease, symptomatic heart failure, or a history of stroke -- limiting the study's generalizability.

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