Keeping Intensive Blood Pressure Goals in MIND: Does it Impact Cognitive Decline?

Author(s)
Michelle Balli, PharmD, BCACP
Amy Robertson, PharmD, BCACP

Reviewed By
Sally Earl, PharmD, BCPS
Daniel Longyhore, PharmD, BCACP

Citation
Williamson JD, Pajewski NM, Auchus AP, et al. Effect of Intensive vs Standard Blood Pressure Control on Probable Dementia: A Randomized Clinical Trial. JAMA. 2019;321(6):553-561.

The Problem

 

Intensive blood pressure (BP) control reduces the risk of cardiovascular events and mortality, but the verdict isn’t in yet on the benefits of intensive control to prevent the development of dementia. Previous studies demonstrate an inconsistent relationship between blood pressure control and cognitive decline.¹ SPRINT-MIND, using data from SPRINT, was designed to evaluate the effects of intensive BP control on cognitive outcomes including probable dementia and mild cognitive impairment (MCI).² What should we keep in MIND when treating patients to a lower systolic blood pressure goal?

 

What’s Known

 

The Alzheimer’s Association estimates that 5.8 million Americans have Alzheimer’s dementia with that number expected to increase as the baby boomers age.³ High blood pressure has been identified as a risk factor for Alzheimer’s disease.⁴ Current guidelines advocate for a more aggressive BP goal of less than 130/80 mmHg for most patients to reduce cardiovascular morbidity and mortality.⁵ But some worry that intensive blood pressure control will lead to more adverse effects and polypharmacy, particularly in older adults. The SPRINT trial is often used to support the argument in favor of more aggressive treatment targets. In SPRINT, adult patients at increased cardiovascular risk, without diabetes or history of a stroke, were randomized to intensive (systolic BP goal < 120 mmHg) versus standard (goal < 140 mmHg) control. Intensive control demonstrated significant reductions in cardiovascular event rates and mortality.²

 

Currently, there are no known strategies that clearly prevent the development of dementia or MCI.⁶ The data regarding the association between blood pressure lowering and cognitive decline are conflicting.^7-9 One trial found that lower SBP increased the progression of cognitive decline in patients with dementia and MCI.⁷  This cohort study raised concerns about the risk of hypotension and cerebral hypoperfusion.

 

Conversely, the Vascular Dementia Project, an arm of the Systolic Hypertension in Europe (Syst-Eur) trial, found a 50% risk reduction in the development of dementia with blood pressure lowering with a calcium channel blocker over a 2-year period.  However, the study represented a small subset of patients over the age of 60 enrolled in Syst-Eur. The trial was initially designed to evaluate the effects of blood pressure lowering with a calcium channel blocker, ACE inhibitor, or thiazide diuretic on cardiovascular outcomes. Antihypertensives were titrated to reduce SBP to less than 150 mmHg – a goal far higher than what is currently recommended.⁸

 

The Hypertension in the Very Elderly Trial (HYVET) evaluated the effects of blood pressure lowering in adults over the age of 80. Similar to Syst-Eur, antihypertensive medications were titrated to achieve a SBP less than 150 mmHg and included an arm that evaluated cognitive function and decline. But unlike Syst-Eur, investigators did not find a difference in the incidence of new onset dementia.⁹ Thus, more data are needed to sort out whether intensive blood control is helpful … or harmful … in older adults who are at high risk of dementia.

 

What’s New?

 

The SPRINT-MIND Investigators, part of the SPRINT Research Group, analyzed data from patients enrolled in the original multicenter randomized controlled SPRINT trial to determine the impact of intensive blood pressure control on cognitive outcomes. Patients ≥ 50 years of age with a SBP between 130-180 mmHg were included. Nursing home residents, those with dementia, persons treated with dementia medications, and those with diabetes mellitus or history of stroke were excluded. Participants were randomized in a 1:1 ratio to intensive treatment with a SBP goal < 120 mmHg or standard treatment with a SBP goal < 140 mmHg.

 

The primary outcome was occurrence of probable dementia. Secondary outcomes included occurrence of MCI, composite occurrence of MCI or probable dementia, and a post-hoc outcome of time to first occurrence of MCI. Cognitive assessments were planned at baseline, at 2 and 4 years, and at study closeout. In-person cognitive screening tests included the Montreal Cognitive Assessment (MoCA) and other tests to measure global cognitive function, learning, memory, and processing speed. An extended cognitive battery was administered to participants scoring below a pre-specified cut-point on the MoCA. An expert panel adjudicated the cognitive assessments and classified participants as no cognitive impairment, MCI, or probable dementia.

 

The final analysis included 4,278 participants in the intensive and 4,285 in the standard treatment groups. Baseline characteristics, including cognitive assessment scores, were similar. The majority of participants were male and the mean age was nearly 68 years.  More than a quarter of the participants were aged 75 years or older. The mean baseline SBP was 139.7 mmHg in both groups. The median follow-up was 5.11 years. At the conclusion of SPRINT, the mean SBP achieved was 121.5 mmHg in the intensive and 134.6 mmHg in the standard group. The mean number of blood pressure medications required in the intensive control group was 2.8 and 1.8 in the standard control group.

 

The primary outcome revealed a non-significant difference in the occurrence of probable dementia between the two treatment groups: 7.2 per 1000 person-years in the intensive versus 8.6 per 1000 person-years in the standard treatment groups (HR 0.83, 95% CI 0.67-1.04, p=0.10). However, intensive treatment led to a significantly lower incidence of MCI (14.6 versus 18.3 per 1000 person-years, HR 0.81, 95% CI 0.69-0.95, p=0.007, NNT=275). Moreover, there was a significant difference in the composite of MCI or probable dementia with intensive control (20.2 versus 24.1 per 1000 person-years [HR 0.85, CI 0.74-0.97, p=0.01, NNT=263]). There was a significant reduction in time to onset of MCI in the intensive group (p=0.02) but this difference did not remain significant in the multiple imputation analyses. Safety data revealed a higher incidence of hypotension and syncope resulting in more frequent serious adverse effects and emergency visits in the intensive group (158 versus 93 patients, HR 1.70, p < 0.001 and 163 versus 113 patients, HR 1.44, p=0.003 respectively).³

 

My (Our) Critical Appraisal

 

This trial has a strong study design including large sample size, multiple sites, randomization, blinding of adjudicators, and enrollment of patients with dementia risk factors. In addition, tests assessing multiple cognitive domains were used to obtain a thorough assessment of cognitive function. Moreover, an expert adjudication panel used a consistent method for classifying participants with MCI or probable dementia.

 

Unfortunately, the parent trial was stopped early due to the significant benefits of intensive control on cardiovascular outcomes which may have muted the other benefits between treatment groups which might have emerged over time. This likely affected the power to detect a difference in the incidence of probable dementia. Patients with a history of diabetes, stroke, chronic kidney disease, and symptomatic heart failure were excluded, limiting applicability of the SPRINT and SPRINT-MIND study to these patient populations. In addition, the adjudication panel did not assess for MCI at baseline, so no conclusions can be made on the effect of baseline MCI on trial outcomes. Lastly, this study was not designed to test the benefits (or risks) of specific antihypertensive medications, limiting the ability to discern which medication might have the greatest impact on occurrence of MCI or dementia.

 

SPRINT, HYVET, and Syst-Eur were designed to assess the effects of blood pressure lowering on cardiovascular outcomes, but each performed additional analyses that assessed effects on cognitive decline. All three trials excluded patients with a diagnosis of dementia. However, in the SPRINT-MIND trial, the mean MoCA score at baseline was 23, indicating cognitive impairment in some participants. Similar to the results of SPRINT-MIND, HYVET-COG revealed a similar but non-significant difference in the incidence of dementia between treatment groups (38 versus 33 per 1000 person-years, HR 0.86, 95% CI 0.67-1.09). Unlike SPRINT, HYVET and Syst-Eur did not assess the incidence of MCI. All three trials were stopped early due to the cardiovascular benefits noted in the treatment group.

 

When comparing the results of these studies, it is important to note a few key differences. First, SPRINT established a target SBP of 120 mmHg, well below the target SBP of 150 mmHg in Syst-Eur and HYVET. The mean age was similar in SPRINT and Syst-Eur (around 68-70 years old) while the mean age in HYVET was nearly 84 years. In addition, cognitive function was assessed using different methods. HYVET and Syst-Eur utilized MMSE while SPRINT used MoCA. There are several validated cognitive assessment tools available, but MMSE is used most often in practice.¹⁰ Many of these assessment tools lack well-defined cut points for normal cognition versus MCI or dementia including the MoCA.^11-12

 

The Bottom Line

 

SPRINT-MIND did not find a statistically significant association between intensive blood pressure control and the development of dementia. However, intensive control was associated with a reduction in the incidence of MCI. It is important to note that intensive control did not have a negative impact on cognition.  Thus, intensive BP control has a clear and positive impact on cardiovascular outcomes and might be beneficial in terms of cognitive decline.  While the results of SPRINT-MIND are not conclusive, we believe this study strengthens the case for aggressive blood pressure lowering in community-dwelling older adults. None-the-less, management of hypertension must be patient-specific, taking into account comorbidities, pharmacologic principles, and functional status. What do you think?  Do the results of this trial provide additional justification for treating to the guideline-recommended blood pressure goal in your patients?

 

The Key Points

 

• The 2017 ACC/AHA hypertension guidelines recommend a lower blood pressure goal of 130/80 mmHg for most patients. The benefits of intensive blood pressure lowering on cardiovascular morbidity and mortality were demonstrated in SPRINT.
• Intensive blood pressure control did not conclusively reduce the risk of probable dementia, but did reduced the risk of mild cognitive impairment in SPRINT-MIND. 
• Intensive blood pressure control did not contribute to negative cognitive outcomes.

 

NOTE:  This program will be available for recertification credit through the American Pharmacists Association (APhA) Ambulatory Care Review and Recertification Program.  To learn more, visit https://www.pharmacist.com/ambulatory-care-review-and-recertification-activities.