In the JournalsPerspective

Intensive BP control reduces risk for mild cognitive impairment

Jeff D. Williamson
Jeff D. Williamson

In the SPRINT MIND trial, intensive BP control did not significantly reduce the risk for the primary outcome of probable dementia in patients with hypertension, but was associated with a significant reduction in the risks for secondary outcomes of mild cognitive impairment and a composite of mild cognitive impairment or probable dementia.

Jeff D. Williamson, MD, MHS, chief of the section of geriatric medicine and gerontology in the department of internal medicine at Wake Forest School of Medicine in Winston-Salem, North Carolina, and colleagues noted that “there has been controversy about the benefits and risks associated with lowering systolic BP levels to below 150 mm Hg,” including potential risk for hypotension and cerebral hypoperfusion.

“This trial demonstrates no such negative effect; specifically, these results importantly show that intensive BP control did not result in harm to cognition after a median intervention period of 3.34 years and an overall median follow-up of 5.11 years. Moreover, there is some indication that intensive BP control may be beneficial,” Williamson and colleagues wrote in JAMA.

Older patients with hypertension

The researchers analyzed data from 9,361 patients (mean age, 68 years; 35.6% women; mean systolic BP at baseline, 139.7 mm Hg) with a systolic BP between 130 mm Hg and 190 mm Hg who did not have diabetes or a history of stroke. Enrollment took place between Nov. 8, 2010, and March 2013.

Patients were assigned a systolic BP goal of less than 120 mm Hg (n = 4,678), considered the intensive treatment group, or less than 140 mm Hg (n = 4,683) for the standard treatment group.

Information on cognitive status was collected through a three-step process involving in-person cognitive screening assessments and several questionnaires and batteries. Other status reports that were generated included those on perceived health status, depressive symptoms, quality of life, medical problems, hospitalizations, reported current medications and current health habits.

Patients were originally supposed to undergo planned cognitive assessments at baseline, 2 years and 4 years. The BP intervention was stopped on Aug. 20, 2015, by the director of the NHLBI because the monitoring boundary for the primary outcome of the composite of CV events was exceeded at two consecutive time points. BP management decisions were then given to the patients’ primary care physicians. A cognitive assessment among other assessments were performed at a final extended follow-up visit between October 2017 and July 2018.

The primary cognitive outcome of interest was the occurrence of adjudicated probable dementia. Secondary cognitive outcomes of interest were adjudicated mild cognitive impairment and a composite of the occurrence of probable mild cognitive impairment or dementia.

At least one cognitive assessment during follow-up was completed by 91.4% of patients in the intensive treatment group vs. 91.5% in the standard treatment group. The median follow-up was 5.11 years, and the median intervention period was 3.34 years.

Risks for dementia, cognitive impairment

During follow-up, adjudicated probable dementia was seen in 7.2 cases per 1,000 person-years in the intensive treatment group compared with 8.6 cases per 1,000 person-years in the standard treatment group (HR = 0.83; 95% CI, 0.67-1.04).

Patients assigned intensive BP control had a significant reduction in the risk for mild cognitive impairment compared with those assigned standard BP control (14.6 cases per 1,000 person-years vs. 18.3 cases per 1,000 person-years; HR = 0.81; 95% CI, 0.69-0.95). This was also seen for the risk of the combined rate of probable dementia or mild cognitive impairment (20.2 cases per 1,000 person-years vs. 24.1 cases per 1,000 person-years; HR = 0.85; 95% CI, 0.74-0.97).

“This is the first trial, to our knowledge, to demonstrate an intervention significantly reduces the occurrence of mild cognitive impairment, a well-established risk factor for dementia, as well as the combined occurrence of mild cognitive impairment or dementia.”

However, caution is warranted when interpreting these findings, according to the researchers. Mild cognitive impairment was a secondary outcome in SPRINT MIND and it is unclear how the change in mild cognitive impairment may impact longer-term incidence of dementia, according to Williamson and colleagues.

‘A major leap forward’

In a related editorial, Kristine Yaffe, MD, professor of psychiatry, neurology and epidemiology and the Roy and Marie Scola Endowed Chair and vice chair of research in psychiatry at University of California, San Francisco, discussed the importance of these new data for clinical practice.

“Eventually this modifiable risk factor approach could be combined with disease-modifying drugs so that one day, it will be possible to identify persons at risk of [Alzheimer’s disease] and related dementia (either by biomarkers, genetics or cognitive symptoms) and offer an effective strategy for prevention of cognitive impairment,”Yaffe wrote. “The SPRINT MIND study may not be the final approach for prevention of [Alzheimer’s disease] or other cognitive impairment, but it represents a major leap forward in what has emerged as a marathon journey.” – by Darlene Dobkowski, with additional reporting by Katie Kalvaitis

Disclosures: The SPRINT trial was funded by the NHLBI, the National Institute of Diabetes and Digestive and Kidney Disease, the National Institute on Aging and the National Institute of Neurological Disorders and Stroke, and was supported in part by the U.S. Department of Veterans Affairs and the Intramural Research Program of the National Institute on Aging. Medications used in the study were provided by Takeda Pharmaceuticals with additional support from the Kulynych Family Foundation and the Oristano Family Foundation. Williamson reports he received research support from the NIH and institution funding from Biogen. Yaffe reports she serves on a data safety and monitoring board for Eli Lilly, studies sponsored by the NIH and Takeda and was a member of the Beeson Scholars in Aging scientific advisory board and a senate member of the German Center for Neurodegenerative Disease. Please see the study for all other authors’ relevant financial disclosures.

Jeff D. Williamson
Jeff D. Williamson

In the SPRINT MIND trial, intensive BP control did not significantly reduce the risk for the primary outcome of probable dementia in patients with hypertension, but was associated with a significant reduction in the risks for secondary outcomes of mild cognitive impairment and a composite of mild cognitive impairment or probable dementia.

Jeff D. Williamson, MD, MHS, chief of the section of geriatric medicine and gerontology in the department of internal medicine at Wake Forest School of Medicine in Winston-Salem, North Carolina, and colleagues noted that “there has been controversy about the benefits and risks associated with lowering systolic BP levels to below 150 mm Hg,” including potential risk for hypotension and cerebral hypoperfusion.

“This trial demonstrates no such negative effect; specifically, these results importantly show that intensive BP control did not result in harm to cognition after a median intervention period of 3.34 years and an overall median follow-up of 5.11 years. Moreover, there is some indication that intensive BP control may be beneficial,” Williamson and colleagues wrote in JAMA.

Older patients with hypertension

The researchers analyzed data from 9,361 patients (mean age, 68 years; 35.6% women; mean systolic BP at baseline, 139.7 mm Hg) with a systolic BP between 130 mm Hg and 190 mm Hg who did not have diabetes or a history of stroke. Enrollment took place between Nov. 8, 2010, and March 2013.

Patients were assigned a systolic BP goal of less than 120 mm Hg (n = 4,678), considered the intensive treatment group, or less than 140 mm Hg (n = 4,683) for the standard treatment group.

Information on cognitive status was collected through a three-step process involving in-person cognitive screening assessments and several questionnaires and batteries. Other status reports that were generated included those on perceived health status, depressive symptoms, quality of life, medical problems, hospitalizations, reported current medications and current health habits.

Patients were originally supposed to undergo planned cognitive assessments at baseline, 2 years and 4 years. The BP intervention was stopped on Aug. 20, 2015, by the director of the NHLBI because the monitoring boundary for the primary outcome of the composite of CV events was exceeded at two consecutive time points. BP management decisions were then given to the patients’ primary care physicians. A cognitive assessment among other assessments were performed at a final extended follow-up visit between October 2017 and July 2018.

The primary cognitive outcome of interest was the occurrence of adjudicated probable dementia. Secondary cognitive outcomes of interest were adjudicated mild cognitive impairment and a composite of the occurrence of probable mild cognitive impairment or dementia.

At least one cognitive assessment during follow-up was completed by 91.4% of patients in the intensive treatment group vs. 91.5% in the standard treatment group. The median follow-up was 5.11 years, and the median intervention period was 3.34 years.

Risks for dementia, cognitive impairment

During follow-up, adjudicated probable dementia was seen in 7.2 cases per 1,000 person-years in the intensive treatment group compared with 8.6 cases per 1,000 person-years in the standard treatment group (HR = 0.83; 95% CI, 0.67-1.04).

Patients assigned intensive BP control had a significant reduction in the risk for mild cognitive impairment compared with those assigned standard BP control (14.6 cases per 1,000 person-years vs. 18.3 cases per 1,000 person-years; HR = 0.81; 95% CI, 0.69-0.95). This was also seen for the risk of the combined rate of probable dementia or mild cognitive impairment (20.2 cases per 1,000 person-years vs. 24.1 cases per 1,000 person-years; HR = 0.85; 95% CI, 0.74-0.97).

“This is the first trial, to our knowledge, to demonstrate an intervention significantly reduces the occurrence of mild cognitive impairment, a well-established risk factor for dementia, as well as the combined occurrence of mild cognitive impairment or dementia.”

However, caution is warranted when interpreting these findings, according to the researchers. Mild cognitive impairment was a secondary outcome in SPRINT MIND and it is unclear how the change in mild cognitive impairment may impact longer-term incidence of dementia, according to Williamson and colleagues.

‘A major leap forward’

In a related editorial, Kristine Yaffe, MD, professor of psychiatry, neurology and epidemiology and the Roy and Marie Scola Endowed Chair and vice chair of research in psychiatry at University of California, San Francisco, discussed the importance of these new data for clinical practice.

“Eventually this modifiable risk factor approach could be combined with disease-modifying drugs so that one day, it will be possible to identify persons at risk of [Alzheimer’s disease] and related dementia (either by biomarkers, genetics or cognitive symptoms) and offer an effective strategy for prevention of cognitive impairment,”Yaffe wrote. “The SPRINT MIND study may not be the final approach for prevention of [Alzheimer’s disease] or other cognitive impairment, but it represents a major leap forward in what has emerged as a marathon journey.” – by Darlene Dobkowski, with additional reporting by Katie Kalvaitis

Disclosures: The SPRINT trial was funded by the NHLBI, the National Institute of Diabetes and Digestive and Kidney Disease, the National Institute on Aging and the National Institute of Neurological Disorders and Stroke, and was supported in part by the U.S. Department of Veterans Affairs and the Intramural Research Program of the National Institute on Aging. Medications used in the study were provided by Takeda Pharmaceuticals with additional support from the Kulynych Family Foundation and the Oristano Family Foundation. Williamson reports he received research support from the NIH and institution funding from Biogen. Yaffe reports she serves on a data safety and monitoring board for Eli Lilly, studies sponsored by the NIH and Takeda and was a member of the Beeson Scholars in Aging scientific advisory board and a senate member of the German Center for Neurodegenerative Disease. Please see the study for all other authors’ relevant financial disclosures.

    Perspective
    Carl J. Pepine

    Carl J. Pepine

    The SPRINT MIND investigators evaluated the impact of intensive BP control on risk for dementia. While the overall conclusion of the paper states that intensive BP control “did not result in a significant reduction in the risk of probable dementia,” there are several important points to make.

    The findings show that intensive BP control did not harm cognition. Furthermore, the HR was 0.83 (95% CI, 0.67-1.04) for the primary outcome of adjudicated probable dementia, 0.81 (95% CI, 0.69-0.95) for the secondary outcomes of adjudicated mild cognitive impairment and 0.85 (95% CI, 0.74-0.97) for mild cognitive impairment or probable dementia. The P values for the two secondary outcomes were .007 and .01, respectively and HRs overlap the HR for primary. The point is that these values are all in the same range and, to me, there is clearly an effect on the occurrence of important dementia variables with intensive BP control from a well-conducted trial. 

    Of note, these differences in outcomes between the intensive BP treatment and standard treatment groups did not emerge until about 3 to 4 years, with the differences really widening at longer-term follow-up out to 7 to 8 years. Recall, the overall SPRINT trial was stopped early after a median follow-up of only 3.26 years because of reduction in total mortality. Stopping early most likely dampened these cognitive outcome differences.

    Also notable is that SPRINT MIND included adults aged 50 years and older with hypertension, but no prior stroke or diabetes, which are risk factors for dementia.

    It is also worth mentioning that a substudy of SPRINT MIND looking at the effects of intensive BP lowering on development of white-matter lesions in the brain was recently summarized (Kjeldsen SE, et al. Blood Press. 2018;doi:10.1080/08037051.2018.1507621). The researchers performed MR images in several hundred SPRINT MIND participants and found that brain white-matter lesion volume increases were significantly less in the intensive BP treatment arm (P =  .004). These white-matter lesions are an indicator of impaired microcirculation in the brain and have been shown to clearly predict stroke, dementia and Alzheimer’s disease, as well as mortality. So, this finding that intensive BP lowering also prevents these white-matter lesions is not only consistent with the new findings from SPRINT MIND, but also supports the suggestion that this microvascular finding is at least part of the mechanism contributing to the cognitive benefit. I find it very compelling that intensive BP lowering is, in fact, one of the few things we have to prevent dementia and the lesions that are linked with dementia and other adverse outcomes.

    Although there are hints from other randomized trials, SPRINT MIND is the first trial to clearly show that these dementia outcomes are altered by a period of intensive BP control. These very important contributions fill some important knowledge gaps about cognitive insufficiency that should justify an update to American Heart Association recommendations concluding that there were insufficient data to make evidence-based recommendations (Iadecola C, et al. Hypertension. 2016;doi:10.1161/HYP.0000000000000053).

    • Carl J. Pepine, MD MACC
    • Cardiology Today Chief Medical Editor
      University of Florida, Gainesville

    Disclosures: Pepine reports no relevant financial disclosures.