Systolic blood pressure control prevents cognitive decline and slows development of white matter lesions in the brain: the SPRINT MIND study outcomes

The Systolic Blood Pressure Intervention Trial (SPRINT) tested the hypothesis that intensive systolic blood pressure (BP) control would reduce cardiovascular disease outcomes and mortality to a greater extent than treatment to standard systolic BP target in people with hypertension [1]. The active treatment phase of the trial was stopped after a median follow-up of 3.26 years by the sponsor, the National Heart, Blood and Lung Institute of the US, because of benefit in the intensive treatment arm [2]. Intensive lowering of systolic BP reduced rates of the primary outcome, a composite of acute myocardial infarction (MI), acute coronary syndrome not resulting in MI (non-MI ACS), stroke, acute decompensated heart failure and cardiovascular death, by 25% and the risk of all cause death by 27%. We have discussed the SPRINT findings in previous issues of Blood Pressure [3,4].

The SPRINT Memory and Cognition IN Decreased Hypertension (SPRINT MIND) study tested whether aiming at the lower systolic BP target reduced the risk of developing the incidence of probable dementia, mild cognitive impairment (MCI), and a composite outcome of MCI or probable dementia in a subset of SPRINT participants. Preliminary results were presented at the Alzheimer’s Association International Conference (AAIC) in Chicago on July 25, 2018, and commented upon by us shortly after [5]. The full publications of SPRINT MIND and the associated substudy of development of white matter lesions in the brain have now appeared [6,7].

Among 9361 participants in SPRINT (mean age, 67.9 years, 35.6% women) 91.5% completed at least one follow-up cognitive assessment in the SPRINT MIND study. The median intervention period was 3.34 years. During a total median follow-up of 5.11 years, adjudicated probable dementia occurred in 149 participants in the intensive BP treatment group vs. 176 in the standard BP treatment group (7.2 vs. 8.6 cases per 1000 person-years; hazard ratio (HR) 0.83 with 95% CIs 0.67–1.04). Intensive BP control significantly reduced the risk of MCI (14.6 vs. 18.3 cases per 1000 person-years; HR 0.81 with 95% CIs 0.69–0.95) and the combined rate of MCI or probable dementia (20.2 vs. 24.1 cases per 1000 person-years; HR 0.85 with 95% CIs 0.74–0.97). The SPRINT MIND authors concluded [6] that treating ambulatory adults with hypertension to a systolic BP goal of less than 140 mmHg did not result in a significant reduction in the risk of probable dementia, but because of early study termination and fewer than expected cases of dementia, the study may have been underpowered for this endpoint.

A subset of participants in SPRINT MIND took part in the brain magnetic resonance imaging (MRI) study, which evaluated change in total white matter lesion (WML) volume and total brain volume (TBV) during the active treatment and passive follow-up phases of the trial [7]. MRI was performed on 670 participants at baseline and on 449 participants at 4 years of follow-up. In the intensive BP treatment group, mean WML volume increased from 4.57 to 5.49 cm³ (difference 0.92 cm³ with 95% CIs 0.69–1.14) vs. an increase from 4.40 to 5.85 cm³ (difference 1.45 cm³ with 95% CIs 1.21–1.70) in the standard BP treatment group (difference in change between-groups −0.54 cm³ with 95% CIs −0.87 to −0.20). Mean TBV decreased from 1134.5 to 1104.0 cm³ (difference −30.6 cm³ with 95% CIs −32.3 to −28.8) in the intensive BP treatment group vs. a decrease from 1134.0 to 1107.1 cm³ (difference −26.9 cm³ with 95% CIs −24.8 to −28.8) in the standard BP treatment group (difference in change between-groups −3.7 cm³ with 95% CIs −6.3 to −1.1). The authors concluded [7] that among hypertensive adults, targeting a systolic BP of less than 120 mmHg was significantly associated with a smaller increase in cerebral WML volume and a slightly greater decrease in TBV, although the differences were small.

It is unclear [8] whether the between-group difference in TBV change reflects loss of brain tissue or another factor, such as hydration status, potentially related to differences in the antihypertensive intervention. However, WML are indicative of impaired microcirculation and predict stroke, dementia (likely both vascular dementia and Alzheimer’s disease) and increased mortality. The finding that intensive BP lowering prevents increases in WML volume is consistent with finding of reductions in MCI and in the combined outcome of MCI and probable all-cause dementia in the intensive treatment group [6]. These observations provide a rationale for the argument that high BP should be normalised by drug treatment in order to prevent the development of cognitive decline.

SPRINT MIND [6] demonstrated that intensive BP control did not result in harm and may be beneficial to the brain or cognition after a median intervention period of 3.34 years and an overall median follow-up of 5.11 years. SPRINT MIND is the first trial to identify an intervention that significantly reduces the occurrence of MCI as well as the combined occurrence of MCI or dementia [6].

However, some caution should be exercised in interpreting this result, both because MCI was not the primary cognitive outcome of the trial and because it is not clear what this effect may mean for the longer-term incidence of dementia [6]. Although MCI increases the risk of progression to dementia, such progression is not certain and reversion to normal cognition is also possible. Limitations of SPRINT MIND and the MRI sub-study [6,7] include the limited follow-up time due to early discontinuation of the SPRINT intervention because of cardiovascular disease benefit [2], reducing the time required for the development of probable dementia. The incidence of probable dementia was low in both treatment arms, reducing the ability to detect significant differences between groups, although there was a statistically non-significant reduction in the intensive treatment group. Because of early study termination and fewer than expected cases of dementia, the study was likely underpowered for this end point like it was for cerebral stroke [2].

SPRINT MIND has several other limitations, as pointed out by the authors [6]. The trial did not enrol persons with type 2 diabetes, previous stroke, advanced kidney disease, or symptomatic heart failure. Further, the specific choice of thresholds for the Montreal Cognitive Assessment and the Modified Telephone Interview for Cognitive Status to trigger additional testing and adjudication may have underestimated the frequency of MCI. However, there is no indication that such an under-ascertainment differed by treatment group. Loss to follow-up with the extended follow-up visits, though similar for each treatment group, could have also led to under-ascertainment of outcomes. While prevalent dementia was an exclusion criterion, the trial did not adjudicate baseline cognitive status. Therefore, SPRINT MIND cannot exclude or examine the influence of prevalent MCI at the time of randomisation. Finally, the trial was designed to test 2 different treatment goals and not specific medications, limiting the ability to discern the relative effects of specific antihypertensive medications on MCI or dementia.

Even with all the limitations taken into account, our conclusion is more optimistic than what was stated by the SPRINT MIND authors [6]; SPRINT MIND outcomes rather strongly suggest brain protection and a reduction in the risk of probable dementia by intensive systolic blood pressure lowering. Targeting the lower values recommended by the new American [4] and European Hypertension Guidelines [9] should be favourable for the brain.

Disclosure statement

S.E.K., K.N., M.B. and S.O. are editors of Blood Pressure. S.E.K., K.N. and M.B. report no relevant conflicts of interest to disclose related to this editorial. S.O. reports a conflict as leader in SPRINT and co-author of the SPRINT MIND report [6].