Time in Target Blood Pressure Range and Dementia

The debate over whether lowering blood pressure (BP) measurably decreases the risk of dementia and cognitive decline still awaits firm conclusions, with pro^1,2 and con³ sides exchanging evidence. But a different approach to looking at data has emerged. Using the time in target range (TTR) concept, Li et al⁴ reanalyzed the SPRINT MIND trial (Systolic Blood Pressure Intervention Trial Memory and Cognition IN Decreased hypertension), a randomized clinical trial comparing intensive (<120 mm Hg) and standard (<140 mm Hg) systolic BP lowering interventions in individuals who have hypertension and high cardiovascular risk, but no past history of stroke or dementia. TTR is defined as a proportion of time a patient spends with BPs within a prescribed, desirable range. Here, target range was specified as 110 to 130 mm Hg for the intensive arm, and 120 to 140 mm Hg for the standard. TTR was estimated over the first 3 months of follow-up using linear interpolation. This showed a gradient reduction in dementia risk with every tertile increase in systolic BP TTR, but there was no association with either mild cognitive impairment, or the composite of probable dementia and mild cognitive impairment. In light of original SPRINT MIND results that failed to show the advantage of intensive versus standard BP lowering for reducing the risk of dementia,⁵ are these findings surprising or contradictory? No, if we ask an even more stirring question for hypertension and dementia researchers: Time at What Target? The results of the Li et al study seem to extend the original SPRINT MIND conclusions and to suggest that an systolic BP target of below 140 may be adequate for dementia prevention. But we have to keep in mind that we are looking at 2 entirely different concepts. The analysis of TTR in the current study is not just a comparison between 2 targets of BP: it represents the time spent in a predefined adequate range of BP. The association between increased TTR and dementia was shown when both arms were analyzed together, but it was not statistically significant in either arm analyzed separately within their specific range. As expected, when both arms were regrouped in the same analysis and target range was redefined as 110 to 140, the inverse relationship between longer TTR and dementia was significant.

In one of the largest data sets where systolic BP TTR was assessed, about 15% of patients with newly diagnosed hypertension in the regular care setting never reached the target. It was defined at 140/90 and 150/90 for patients over 60 without diabetes and chronic kidney disease.⁶ On the positive side, there was a gradual reduction in the odds ratio for cardiovascular events with TTR increase. The authors suggested that focusing on already existing BP targets could be more helpful (and realistic) than pursuing more conservative (lower) treatment goals. It remains to be established whether, in the case of cognitive outcomes, the same practical approach is true. The relationship between TTR and dementia in the SPRINT MIND trial is, therefore, quite complex.

Several issues should be considered before assuming that TTR has a causal or even direct relation with dementia. First, TTR could be related to individual blood pressure variability (BPV). Patients with high BPV may deviate from the BP range even if properly treated and monitored. Several studies have shown a relationship between BPV and risk of dementia⁷ or cognitive impairment, including those using the SPRINT MIND data.⁸ Future studies should analyze precisely the relationship between the TTR index and BPV and adjust for BPV to know the residual risk of dementia related to TTR. Accounting for variability would also bring us closer to an understanding of possible mechanisms. TTR encompasses average BP and BPV; however, it does not provide information about the amplitude of BP changes (Figure). If TTR is still significantly related to outcome after adjusting for BPV, it might suggest that the length of time when vessel walls are subjected to mechanical stress from increased pressure is critical. If, on the contrary, the association disappears, it is likely that cerebral blood flow fluctuations and hypoperfusion due to impaired flow regulation play a role. Second, reverse causality cannot be ruled out. The pathological process of dementia extends over several years or even decades. Since neuronal loss can affect the entire central nervous system, including structures involved in BP regulation, the association between TTR and dementia could be bidirectional. Future studies with longer follow-up and a larger number of events could help to rule out reverse causality, or to at least measure its impact.

Third, residual confounding is always possible in observational studies, even if they are based on data extracted from a randomized trial like the current analysis of Li et al. Despite their careful analysis, variables that play a major role in dementia such as education or the ApoE4 polymorphism (which could therefore modify the association between TTR and dementia) were not taken into account in the models.

Despite these uncertainties, which need to be addressed in future studies to clarify the relationship between TTR and dementia, this index could nevertheless be of potential prognostic value for clinicians. Even if the TTR index covers a complex and possibly noncausal association with dementia, it could represent a useful prognostic marker of dementia risk for clinicians. TTR has some interesting features as it combines both BPV, and appropriate ranges of BP, and it is easy to calculate over a period of a few months. Analyzing its prognostic value would require new studies with an entirely different methodology and design than analytical studies like the current study of Li et al.

Even with these limitations, the article by Li et al opens a new field of investigation into the complex relationship between hypertension and dementia. The association between the TTR index and the risk of dementia must now be confirmed in other studies with large samples, if possible; cerebral magnetic resonance imaging scans; longer follow-ups; and the inclusion of both cognitive decline and dementia analysis. Only after this replication, and the assessment of the prognostic value of TTR on dementia risk, will it be possible to assess the true value of the TTR index. The question of the relationship between hypertension and dementia is of such importance in terms of prevention that any new hypothesis is worth pursuing.