Comparison of visit-to-visit blood pressure variability and time in target range in predicting risk for cognitive outcomes in the SPRINT trial

Abstract

Background

Blood pressure (BP) variability (BPV) and time in target range (TTR) are emerging vascular risk factors for dementia, independent of traditionally targeted mean BP.

Objective

Determine whether BPV or TTR is most strongly associated with cognitive risk.

Methods

In this post hoc analysis of the SPRINT trial, 8034 participants underwent repeated BP measurement and cognitive testing at baseline and follow-up. Visit-to-visit BPV was calculated as average real variability. TTR was the percent of time in desired treatment arm target range (standard: 120–140 mmHg systolic BP; intensive: 110–130 mmHg systolic BP). Adjudicated clinical outcomes were no cognitive impairment, mild cognitive impairment (MCI), and probable dementia. We investigated a direct comparison of BPV and TTR in predicting cognitive risk, stratified by BP treatment group.

Results

Elevated BPV was associated with increased risk for MCI (adjusted HR: 1.21 [95% CI 1.10, 1.33], p < 0.001) and MCI/dementia (HR: 1.17 [95% CI 1.07, 1.27], p < 0.001) in the standard group, and dementia (HR: 1.17 [95% CI 1.01, 1.36], p = 0.039) in the intensive group. Higher TTR was related to lower dementia risk (HR: 0.72 [95% CI 0.60, 0.86], p < 0.001) in the intensive group only.

Conclusions

Visit-to-visit BPV outperformed TTR in predicting risk for MCI and MCI/dementia. TTR was more strongly associated with dementia risk under intensive treatment. Findings were independent of mean BP in a cohort with rigorously controlled BP and suggest newer aspects of BP control may be harnessed to further reduce cognitive risk.

Clinical trial information

ClinicalTrials.gov; NCT01206062.

Keywords

Alzheimer's disease blood pressure variability dementia mild cognitive impairment time in target range

Introduction

Blood pressure (BP) remains a promising modifiable vascular risk factor for dementia via pharmacological and non-pharmacological interventions.^1,2 Results from the Systolic Blood Pressure Intervention Trial³ (SPRINT) highlight cardiovascular,⁴ cerebrovascular,⁵ and cognitive⁶ benefits of intensive BP lowering (<120 mmHg systolic BP target) when compared to standard BP treatment (<140 mmHg systolic BP target) in individuals with hypertension. To date, BP clinical trials have largely focused on treating mean BP levels, but there is a growing push to discover other aspects of BP that may further reduce risk. BP variability (BPV), or the fluctuations in BP levels over beat-to-beat to even year-to-year (i.e., visit-to-visit) cycles, has recently become one such target of interest.⁷ BP is highly dynamic and changes represent fine-tuned adjustments to accommodate responses to internal and external stimuli and ensure adequate blood flow to organs and tissues.⁸ Because the brain is highly sensitive to disruptions in blood flow,⁹ a growing literature has sought to understand relationships between BPV and brain health. Several lines of evidence suggest elevated BPV is associated with increased risk for cognitive impairment and dementia,¹⁰ cerebrovascular disease,^11,12 and multi-modal measurements of Alzheimer's disease (AD) pathophysiological change.^13–17 Importantly, many of these studies suggest BPV is independent of, and oftentimes outperforms, mean BP in predicting health outcomes along the heart-brain axis.^10,18 Additionally, recent SPRINT studies report higher BPV remains a risk for cognitive decline,¹⁹ mild cognitive impairment (MCI), and probable dementia^20,21 despite strict control of mean BP levels. This has led to a surge in interest in better understanding BPV and how best to manage it for dementia prevention.

The BPV literature is relatively new when compared to more well-studied aspects of BP such as mean levels, hypertension status, pulse pressure, mean arterial pressure, etc. Time in target range (TTR) is an even newer concept that is gaining attention.²² TTR is the percentage of time an individual's BP is within a desired BP target range. A recent post hoc analysis of the SPRINT trial suggests a higher TTR, independent of mean BP levels, is associated with decreased risk for probable dementia.²³ This finding further highlights the need to understand BP dynamics more closely when searching for novel ways to reduce dementia risk. With both BPV and TTR emerging as highly accessible, relatively modifiable, and potentially useful targets for dementia prevention, it remains unclear which index is more strongly associated with risk. And while TTR takes into account mean BP levels, reflects aspects of BP fluctuations, and is affected by the prescribed target range, BPV is independent of mean BP levels and is not necessarily restricted to cohorts with rigorously controlled BP. Therefore, the two indices are distinct and warrant detailed comparison. Additionally, the relationship between BPV and TTR is seemingly logical (i.e., more variable BP is likely to also be out of target range) but has not been specifically analyzed. Furthermore, no studies have determined whether the effect of either BP measure is altered when controlling for the other, which could reveal insights into mechanisms and usefulness in implementing these measures into clinical practice.²⁴ To investigate, we conducted a post hoc analysis of the SPRINT trial to examine a direct comparison of visit-to-visit BPV and TTR in predicting cognitive outcomes in a cohort with rigorously controlled mean BP.

Methods

Participants

Data were obtained from the SPRINT trial, a publicly available deidentified dataset from the National Heart, Lung, and Blood Institute that has been described in detail elsewhere.³ The present investigation was a post hoc analysis of this data. SPRINT was a multicenter randomized, controlled study cohort trial in the United States and Puerto Rico conducted between November 2010 and March 2013 investigating whether intensive BP lowering could reduce cardiovascular risk when compared to standard BP treatment. Participants were recruited from the local community and a variety of clinical settings, such as primary care, nephrology, and geriatrics. At screening, participants were ≥50 years old, hypertensive (systolic BP 130 mmHg – 180 mmHg), and at risk for cardiovascular disease (≥1 of the following risk factors: history of cardiovascular disease, chronic kidney disease [estimated glomerular filtration rate < 60 mL/min per 1.73 m²], 10-year Framingham cardiovascular disease risk²⁵ ≥15%, ≥75 years of age). Participants were excluded for history of stroke, diabetes, or heart failure, residing in a nursing home, diagnosis of dementia based on medical record review, or receiving medication primarily used to treat dementia. Participants were randomized 1:1 to either standard treatment (<140 mmHg systolic BP target) or intensive treatment (<120 mmHg systolic BP target).

Standard protocol approvals, registrations, and patient consents

The SPRINT study was approved by an Institutional Review Board at each site. All participants provided their informed consent before treatment randomization. Analyses of this data was approved by the Institutional Review Board at USC.

Measures

BP assessment. As previously described,^3,4,6,26,27 BP was measured using an automated BP device (Professional Digital Blood Pressure Monitor [Omron Healthcare; model 907XL]) at study baseline, 1-, 2-, and 3-months follow-up, and then every 3 months for up to 6 years follow-up. BP values from each visit were recorded as the average of 3 serial seated BP measurements after a 5-min period of rest. Participants were prohibited from completing questionnaires, talking, or texting during the rest period and BP collection. BP levels reached a relatively stable plateau in both treatment groups at 3-months follow-up.²⁸ To minimize the effect of initial BP fluctuation in the intensive treatment group, we calculated BPV and TTR from BP measurements collected at 3-, 6-, 9-, and 12-months follow-up. This is consistent with other recent BPV studies using the SPRINT dataset.^19,28,29 Intraindividual visit-to-visit BPV was calculated from the 4 BP measurements (e.g., from 3-, 6-, 9-, and 12-months follow-up visits) as average real variability (ARV). ARV is the mean of absolute changes between consecutive BP readings and therefore captures variability itself and temporal aspects of variability, which may be especially important when comparing with TTR. We also calculated the standard deviation (SD), coefficient of variation ([CV] 100 × SD/mean), and variability independent of mean³⁰ (VIM) indices of BPV and report findings in Supplemental Material. Mean BP was calculated from BP values collected over the same 9-month period as BPV (e.g., 3-, 6-, 9-, 12-months follow-up). Consistent with two recent TTR studies using the SPRINT dataset,^23,31 TTR was calculated as the percent of time an individual's BP was in the desired target range: intensive treatment group = 110–130 mmHg systolic BP; standard treatment group = 120–140 mmHg systolic BP. Also consistent with a SPRINT TTR study,²³ we defined 110–140 mmHg systolic BP TTR²³ for the combined study sample for additional analyses (see main text and Supplemental Material). Finally, we categorized participants into 3 groups defined by high/low (based on the mean) visit-to-visit BPV and TTR: 1) low BPV*high TTR (i.e., likely best BP control); 2) high BPV*low TTR (i.e., likely poorest BP control); 3) intermediate BPV/TTR (low BPV*low TTR and high BPV*high TTR), consistent with a recent prospective cardiovascular risk study of hypertensive individuals³² (see main text and Supplemental Material).

Cognitive assessment. The SPRINT cognitive assessment protocol has been previously described in detail.^3,6 Briefly, participants underwent cognitive testing at study baseline and every 2 years during the planned 4-year follow-up, and study closeout if it was >1 year after the planned 4-year follow-up. The cognitive battery included: Montreal Cognitive Assessment (MoCA), Logical Memory I and II, Digit Symbol Coding, Hopkins Verbal Learning Test – Revised, Modified Rey-Osterrieth Complex Figure, 15-item Boston Naming Test, Category Fluency – Animals, Trail Making Test parts A and B, and Digit Span. As previously described,⁶ clinicians masked to treatment group classified participants into one of three adjudicated clinical outcomes based on cognitive test scores and other health information (mood, sleep, functional abilities, medications, hospitalizations, informant report of participant functional status): no cognitive impairment, MCI, or probable dementia. An MCI/probable dementia composite was also determined. Standardized diagnostic criteria for MCI³³ and probable dementia³⁴ were used, as previously reported.⁶

Other measurements. The following variables were determined at study baseline: race (Black; Hispanic; White; other), body mass index (BMI [kg/m²]), number of antihypertensive medications used (all classes), Framingham 10-year CVD risk score, history of smoking (never versus former versus current).

Statistical analysis

First, we used ordinal logistic regression to directly examine the relationship between visit-to-visit BPV and TTR. Although recent SPRINT studies^20,21,23 analyzed visit-to-visit BPV and TTR separately in their association with dementia risk, BP was measured over different timescales across these studies, including immediately following treatment initiation which may influence both BPV and TTR. Additionally, different indices of BPV (e.g., SD, CV, ARV, maximum minus minimum) were used among the SPRINT BPV studies. Thus, a direct comparison is needed. Therefore, we next used Cox proportional hazards models to investigate the potential effects of visit-to-visit BPV and TTR separately on the rate of cognitive outcomes. Next, to explore residual risk, we ran Cox proportional hazards models with adjustment for the other index (i.e., BPV models adjusted for TTR and TTR models adjusted for BPV). Finally, to explore combined risk of visit-to-visit BPV and TTR, we ran Cox proportional hazards models exploring cognitive risk in the 3 high/low BPV/TTR groups. Analyses using the SD, CV, and VIM indices of BPV are reported in the Supplemental Material. Sensitivity and combined risk models combined BP intervention arms and used a TTR range of 110–140 mmHg (see main text and Supplemental Material). Given the focus on systolic BP in the SPRINT trial³ and consistent with other recent SPRINT BPV^19,20,28 and TTR^23,31 studies, we focused our analyses on systolic BPV and systolic TTR. Models examining individual BPV or TTR risk were stratified by standard versus intensive treatment group, while the total sample was used in models examining combined BPV/TTR risk. All stratified models adjusted for age, sex, education, race/ethnicity, baseline MoCA total score, and mean systolic BP. All models using the total sample additionally controlled for treatment arm. The no cognitive impairment group was set as the reference group among the three adjudicated clinical outcomes. The low BPV*high TTR (i.e., likely best BP control) group was set as the reference group for combined risk analyses. Standardized hazard ratios are presented to reflect risk per 1-SD increase in BPV/TTR. Concordance statistics (C-statistics) for Cox proportional hazards models are also reported to reflect predictive accuracy. All analyses were 2-tailed with significance set at p < 0.05 and were carried out in R.³⁵

Results

8034 participants (n = 4019 in the standard treatment group, n = 4015 in the intensive treatment group) were included in the present study (Table 1). The median (range) follow-up time after treatment randomization was 1816 (382–2712) days for participants in the intensive treatment group and 1614 (415–2704) days for participants in the standard treatment group. In the intensive treatment group, 134/4015 participants developed probable dementia and 262/4015 participants developed MCI during follow-up. In the standard treatment group, 156/4019 participants developed probable dementia and 324/4019 participants developed MCI during follow-up. As shown in Table 1, 82.7% of participants in the intensive treatment group and 78.8% of participants in the standard treatment group had BP levels in their respective desired target range ≥ 50% of the time. Mean (SD) visit-to-visit systolic BPV (ARV) was 11.2 (7.5) mmHg in the intensive treatment group and 12.5 (7.9) mmHg in the standard treatment group.

Table 1.

Baseline clinical and demographic information.

	Intensive (n = 4015)	Standard (n = 4019)	F or χ²	p
Age (y)	68.0 (9.3)	67.9 (9.3)	0.016	0.899
Sex (n, % female)	1420 (35.4%)	1374 (34.2%)	1.181	0.277
Race/ethnicity (n, %)			5.53	0.137
Black	1125 (28.0%)	1174 (29.2%)
Hispanic	441 (11.0%)	423 (10.5%)
White	2367 (59.0%)	2364 (58.8%)
Other	82 (2.0%)	58 (1.4%)
Education (n, %)			0.20	0.903
Less than college/other	2423 (60.4%)	2407 (59.9%)
College	586 (14.6%)	598 (14.9%)
Graduate school	1006 (25.1%)	1014 (25.2%)
MoCA total score	23.0 (4.1)	23.0 (4.1)	0.37	0.544
BMI (kg/m²)	30.0 (5.8)	29.8 (5.7)	1.87	0.172
FRS 10-year risk score	20.0 (10.9)	20.1 (10.8)	0.12	0.729
History of cardiovascular disease* (n, %)	817 (20.4%)	797 (19.8%)	0.30	0.581
Medication use (n, %)
Antihypertensive agents	3642 (90.7%)	3620 (90.1%)	0.87	0.351
No. antihypertensive agents used (median, IQR)	2 (2)	2 (2)	1.38	0.241
Systolic TTR (n, %)			64.4	<0.001
0%	184 (4.6%)	180 (4.5%)
25%	509 (12.7%)	672 (16.7%)
50%	1066 (26.6%)	1194 (29.7%)
75%	1313 (32.7%)	1266 (31.5%)
100%	943 (23.5%)	707 (17.6%)
Systolic BP (mmHg)
Mean	121.6 (9.0)	134.9 (8.2)	4734.0	<0.001
Visit-to-visit ARV	11.2 (7.5)	12.5 (7.9)	54.09	<0.001
Diastolic BP (mmHg)
Mean	68.5 (8.5)	75.3 (9.4)	1157.0	<0.001
Visit-to-visit ARV	7.0 (4.2)	7.5 (4.3)	31.33	<0.001

Means and SDs shown unless otherwise indicated.

*SPRINT history of cardiovascular disease is defined as presence of clinical cardiovascular disease (other than stroke; a) previous myocardial infarction, percutaneous coronary intervention, coronary artery bypass grafting, carotid endarterectomy, carotid stenting; b) peripheral disease with revascularization; c) acute coronary syndrome with or without resting ECG change, ECG changes on a graded exercise test, or positive cardiac imaging study; d) at least 50% diameter stenosis or a coronary, carotid, or lower extremity artery; e) abdominal aortic aneurysm ≥5 cm with or without repair) or subclinical cardiovascular disease (a) coronary artery calcium score ≥400 Agatston units within the past 2 years; b) ankle brachial index ≤0.90 within the past 2 years; c) left ventricular hypertrophy by ECG [based on computer reading], echocardiogram report, or other cardiac imaging procedure report within the past 2 years) at study baseline.

ARV: average real variability; BMI: body mass index; BP: blood pressure; ECG: electrocardiogram; FRS: Framingham risk score; IQR: interquartile range; MoCA: Montreal Cognitive Assessment; TTR: time in target range.

Relationship between visit-to-visit BPV and TTR

In ordinal logistic regression analyses, elevated visit-to-visit systolic BPV was related to significantly lower systolic TTR in both the intensive treatment group (standardized, adjusted odds ratio [OR]: 0.36 [95% CI 0.34, 0.39; p < 0.001]) and in the standard treatment group (OR: 0.35 [0.32, 0.37]; p < 0.001) (Figure 1).

Figure 1.

Higher visit-to-visit BPV is associated with lower TTR. Boxplots display the results of the ordinal logistic regression of visit-to-visit systolic BPV predicting systolic TTR. Models adjusted for age, sex, race/ethnicity, education, baseline Montreal Cognitive Assessment total score, and mean systolic blood pressure. BPV: blood pressure variability; TTR: time in target range.

Direct comparison of visit-to-visit BPV and TTR in predicting risk for cognitive outcomes

Visit-to-visit BPV. As shown in Figure 2, elevated visit-to-visit systolic BPV was associated with increased risk for MCI (standardized, adjusted hazard ratio [HR]: 1.21 [95% CI 1.10, 1.33], p < 0.001) and the MCI/probable dementia composite (HR: 1.17 [95% CI 1.07, 1.27], p < 0.001), but not probable dementia (HR: 1.12 [95% CI 0.97, 1.29], p = 0.119) in the standard treatment group. Elevated visit-to-visit systolic BPV was related to increased risk for probable dementia (HR: 1.17 [95% CI 1.01, 1.36], p = 0.039) but not MCI (HR: 0.95 [95% CI 0.85, 1.07], p = 0.397) or MCI/probable dementia composite (HR: 1.01 [95% CI 0.92, 1.10], p = 0.903) in the intensive treatment group. Concordance was very good (concordance statistics = 0.85–0.89) for all BPV models.

Figure 2.

Direct comparison of visit-to-visit BPV and TTR in predicting risk for cognitive outcomes. Adjusted hazard ratios ([HR] 95% CI) of visit-to-visit systolic BPV and systolic TTR in predicting risk for cognitive outcomes. Models adjusted for age, sex, race/ethnicity, education, baseline Montreal Cognitive Assessment total score, and mean systolic blood pressure. BPV: blood pressure variability; TTR: time in target range; MCI: mild cognitive impairment.

TTR. As shown in Figure 2, systolic TTR was not significantly associated with any cognitive outcomes under standard BP lowering (ps = 0.220–0.477). Under intensive BP lowering, higher systolic TTR was related to lower risk for probable dementia (HR: 0.72 [95% CI 0.60, 0.86], p < 0.001) but not MCI (HR: 1.04 [95% CI 0.91, 1.19], p = 0.568) or MCI/probable dementia composite (HR: 0.92 [95% CI 0.82, 1.03], p = 0.127). Concordance was very good (concordance statistics = 0.85–0.89) for all TTR models.

Residual risk for cognitive outcomes

As shown in Table 2, residual visit-to-visit systolic BPV risk remained significant, and even strengthened, for MCI and MCI/probable dementia when additionally controlling for systolic TTR (risk for probable dementia was no longer significant [p = 0.313]). Residual systolic TTR risk for probable dementia was consistent when additionally controlling for visit-to-visit systolic BPV, albeit slightly attenuated.

Table 2.

Residual risk model estimates (adjusted HR [95% CI]) of visit-to-visit systolic BPV (ARV) and systolic TTR predicting cognitive outcomes, with adjustment for the other BP index.

	HR [95% CI] p
Standard treatment
Probable dementia
BPV	1.11 [0.95, 1.30] 0.20
TTR	0.97 [0.81, 1.17] 0.77
MCI
BPV	1.23 [1.11, 1.36] <0.001
TTR	1.04 [0.91, 1.18] 0.59
MCI/probable dementia
BPV	1.19 [1.08, 1.31] <0.001
TTR	1.06 [0.94, 1.18] 0.35
Intensive treatment
Probable dementia
BPV	1.08 [0.93, 1.27] 0.313
TTR	0.74 [0.61, 0.89] 0.002
MCI
BPV	0.96 [0.85, 1.08] 0.47
TTR	1.03 [0.89, 1.18] 0.73
MCI/probable dementia
BPV	0.98 [0.89, 1.08] 0.73
TTR	0.91 [0.81, 1.02] 0.12

Beta (β) and 95% confidence intervals shown unless otherwise indicated.

Bolded items indicate visit-to-visit systolic BPV or systolic TTR is significantly associated with risk for specified cognitive outcome, after additionally controlling for the other BP index.

All models adjusted for age, sex, race, education, baseline MoCA total score, and mean systolic BP. Visit-to-visit BPV models also adjusted for TTR while TTR models also adjusted for BPV.

ARV: average real variability; BP: blood pressure; BPV: blood pressure variability; CI: confidence interval; HR: hazard ratio; MCI: mild cognitive impairment; MoCA: Montreal Cognitive Assessment; TTR: time in target range.

Combined visit-to-visit BPV/TTR risk for cognitive outcomes

The 3 high/low BPV/TTR combined risk groups did not significantly differ in their risk for cognitive outcomes (ps = 0.077–0.492) (Table 3).

Table 3.

Model estimates (adjusted HR [95% CI]) of BPV/TTR risk groups predicting cognitive outcomes in a combined study sample.

	HR [95% CI] p
Probable dementia
Low BPVhigh TTR*	Reference
Intermediate	1.14 [0.83, 1.55] 0.420
High BPVLow TTR*	1.32 [0.97, 1.78] 0.077
MCI
Low BPVhigh TTR*	Reference
Intermediate	1.17 [0.95, 1.45] 0.136
High BPVLow TTR*	1.13 [0.92, 1.40] 0.247
MCI/probable dementia
Low BPVhigh TTR*	Reference
Intermediate	1.07 [0.89, 1.28] 0.492
High BPVLow TTR*	1.13 [0.94, 1.35] 0.196

Beta (β) and 95% confidence intervals shown unless otherwise indicated.

Bolded items indicate BPV/TTR risk group is significantly associated with risk for specified cognitive outcome in a combined study sample of intensive and standard treatment groups. Here, systolic TTR is defined as 110–140 mmHg systolic BP.

All models adjusted for age, sex, race, education, baseline MoCA total score, mean systolic BP, and treatment group.

BP: blood pressure; BPV: blood pressure variability; CI: confidence interval; HR: hazard ratio; MCI: mild cognitive impairment; MoCA: Montreal Cognitive Assessment; TTR: time in target range.

Supplemental analyses

Analyses using the SD, CV, and VIM indices of BPV revealed consistent findings (see Supplemental Table 1).

Sensitivity analyses

Visit-to-visit systolic BPV and systolic TTR findings were consistent in a combined study sample with TTR defined as 110–140 mmHg systolic BP (see Supplemental Table 2). Residual visit-to-visit systolic BPV risk was similar to stratified analyses, whereas residual systolic TTR risk was no longer significantly associated with cognitive outcomes in the combined study sample (see Supplemental Table 3).

Discussion

To the best of our knowledge, this was the first direct comparison of visit-to-visit BPV and TTR in predicting risk for cognitive impairment and dementia. Findings suggest visit-to-visit BPV outperforms TTR in predicting risk for MCI and the MCI/probable dementia composite, particularly under standard BP lowering and in the combined study sample. TTR was more strongly associated with risk for probable dementia under intensive BP lowering, but this risk was similar for both BP indices in the combined study sample. Specifically, for an increase of 1 SD in visit-to-visit BPV under standard treatment, there was 21% increased odds for MCI and 17% increased odds for MCI/probable dementia composite. Under intensive treatment, there was 17% increased odds of probable dementia. On the other hand, an increase of 1 SD in TTR was associated with 28% decreased odds for probable dementia under intensive treatment, but TTR was not associated with risk for other cognitive outcomes. Analyses of residual risk suggest visit-to-visit BPV and TTR generally remain associated with risk for cognitive outcomes in stratified analyses, but in the combined study sample, only visit-to-visit BPV was related to cognitive risk when additionally controlling for the other BP index. Additionally, the combined BPV/TTR risk groups did not significantly differ in their risk for cognitive outcomes.

Importantly, study findings were independent of traditionally studied and targeted mean BP levels, even in a cohort with rigorously controlled mean BP levels. It remains uncertain why BPV and TTR predict dementia risk beyond mean BP levels. It has been hypothesized that greater fluctuations in BP, regardless of mean levels or desired target range, may stress arterial walls and promote opportunities for altered pulse wave dynamics, microvascular insult, blood-brain barrier leakage, and hypoperfusion.^10,18 Lower TTR may also indicate marked changes in BP levels that exceed a desired target range likely intended to protect cardiovascular and cerebrovascular health. Both ARV in BP and TTR reflect temporal aspects of BP changes. But unlike TTR, BPV also provides information about the amplitude of BP fluctuations. In this study, visit-to-visit BPV and TTR were both associated with risk for cognitive decline, and the observed risk was generally preserved when accounting for the other BP index (at least in stratified analyses). This suggests the magnitude and amount of time arterial walls are stressed from widely fluctuating BP levels may be important. However, visit-to-visit BPV outperformed TTR in predicting risk for MCI, oftentimes a precursor for dementia, and MCI/probable dementia composite. Additionally, TTR was no longer associated with cognitive risk in the combined study sample after controlling for visit-to-visit BPV. Although all visit-to-visit BPV indices (ARV, SD, CV, VIM) were associated with cognitive outcomes, ARV, which also captures the temporal order of fluctuations, consistently predicted the strongest risk. Together these findings suggest the BP fluctuations themselves may be most critical to brain health. Indeed, many recent studies report strong links between higher BPV and cerebrovascular¹² and neuropathological burden,¹⁷ which may accumulate years or even decades before cognitive symptoms emerge.³⁶ The current study was a post hoc analysis of the SPRINT trial and was therefore not able to test causality or underlying mechanisms. Additionally, TTR is understudied relative to BPV, and future TTR and TTR-BPV comparison studies that can address pathology are needed to further identify possible mechanisms and targets for intervention.

Interestingly, visit-to-visit BPV was mostly associated with cognitive outcomes in the standard treatment group, whereas TTR was related to risk for only one cognitive outcome in the intensive treatment group. A consistent pattern emerged in the combined study sample. Both treatment groups had the same target window width (e.g., 20 mmHg), yet fluctuations under standard BP lowering were more strongly associated with risk for cognitive decline. It is possible that this may be related to a basal effect in the intensive treatment group, where lower BPs have been shown to have cognitive benefit in the SPRINT trial.⁶ However, TTR and visit-to-visit BPV were inversely related in both treatment groups, which suggests the two indices are associated to some degree regardless of lowering strategy. Interestingly, the combined BPV/TTR risk groups did not significantly differ in their risk for cognitive outcomes, whereas analyses of individual visit-to-visit BPV or TTR risk showed a clear split in risk profile. This suggests specific aspects of BP control may be more or less related to cognitive functioning, rather than their combined effect. Findings further raise the question of how best to manage BP for brain health. Some evidence suggests antihypertensive class effects on BPV for stroke risk,³⁷ potentially favoring calcium-channel blockers.^38,39 A recent study reports this effect may also be related to dementia risk.⁴⁰ Whether BPV or TTR respond better to antihypertensive treatment, or even how TTR is affected by different antihypertensive therapies, is not well known and represents areas for further research. Additionally, the present study determined visit-to-visit BPV and TTR from gold-standard in-office BP measurements, consistent with many other BPV⁸ and TTR studies.^23,31 New technological advances in ambulatory BP monitoring, which can capture shorter-term and longer-term BP fluctuations, in real-world settings could offer more data and more opportunities/windows for intervention for possibly multiple aspects of BP simultaneously, including mean BP, BPV, and TTR. Future studies comparing shorter-term and longer-term BPV and risk are warranted and could help elucidate potential mechanisms.

The present direct comparison of visit-to-visit BPV and TTR adds to prior independent studies of the BP indices. Findings provide novel evidence that visit-to-visit BPV outperforms TTR in predicting risk for MCI and MCI/probable dementia and that TTR may have an advantage over visit-to-visit BPV in predicting probable dementia risk, particularly under intensive BP lowering. Additionally, residual risk and the relationship between visit-to-visit BPV and TTR were directly assessed, which provides new information that is potentially relevant to translating these findings into clinical practice. The current study is strengthened by the rigorously defined cognitive outcomes, longitudinal design, and length of follow-up in a cohort with rigorously controlled mean BP levels. This allowed for a comparison of visit-to-visit BPV and TTR that may be more precise than studies relying on observational cohorts with less strict/characterized BP control. Furthermore, unlike other SPRINT BPV^20,21 and TTR studies,²³ visit-to-visit BPV and TTR in the present investigation were derived from BP measurements collected after 3 months follow-up, when BP levels generally stabilized after treatment initiation,²⁸ and therefore may better reflect BP dynamics versus initial adjustment to treatment regimen. However, risk for probable dementia in the total sample was similar for TTR in both studies (13% in current study versus 14% in recent SPRINT TTR study²³). More research is needed to further specify standardized timeframes to measure TTR and/or BPV. The present study also covaried for factors relevant to dementia risk, including education and treatment arm. Additionally, SPRINT participants were racially/ethnically and geographically diverse and had varied levels of educational attainment.

The present study has several limitations worth noting. As noted, we did not test antihypertensive class effects due to being underpowered for this type of analysis. We anticipate that these types of studies will help to guide the BPV field forward. Data on apolipoprotein E (APOE) genotype, a strong genetic risk factor for Alzheimer's disease,⁴¹ was not available, which limited our ability to assess how APOE may relate to the observed relationships between visit-to-visit BPV, TTR, and dementia risk. However, growing evidence suggests BPV may be associated with brain and cognitive outcomes especially in APOE ε4 carriers.^13,14,42,43 Additionally, visit-to-visit BPV and TTR were determined from BP measurements collected within 1 year after treatment randomization, whereas cognitive assessments were collected at baseline and then every 2 years follow-up. Although cognitive events were identified after BP metrics were summarized, it is possible that cognitive changes occurred during the same period when BP was collected. While clinical diagnosis was determined by a panel of expert clinicians based on multiple sources of information (e.g., cognitive test scores, information on mood, sleep, functional abilities, medications, hospitalizations, informant report of participant functional status), neuroimaging or other biomarker data was not considered in the differential. Finally, the present study was a post hoc analysis of a clinical trial focused on controlling mean BP levels which also precluded us from examining potential underlying mechanisms. Findings highlight the need for identifying additional BP targets for dementia prevention.

Conclusions

In a direct comparison of visit-to-visit BPV and TTR, visit-to-visit BPV outperformed TTR in predicting risk for MCI and MCI/probable dementia, and TTR may have an advantage over visit-to-visit BPV in predicting probable dementia risk, particularly under intensive BP lowering. Residual risk remained for both BP indices in stratified analyses, but in the combined study sample, only visit-to-visit BPV remained associated with cognitive risk when additionally controlling for the other BP index. Additionally, combined BPV/TTR risk groups did not significantly differ in their risk for cognitive outcomes, suggesting individual risk may be more relevant to brain health rather than their combined effect. Findings were independent of mean BP, even in a cohort with rigorously controlled BP. Study findings suggest non-traditional aspects of BP control could be harnessed for therapeutic strategies aimed at reducing dementia risk.

Supplemental Material

sj-docx-1-alz-10.1177_13872877241303378 - Supplemental material for Comparison of visit-to-visit blood pressure variability and time in target range in predicting risk for cognitive outcomes in the SPRINT trial

Supplemental material, sj-docx-1-alz-10.1177_13872877241303378 for Comparison of visit-to-visit blood pressure variability and time in target range in predicting risk for cognitive outcomes in the SPRINT trial by Isabel J Sible and Daniel A Nation in Journal of Alzheimer's Disease

Footnotes

Acknowledgments

We would like to thank the participants and their families, investigators, and researchers from the SPRINT and SPRINT MIND trial/study.

ORCID iDs

Isabel J Sible

Daniel A Nation

Author contributions

Isabel J Sible (Conceptualization; Formal analysis; Visualization; Writing – original draft); Daniel A Nation (Conceptualization; Writing – review & editing).

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The study data analysis was supported by NIH/NIA grants (R01AG064228, R01AG060049, R01AG082073, P30AG066530, P01AG052350).

Declaration of conflicting interests

Daniel Nation is an Editorial Board Member of this journal but was not involved in the peer-review process of this article nor had access to any information regarding its peer-review. The remaining author declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Data availability

The data supporting the findings of this study are openly available in SPRINT at . These data were derived from the following resources available in the public domain: https://biolincc.nhlbi.nih.gov/studies/sprint/.

Supplemental material

Supplemental material for this article is available online.

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