Abstract
Background
The Systolic Blood Pressure Intervention Trial (SPRINT) randomized patients to a goal systolic blood pressure (SBP) <120 mm Hg vs. <140 mm Hg. In a subset of participants, the SPRINT MIND ancillary study performed a baseline MRI and measured white matter hyperintensity volume (WMHv). In this secondary analysis, we evaluated the association between baseline WMHv and cardiovascular events during follow-up in the overall sample.
Methods
The primary outcome was the same as SPRINT, a composite of stroke, myocardial infarction, acute coronary syndrome, decompensated congestive heart failure, or cardiovascular death. We fit Cox models to the primary outcome and report adjusted hazard ratios (HR) for log-transformed WMHv and quartiles of WMHv.
Results
Among 717 participants, the median (IQR) baseline WMHv was 1.62 (0.66–3.98) mL. The primary outcome occurred in 51/719 (7.1%). The median WMHv was higher in patients with the primary outcome (3.40 mL versus 1.56 mL, p<0.001). In adjusted models, WMHv as a log-transformed continuous variable was associated with the primary outcome (HR 1.44, 95% CI 1.15–1.80). The highest quartile of WMHv, compared to the lowest, was also independently associated with the primary outcome (HR 3.21, 95% CI 1.27–8.13).
Conclusions
We found that the baseline volume of WMH was associated with future CVD risk in SPRINT MIND. Prospective clinical trials with larger sample sizes than the current study are needed to determine whether intensive BP lowering can reduce the high cardiovascular risk in patients with WMH.
Keywords: White matter hyperintensity, cardiovascular diseases, Outcome, SPRINT MIND
Introduction
White matter hyperintensities (WMH) are brain lesions that are visualized as foci of increased signal on T2-weighted magnetic resonance imaging (MRI).1 Systolic hypertension is the most established modifiable risk factor for WMH and cardiovascular disease.2 The Systolic Blood Pressure Intervention Trial (SPRINT) randomized patients to a goal systolic blood pressure (SBP) <120 versus <140 mm Hg.3 In the ancillary SPRINT MIND study, which examined the effect of the different SBP goals on the rate of incident dementia and mild cognitive impairment (MCI), a baseline MRI was performed on which they measured WMH volume (WMHv).4 Prior studies have shown that WMHv is an independent risk factor for cardiovascular disease, but the association has not been examined in a cohort of patients with excellent blood pressure control.5 To address this knowledge gap, we evaluated the association between baseline WMHv and future cardiovascular events in SPRINT MIND.
Methods
Study population
After obtaining a local IRB waiver, we obtained the SPRINT MIND dataset from the NHLBI Biologic Specimen and Data Repository Information Coordinating Center to perform secondary analyses. Of the 9,361 patients enrolled in SPRINT MIND, we included the subset of SPRINT MIND patients (n=717) who had a baseline MRI on which WMHv was measured using validated methodology that has been previously described6 and available demographic and outcome data.
Study Outcomes and Predictors
The primary outcome of this study was the same as SPRINT, a composite of myocardial infarction, acute coronary syndrome, decompensated congestive heart failure, stroke, or death from cardiovascular causes. The secondary outcome was incident stroke, including ischemic and hemorrhagic events. The primary predictor was the WMHv at baseline as a log-transformed continuous value in mL and we additionally compared the top to the bottom quartile.
Statistical Analysis
We report the median and interquartile range of WMHv, which we tested for significant differences in our outcome categories using the Wilcoxon rank sum test. We fit Cox proportional hazards models to estimate the hazard ratios (HR) for our primary and secondary outcomes. In the model fit to the primary outcome, we adjusted for patient age, sex, race, history of heart attack, history of congestive heart failure, current cigarette smoking, and high-density lipoprotein (HDL) cholesterol. To avoid overfitting the model of the secondary outcome, we only adjusted for age and diabetes. We verified the proportional-hazards assumption of our Cox models, and found that the SPRINT randomization arm violated that assumption. Thus, we also presented the results of the adjusted Cox model after stratification by the SPRINT randomization arm. Without the randomization arm variable, the global test of the proportional hazards’ assumption was p>0.1 for both models and for all covariates in either model.
Results
Baseline demographics of the 717 included patients are shown in Table 1. The baseline median (IQR) WMH was 1.62 (0.66–3.98) mL and in the WMHv quartiles was 0.34 (0.16–0.50), 1.07 (0.86–1.31), 2.47 (1.95–3.19), and 7.98 (5.35–14.18) mL. The mean (SD) years of follow-up were 3.61 (0.92). The primary outcome occurred in 51 (7.1%) patients and the secondary outcome in 10 (1.4%) patients. The median (IQR) WMHv was higher in patients with the primary outcome versus in those without (3.40 mL versus 1.56 mL, p<0.001) and approached significance in those with the secondary outcome versus in those without (3.73 ml versus 1.59 mL, p=0.074).
Table 1.
Baseline demographics and stratification by the primary outcome.
| Variable | Full Cohort (n=717) | Primary outcome (n=51) | No primary outcome (n=667) | p value* |
|---|---|---|---|---|
| Age | 67.8 (8.3) | 69.0 (8.7) | 67.7 (8.3) | 0.295 |
| White race | 485, 67.6% | 31, 60.8% | 454, 68.2% | 0.277 |
| Male sex | 436, 60.8% | 31, 60.8% | 405, 60.8% | 0.997 |
| Diabetes | 12, 1.7% | 2, 3.9% | 10, 1.5% | 0.194 |
| Atrial fibrillation | 48, 6.7% | 4, 7.8% | 44, 6.6% | 0.733 |
| Congestive heart failure | 16, 2.2% | 4, 7.8% | 12, 1.8% | 0.005 |
| Peripheral vascular disease | 35, 4.9% | 1, 2% | 34, 5.1% | 0.315 |
| Prior heart attack | 33, 4.6% | 9, 17.7% | 24, 3.6% | <0.001 |
| Prior transient ischemic attack or stroke | 27, 3.8% | 4, 7.8% | 23, 3.5% | 0.112 |
| Prior cancer | 98, 13.7% | 4, 7.8% | 94, 14.1% | 0.209 |
| Aspirin use | 366, 51% | 25, 49% | 341, 51.1% | 0.772 |
| Alcohol use | 494, 68.9% | 31, 60.8% | 463, 69.5% | 0.194 |
| Cigarette smoking | 96, 13.4% | 14, 27.5% | 82, 12.3% | 0.002 |
| Total cholesterol | 191.4 (51.8) | 185.7 (52.2) | 191.8 (51.8) | 0.417 |
| HDL cholesterol | 52.5 (16.4) | 48.8 (15.6) | 52.8 (16.4) | 0.095 |
Mean (SD) shown for continuous variables and n, % shown for binary variables. Student t-test used to test intergroup differences (primary outcome vs. no primary outcome) for continuous variables and the chi-squared test for binary variables.
The Kaplan-Meier curve in Figure 1 shows the increased risk of the primary outcome in the higher quartiles of baseline WMHv (log-rank, p=0.015). In the adjusted Cox models, log-transformed WMHv was associated with both the primary and secondary outcomes (Table 2). For the primary outcome, the hazard ratio comparing the highest quartile of WMHv to the lowest was 3.21 (95% CI 1.27–8.13). However, for the secondary outcome of stroke, the direction of the association for the top quartile was the same, but was not significant (HR 6.51, 95% CI 0.70–60.3).
Figure 1.
Kaplan-Meier curve for the quartiles of white matter hyperintensity volume, fit to the primary outcome (composite of stroke, myocardial infarction, acute coronary syndrome, decompensated congestive heart failure, or death from cardiovascular disease).
Table 2.
Cox proportional hazards model fit to the outcomes with quartiles of baseline white matter hyperintensity volume as the primary predictor.
| Outcome | Predictor | Hazard ratio* | 95% CI | P value |
|---|---|---|---|---|
| Composite of stroke, MI, ACS, decompensated CHF, or death from CVD | WMHv continuous (log-transformed) | 1.44 | 1.15–1.80 | 0.001 |
| Quartiles of WMHv | ||||
| First quartile | ref | ref | ||
| Second Quartile | 1.62 | 0.58–4.50 | 0.008 | |
| Third Quartile | 1.97 | 0.75–5.19 | ||
| Fourth Quartile | 3.21 | 1.27–8.13 | ||
| Incident stroke | WMHv continuous (log-transformed) | 1.84 | 1.09–3.10 | 0.023 |
| Quartiles of WMHv | 0.034 | |||
| First quartile | ref | ref | ||
| Second Quartile | 1.07 | 0.07–17.14 | ||
| Third Quartile | 5.15 | 0.57–46.41 | ||
| Fourth Quartile | 6.51 | 0.70–60.28 |
Composite outcome was adjusted for patient age, race, sex, history of heart attack, history of congestive heart failure, current cigarette smoking, HDL cholesterol, and SPRINT randomization arm. Stroke was adjusted for patient age and diabetes.
To allow consideration of the effect of the SPRINT randomization arm, which violated the proportional hazards assumption in the main Cox model, we fit the adjusted Cox model to the primary outcome after stratification by the randomization arm. The hazard ratio of log-transformed WMHv for patients in the standard treatment arm (n=336) was 1.56 (95% CI 1.15–2.12) and for patients in the intensive treatment arm (n=381) was 1.34 (95% CI 0.95–1.88). The interaction term of treatment arm*log-transformed WMHv was not significant (p=0.867), although this analysis was likely underpowered.
Discussion
We found an association between baseline WMH volume and future risk of cardiovascular disease and stroke in the SPRINT-MIND trial. While the association between WMH volume and future stroke has been described in prior studies,5,7 the association with a composite cardiovascular outcome has not been previously reported to our knowledge.8 The risk factors for WMH include the shared cardiovascular risk factors of hypertension, hyperlipidemia, smoking, and diabetes. Furthermore, previous neurohistopathological studies have shown that WMH is associated with atherosclerosis and impaired cerebrovascular reactivity.9,10 Thus, the mechanistic causes and medical sequelae of WMH have biological plausibility as predisposing to cardiovascular disease.
Analyses of the SPRINT and Action to Control Cardiovascular Risk in Diabetes (ACCORD) trials recently showed that intensive blood pressure control reduced progression of WMH.6,11 Although the impact of WMH on CVD risk appeared similar for those with and without intensive BP control, the elevated risk in the subgroup with intensive BP control was no longer statistically significant (HR 1.34, 95% CI 0.95–1.88 for log-transformed WMHv), most likely due to small numbers. Adequately powered clinical trials in patients with WMH are needed, to investigate if intensive blood pressure control reduces cardiovascular, cerebrovascular and cognitive sequelae, and the mechanism that mediates the risk reduction. There remains significant uncertainty regarding the optimal medical treatment for this patient population.14
Our study is unique in that we used the SPRINT-MIND data to investigate the association between WMH burden and subsequent cardiovascular events in the setting of the SPRINT trial, which had excellent SBP control with an intensive reduction arm targeting <120 mm Hg. Although this is a secondary analysis of a subgroup in a randomized trial, which introduces obvious limitations, we view the results as hypothesis generating regarding the potential for benefit from intensive blood pressure lowering in higher risk patients with a larger WMH burden at baseline.
Conclusion
Baseline WMH burden in the SPRINT MIND study was associated with future cardiovascular disease, with higher volumes resulting in higher risk. Trials are needed to determine if intensive blood pressure control can reduce cardiovascular events in patients with a preexisting WMH burden, who are at increased risk and have not been the subject of dedicated prevention trials.
Acknowledgements
This article was prepared using SPRINT Research Materials obtained from the NHLBI Biologic Specimen and Data Repository Information Coordinating Center and does not necessarily reflect the opinions or views of SPRINT, SPRINT MIND or the NHLBI.
Funding
Dr. de Havenon is supported by NIH-NINDS K23NS105924. Dr. Turan receives support from NIH-NINDS (U24NS107232 & U01NS080168) and NCATS (UL1 TR001450). Dr. Rost is in part supported by NIH-NINDS (R01NS082285, R01NS086905, U19NS115388). Dr. Prabhakaran receives NIH support (R01NS084288, AHRQ R18HS025359, AHRQ R18HS027264, U24NS10723). Dr. Gottesman receives NIH support (R01 AG040282, RF1 AG040745, K24 AG052573, U01 HL096812, U19NS115388). Dr. Yeatts receives funding from the NIH/NINDS.
Disclosures
Dr. de Havenon has received funding from AMAG and Regeneron pharmaceuticals for investigator-initiated research. Dr. Turan has received compensation from Pfizer for serving on a blinded events adjudication committee for a clinical trial of a diabetes drug. Dr. Rost has nothing to disclose. Dr. Gottesman was an Associate Editor for the journal Neurology.
Footnotes
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