Association between blood pressure variability and outcomes after endovascular thrombectomy for acute ischemic stroke: An individual patient data meta-analysis

Abstract

Introduction:

Data on the association between blood pressure variability (BPV) after endovascular thrombectomy (EVT) for acute ischemic stroke (AIS) and outcomes are limited. We sought to identify whether BPV within the first 24 hours post EVT was associated with key stroke outcomes.

Methods:

We combined individual patient-data from five studies among AIS-patients who underwent EVT, that provided individual BP measurements after the end of the procedure. BPV was estimated as either systolic-BP (SBP) standard deviation (SD) or coefficient of variation (CV) over 24 h post-EVT. We used a logistic mixed-effects model to estimate the association [expressed as adjusted odds ratios (aOR)] between tertiles of BPV and outcomes of 90-day mortality, 90-day death or disability [modified Rankin Scale-score (mRS) > 2], 90-day functional impairment (⩾1-point increase across all mRS-scores), and symptomatic intracranial hemorrhage (sICH), adjusting for age, sex, stroke severity, co-morbidities, pretreatment with intravenous thrombolysis, successful recanalization, and mean SBP and diastolic-BP levels within the first 24 hours post EVT.

Results:

There were 2640 AIS-patients included in the analysis. The highest tertile of SBP-SD was associated with higher 90-day mortality (aOR:1.44;95% CI:1.08–1.92), 90-day death or disability (aOR:1.49;95% CI:1.18–1.89), and 90-day functional impairment (adjusted common OR:1.42;95% CI:1.18–1.72), but not with sICH (aOR:1.22;95% CI:0.76–1.98). Similarly, the highest tertile of SBP-CV was associated with higher 90-day mortality (aOR:1.33;95% CI:1.01–1.74), 90-day death or disability (aOR:1.50;95% CI:1.19–1.89), and 90-day functional impairment (adjusted common OR:1.38;95% CI:1.15–1.65), but not with sICH (aOR:1.33;95% CI:0.83–2.14).

Conclusions:

BPV after EVT appears to be associated with higher mortality and disability, independently of mean BP levels within the first 24 h post EVT. BPV in the first 24 h may be a novel target to improve outcomes after EVT for AIS.

Graphical abstract.

Background

Blood pressure (BP) after endovascular treatment (EVT) for acute ischemic stroke (AIS) attributed to large vessel occlusion (LVO) has been considered an independent predictor of stroke outcomes, with higher levels of systolic blood pressure (SBP) being associated with increased final infarct volume, increased likelihood of symptomatic intracranial hemorrhage (sICH), higher odds of 3-month mortality, and lower likelihood of 3-month favorable functional outcomes.^1–5 Conversely, intraprocedural BP reduction has been related to larger infarct volumes and adverse clinical outcomes, with even a 10% BP drop from baseline being associated with worse functional outcomes.^6,7 Recently completed randomized-controlled clinical trials (RCTs),^8–11 investigating the safety and efficacy of a stricter BP control among EVT-treated patients compared to standard of care have demonstrated that intensive BP lowering did not reduce the odds of sICH and was associated with adverse 3-month clinical outcomes.

BP variability (BPV) may act as an additional, independent component of BP dysregulation, in addition to hypertension and hypotension.^12,13 Systolic BPV has been associated with adverse outcomes in patients treated either conservatively ¹⁴ or with acute reperfusion therapies. ¹⁵ Several studies investigating the association of systolic BPV and clinical outcomes post EVT have been published, with a recent study-level meta-analysis demonstrating that systolic BPV was associated with poor functional outcomes at 3 months, while it was not related to sICH or 3-month mortality. ¹⁶ However, this meta-analysis was limited by the fact that the included studies inconsistently reported different measures of systolic BPV (with the exception of the standard deviation (SD) that was consistently measured), and evaluation for baseline characteristics (including SBP levels) was not pursued.

We sought to further explore and provide high-quality data regarding the association of systolic BPV with clinical outcomes post EVT, by capitalizing on previously collected data of a large individual patient-data meta-analysis. ⁴

Methods

We used previously collected data of an individual patient data meta-analysis, that included seven published studies consisting of 5874 patients and investigated the association among mean SBP during the first 24 h post-EVT and clinical outcomes. ⁴ For the present analysis, we maintained patient data, for which at least four hourly SBP measurements were available. SBP SD and SBP coefficient of variation (CV) within the first 24 h post EVT were calculated as follows: SBP SD = $\sqrt{\frac{1}{(n-1)}\sum _{(i=1)}^{(n)}{\left(SBPi-SBPmean\right)}^2}$ and SBP CV = $\frac{SDSBP}{SBPmean}*100$ . ¹⁷ Patients were divided into equally distributed tertiles stratified for SBP SD and SBP CV.

Individual baseline characteristics were collected, including age, sex, stroke severity, co-morbidities, mode of anesthesia (general anesthesia vs conscious sedation), successful recanalization [defined as Thrombolysis in Cerebral Infarction (TICI) 2b or higher], intravenous thrombolysis (IVT), and mean SBP and mean diastolic blood pressure (DBP) as recorded within the first 24 h post EVT. The following outcomes of interest were evaluated: 90-day mortality, 90-day death or disability [as defined by modified Rankin Scale score (mRS) > 2], 90-day functional impairment (⩾1-point increase across all mRS-scores), and sICH. The definitions of these safety and efficacy outcomes have been previously described in detail. ⁴

Statistical analysis

Categorical variables were presented as number of patients with corresponding percentages, while continuous variables with their means and SDs (when normally distributed) or medians and interquartile ranges (IQR; for skewed distribution). Statistical comparisons between tertiles were performed for categorical variables using the χ² test and for continuous variables by the one-way ANOVA or the Kruskal-Wallis tests, accordingly. To account for clustering, a logistic mixed-effects model after adjustment for baseline variables (demographics, comorbidities, stroke severity, IVT pretreatment, successful recanalization, mean SBP and DBP within the first 24 h post-procedure) was performed to estimate the associations between tertiles of BPV and the outcomes of interest and was expressed as adjusted odds ratios (aOR). Statistical significance was achieved if the p-value was <0.05. All statistical analyses were conducted with the Stata Statistical Software Release 17.0 (College Station, TX, StataCorp LP).

Results

A total of 2640 patient data from five observational studies, for which at least four hourly SBP measurements were available, were identified.^1,18–21 Included studies along with their respective BP measurement protocols and the patient data provided are presented in eTable 1. Included patients had a mean age of 69.2 ± 13.6 years and 50.1% were women. Previous medical history is presented in Table 1. Importantly, more than two-thirds of the patients had arterial hypertension. Mean baseline National Institutes of Health Stroke Scale (NIHSS) was 15.2 ± 6.5 points. Pretreatment with intravenous thrombolysis (IVT) was administered in 84.9% of the study population, the majority of the patients (72.2%) received conscious sedation as opposed to general anesthesia, and 79.6% of the patients achieved successful recanalization. Mean SBP and DBP within the first 24 hours post EVT were 131.5 ± 16.8 mmHg and 70.1 ± 10.9 mmHg, respectively, while SBP SD and SBP CV were 13.6 ± 6.3 mmHg and 10.3 ± 4.6%, respectively. Baseline characteristics and BP variables are presented for the total population and the different tertiles in Table 1. At 90 days, 18.4% of the patients had died, and 56.8% were dead or disabled. The median mRS score at 90 days was 3 (IQR: 1–5). Finally, 5% of the patients were complicated with sICH.

Table 1.

Baseline and outcome variables among the total included population and among the different tertiles.

	Total Population	SBP SD				SBP CV
		Tertile 1	Tertile 2	Tertile 3	p value	Tertile 1	Tertile 2	Tertile 3	p value
Number	2640	882	880	878	-	881	879	880	-
Baseline variables
Age; years; mean (SD)	69.2 (13.6)	66.0 (14.9)	69.1 (13.0)	72.5 (12.1)	<0.001	66.9 (14.8)	68.9 (13.1)	71.8 (12.4)	<0.001
Female sex; n (%)	1323 (50.1)	413 (46.8)	435 (49.4)	475 (54.1)	0.008	424 (48.1)	427 (48.6)	472 (53.6)	0.037
Baseline NIHSS; mean (SD)	15.2 (6.5)	14.9 (6.5)	15.2 (6.4)	15.4 (6.5)	0.300	15.2 (6.6)	15.0 (6.3)	15.3 (6.5)	0.640
Atrial fibrillation; n (%)	810 (30.8)	234 (26.6)	280 (32.0)	296 (33.9)	0.003	239 (27.2)	277 (31.7)	294 (33.6)	0.012
Diabetes; n (%)	572 (21.7)	155 (17.6)	193 (22.0)	224 (15.6)	<0.001	173 (19.7)	185 (21.1)	214 (24.5)	0.044
Hypertension; n (%)	1776 (67.4)	505 (57.3)	599 (68.2)	672 (76.7)	<0.001	532 (60.4)	593 (67.5)	651 (74.2)	<0.001
Smoking; n (%)	472 (18.3)	162 (18.7)	168 (19.6)	142 (16.7)	0.290	158 (18.4)	172 (20.0)	142 (16.6)	0.180
IVT pretreatment; n (%)	2234 (84.9)	763 (86.8)	710 (81.0)	761 (86.9)	<0.001	774 (88.1)	707 (80.8)	753 (85.8)	<0.001
Successful recanalization; n (%)	2100 (79.6)	716 (81.3)	711 (80.8)	673 (76.7)	0.035	695 (79.0)	714 (81.2)	691 (78.6)	0.340
Mean SBP; mmHg; mean (SD)	131.5 (18.8)	126.0 (16.8)	131.7 (16.0)	136.8 (15.9)	<0.001	131.5 (17.9)	130.9 (16.5)	132.1 (16)	0.340
Mean DBP; mmHg; mean (SD)	70.1 (10.9)	69.6 (10.8)	70.6 (11.0)	70.1 (11.1)	0.160	71.7 (11.1)	70.0 (10.7)	70.8 (10.8)	0.130
SBP SD; mmHg; mean (SD)	13.6 (6.3)	7.4 (2.1)	12.7 (1.4)	20.6 (5.0)	<0.001	7.7 (2.4)	12.8 (2.1)	20.3 (5.3)	<0.001
SBP CV; %; mean (SD)	10.3 (4.6)	6.0 (1.8)	9.8 (1.5)	15.2 (3.8)	<0.001	5.8 (1.6)	12.8 (2.1)	20.3 (5.3)	<0.001
Outcome variables
90-day mortality; n (%)	465 (18.4)	122 (14.4)	142 (16.8)	201 (24.1)	<0.001	145 (17.1)	127 (15.1)	193 (23.1)	<0.001
90-day death or disability; n (%)	1407 (56.8)	408 (49.0)	473 (56.9)	526 (64.8)	<0.001	427 (51.6)	468 (56.4)	512 (62.6)	<0.001
90-day mRS; median (IQR)	3 (1–5)	2 (1–4)	3 (1–5)	4 (2–5)	<0.001	3 (1–4)	3 (1–4)	4 (1–5)	<0.001
sICH; n (%)	130 (5.0)	35 (4.0)	44 (5.1)	51 (5.9)	0.180	34 (3.9)	48 (5.5)	48 (5.6)	0.490

BP: blood pressure; SD: standard deviation; CV: coefficient of variation; mRS: modified Rankin Scale; sICH: symptomatic intracranial hemorrhage; NIHSS: National Institutes of Health Stroke Scale; SBP: systolic blood pressure; DBP: diastolic blood pressure; IVT: intravenous thrombolysis; IQR: interquartile range.

Patients in the highest SBP SD tertile were older and more often women, had more often atrial fibrillation, diabetes and arterial hypertension, achieved less frequently successful recanalization, and presented significantly higher values of mean SBP within the first 24 h post EVT (Table 1). The rates of death, and death or disability at 90 days (Figure 1) were higher among the patients in the highest tertile, while sICH was similar among the SBP SD tertiles.

Figure 1.

Distribution of mRS-scores at 90 days among different SBP SD tertiles.

mRS: modified Rankin Scale; SBP SD: systolic blood pressure standard deviation.

After adjustment for all baseline variables, SBP SD was independently associated with higher odds of 90-day mortality (aOR: 1.44; 95% CI: 1.08–1.92; p = 0.012), 90-day death or disability (aOR: 1.49; 95% CI: 1.18–1.89; p = 0.001), and 90-day functional impairment (adjusted common OR for ⩾1-point increase across all mRS scores: 1.42; 95% CI: 1.18–1.72; p < 0.001), but not with sICH (aOR: 1.22; 95% CI: 0.76–1.98; p = 0.414) (Figure 2(a)). Adjusted associations of SBP SD with all outcomes are summarized in Table 2.

Figure 2.

Predicted probability of 90-day mortality, 90-day death or disability, and sICH among different tertiles of SBP SD (Panel (a)) and SBP CV (Panel (b)).

sICH: symptomatic intracranial hemorrhage; SBP SD: systolic blood pressure standard deviation; SBP CV: systolic blood pressure coefficient of variation.

Table 2.

Summary of adjusted associations of SBP SD and SBP CV with the outcomes of interest.

	SBP SD (highest vs. lowest tertile)			SBP CV (highest vs. lowest tertile)
	aOR	95% CI	p value	aOR	95% CI	p value
90-day mortality	1.44	1.08–1.92	0.012	1.33	1.01–1.74	0.043
90-day death or disability	1.49	1.18–1.89	0.001	1.50	1.19–1.89	0.001
90-day mRS	1.42*	1.18–1.72	<0.001	1.38 a	1.15–1.65	0.001
sICH	1.22	0.76–1.98	0.414	1.33	0.83–2.14	0.233

Adjusted for: age, sex, baseline NIHSS, atrial fibrillation, diabetes, hypertension, smoking, successful recanalization, mean SBP, mean DBP, and IVT pretreatment.

BP: blood pressure; SD: standard deviation; CV: coefficient of variation; mRS: modified Rankin Scale; sICH: symptomatic intracranial hemorrhage; aOR: adjusted odds ratio; CI: confidence interval; NIHSS: National Institutes of Health Stroke Scale; SBP: systolic blood pressure; DBP: diastolic blood pressure; IVT: intravenous thrombolysis.

^aAdjusted common odds ratio.

Patients in the highest SBP CV tertile were older and more often women, and had more often atrial fibrillation, diabetes and arterial hypertension. The rates of death, and death or disability at 90 days (Figure 3), were higher among the patients in the highest tertile, while sICH was similar among the SBP CV tertiles.

Figure 3.

Distribution of mRS-scores at 90 days among different SBP CV tertiles.

mRS: modified Rankin Scale; SBP CV: systolic blood pressure coefficient of variation.

After adjustment for all baseline variables, SBP CV was independently associated with higher odds of 90-day mortality (aOR: 1.33; 95% CI: 1.01–1.74; p = 0.043), 90-day death or disability (aOR: 1.50; 95% CI: 1.19–1.89; p = 0.001), and 90-day functional impairment (adjusted common OR for ⩾1-point increase across all mRS scores: 1.38; 95% CI: 1.15–1.65; p = 0.001), but not with sICH (aOR: 1.33; 95% CI: 0.83–2.14; p = 0.233) (Figure 2(b)). Adjusted associations of SBP CV with all the outcomes are summarized in Table 2.

To assess for potential overadjustment bias, sensitivity analyses were performed for all associations of both SBP SD and SBP CV with outcomes of interest by excluding mean DBP from the multivariate models, providing similar results to the main analysis.

Discussion

The present individual patient-data meta-analysis of 2640 patients has shown that both SBP SD and SBP CV, as measures of BPV within the first 24 h post-EVT for AIS, were independently associated with 90-day mortality and disability, while there was no correlation with sICH. More specifically, patients within the highest tertile of SBP SD and SBP CV had significantly higher odds of 90-day mortality, 90-day death or disability, and 90-day functional impairment compared to the patients of the lowest tertile. Importantly, the above associations persisted after adjustments for baseline characteristics, which included the mean BP levels as recorded within the first 24 h post EVT.

In our study, increased BPV was more pronounced among older patients, supporting the previously reported linear correlation between BPV and increasing age.^22,23 It has been suggested that several factors that are related to aging, such as hemodynamic instability, arterial stiffness, endothelial dysfunction, and subclinical inflammation (“inflammaging”), may act as the pathophysiological background of increased BPV as well. ²⁴ Additionally, patients within the highest SBP-SD and SBP-CV tertiles were more often women compared to the lower tertiles. Indeed, large cohorts, including patients with and without hypertension, have previously reported that women have higher BPV compared to men.^25,26 Several factors may account for this gender-associated disparities in BPV, including hormonal fluctuations, different stress response and differences in the endothelial function and microvascular reactivity.^27,28 Furthermore, in our analysis, patients included in the third BPV tertile had a higher prevalence of comorbid hypertension, atrial fibrillation, and diabetes compared to the patients of the lowest or medium BPV tertile. The association of BPV with vascular comorbidities has been previously reported in the literature, but it should be underscored that BPV is an independent predictor of adverse cardiovascular events not only among individuals with hypertension and other comorbidities, but also in those without. ²⁹ Finally, lower recanalization rate was evident among patients in the highest SBP SD tertile. This finding is consistent with a previous study that showed that BPV increased with and partly due to lower recanalization status. ³⁰ Whether successful recanalization may modulate the effect of BPVon outcomes is conflicting ^21,31,32; yet, in our study BPV was independently associated with adverse clinical outcomes, regardless of recanalization status.

Mean SBP levels within the first 24 hours post EVT were higher among patients of the highest SBP SD tertile compared to the low and medium tertiles. Mean SBP levels have been previously associated with adverse clinical outcomes post-EVT, including higher odds of 3-month mortality, worse 3-month functional outcomes, early neurologic deterioration, but also sICH.^4,5 In our multivariate analysis, after adjusting for potential confounders that included mean SBP levels within the first 24 h post EVT, systolic BPV remained an independent predictor of 90-day mortality, 90-day death or disability and 90-day neurological impairment, while the association between mean SBP levels and 90-day mortality was neutralized. In the majority of the observational studies investigating the association of BPV with outcomes post-EVT, adjusted associations controlling for SBP levels have not been conducted at all,^{3,21,30,33,34} or they included the initial SBP levels (at admission) as the sole BP covariate.^1,20,35,36 The study of Mistry et al. has included the mean SBP levels in the adjusted models and showed that systolic BPV could predict adverse clinical outcomes post-EVT independently from mean SBP, similar to our results. ¹⁷ Unfortunately, this study, that could potentially further strengthen our results, was not included in the present analysis, since no serial BP measurements were available.^4,17

Based on these results, trials assessing the optimal BP management post-EVT should integrate in their design the potential associations of BPV with clinical outcomes, that seem to be independent from the mean BP levels.^37,38 Most of the RCTs, that have been concluded so far, have failed to show that stricter BP control may lead to better clinical outcomes compared to standard of care.^8–11,39 On the contrary, a number of those have raised concerns, since higher odds of poor functional outcomes were noticed in the intensive arm.^9,10 Yet, these RCTs had structured the BP control based on SBP lowering, without considering BPV. Regarding future study designs incorporating the target of BPV, the question arises how to select patients of high BPV-risk and how to manage them. Several clinical prediction models of BPV have been proposed that offer only a limited prognostic ability, ¹⁷ and, therefore, further optimization is warranted, with the potential to be supported by artificial intelligence and machine learning.^40,41 Rapid assessment of BPV by spectral analysis has also emerged as a promising method to promptly identify these patients, without requiring long BP recordings. ⁴² Furthermore, evidence is scarce regarding BPV management as well. Radiological measures, including the assessment of recanalization status post-EVT, but also by evaluating dynamic brain autoregulation in real time though near-infrared spectroscopy-derived tissue oxygenation ⁴³ or transcranial doppler ⁴⁴ may also be used to guide BP management within targeted and tighter ranges, thus avoiding increased systolic BPV. Regarding antihypertensive treatment, calcium channel blockers and non-loop diuretic drugs either alone or as additives to other antihypertensive agents have been shown to significantly, albeit modestly, reduce BPV, whereas b-blockers have been associated with elevated BPV.^45,46 Apart from antihypertensive agents, atorvastatin has been previously associated with BPV reduction among hypertensive patients. ⁴⁷ However, these results are based on studies that have been conducted in the outpatient setting, and not during acute stroke management. Yet, it would be of interest to further evaluate for the potential effects of statins and antihypertensive agents on BPV, either alone or in synergy, in future studies conducted in the acute stroke setting. In any case, it would be reasonable to avoid any iatrogenic BPV increase, by limiting the use of very potent, short-acting antihypertensive drugs, and promote adherence to previous antihypertensive medications, when possible.^37,48 Similarly, hypotension should be avoided, while volume restoration in depleted patients may be employed, further guided by BPV indices.

Interestingly, although BPV was associated with 90-day mortality and disability, there was no correlation between the highest BPV tertile and sICH. This finding is consistent in the majority of the previous published studies in this field^3,20 and has been further confirmed in a recent study-level meta-analysis. ¹⁶ In another study, it was shown that, although BP SD and BP CV could not predict sICH, the time rate (TR) of BPV was indeed associated with sICH. ³⁴ TR is a BPV index capable of determining not only the grade of BPV, but also the speed of BP fluctuations, a rapid surge of which could lead to further disruption of the blood-brain barrier and potentially sICH. ³⁴ However, mean SBP was again not included as a covariate in the adjustment models of this study, rendering the independent association of TR with sICH inconclusive. Unfortunately, since TR was not available in our study, we could not further examine this correlation. The independent association of BPV with clinical outcomes, but not with sICH, could be partly explained by the possibility of sustained hypoperfusion despite EVT (leading in turn to reactive BP elevation and variability),^49,50 rather than the reperfusion injury and sICH per se. This hypothesis argues against the intensive BP lowering to avoid the latter and to improve clinical outcomes among EVT-treated patients.

Despite the strengths of our study, being the first individual patient-data meta-analysis investigating the effect of systolic BPV on clinical outcomes post-EVT, there are some limitations that need to be considered. First, our work was based on observational data, bearing inherent limitations in terms of their susceptibility to bias and confounding. Yet, to ensure data quality regarding BPV evaluation, we used patient data for which at least four hourly SBP measurements were available within the first 24 h post-EVT. Furthermore, all of our associations were examined and presented after adjustments for baseline variables, including the mean SBP levels. However, the mode of anesthesia selected for the EVT procedure was available in only four of the included studies,^1,18,19,21 resulting in a significant proportion (15%) of missing data for this potential confounder, that precluded its inclusion in our multivariate analyses. Additionally, data regarding the baseline ischemic core volume as estimated by either the Alberta stroke program early CT score or volumetric methods were not available in the dataset and could also not be included in the analyses. Second, increased chronic BPV among hypertensive patients in the outpatient setting has been previously correlated with higher risk of cardiovascular events and death, independently from baseline characteristics and previous risk factors. ⁵¹ It is possible that this association may expand and partly interfere with the outcomes after EVT in the post-stroke setting as well. Although our analyses have been adjusted for several baseline characteristics and previous comorbidities, the status of BPV prior to stroke was not known and, hence, was not included in the analysis. Importantly, no causal relationship between BPV and clinical outcomes can be inferred based on our results. Though, considering the neutral or negative results of the recent RCTs on BP management post-EVT, it would be reasonable to hypothesize that additional, novel BP targets are needed than the simple SBP lowering. BPV could be tested as such a novel BP target in future RCTs, designed to select and manage patients in high risk for increased BPV. Third, all presented associations were related to systolic BPV and should be interpreted in this context, while indices of diastolic BPV were not evaluated. Although diastolic BPV may have a role regarding cardiovascular outcomes in the outpatient clinic, ⁴⁸ previous studies conducted in the acute stroke setting and, specifically, following endovascular thrombectomy have not disclosed any associations between different indices of diastolic BPV and post-stroke outcomes.^3,17 Finally, information regarding the administration of antihypertensive treatments (that could have influenced BPV) was not available in our dataset and, thus, could not be evaluated.

Conclusions

In conclusion, BPV in the first 24 h after EVT for AIS appears to be associated with higher mortality and disability at 90 days, independently of mean SBP levels. Therefore, BPV may be a novel target to guide optimal BP management and improve outcomes after EVT in future RCTs.