Abstract
Introduction
To assess the association between 24 h blood pressure variability (BPV) on functional outcome and treatment effect of intravenous alteplase in acute ischaemic stroke.
Patients and methods
In all patients with acute ischaemic stroke of unknown onset randomised in the WAKE-UP (Efficacy and Safety of magnetic resonance imaging [MRI]-based Thrombolysis in Wake-Up Stroke) trial, blood pressure (BP) was measured before randomisation and after initiation of treatment at regular intervals up to 24 hours. Individual BPV was measured by coefficient of variation (CV) of all BP values. Primary outcome measure was favourable outcome defined by a modified Rankin Scale (mRS) score 0 or 1 at 90 days after stroke.
Results
BP measurements were available for 498 of 503 patients randomised (177 women [35.5%], mean age [SD] of 65.2 [11.5] years). Systolic BPV was not associated with the treatment effect of thrombolysis (test for interaction, p = 0.46). The adjusted odds ratio (aOR) for favourable outcome with alteplase, adjusted for age, stroke severity and baseline BP on admission, did not show an association across the quintiles of increasing systolic BPV with an aOR 1.89 (95% confidence interval [CI], 0.76–4.70) in the lowest quintile to aOR 1.05 (95% CI, 0.43–2.56) in the highest quintile. Higher mean systolic BP was associated with a smaller treatment effect of thrombolysis with a significant interaction (p = 0.033). The aOR for favourable outcome with alteplase decreased with quintiles of increasing mean systolic BP from aOR 3.16 (95% CI, 1.26–7.93) in the lowest quintile to aOR 0.84 (95% CI, 0.34–2.10) in in the highest quintile.
Conclusions
There was a significant interaction between mean systolic BP and treatment effect of thrombolysis with higher mean systolic BP being associated with poorer outcome. BPV was not associated with outcome after thrombolysis.
ClinicalTrials.gov identifier NCT01525290.
Keywords: Blood pressure, ischaemic stroke, thrombolysis, treatment effect, WAKE-UP
Introduction
Blood pressure (BP) is an important prognostic factor in acute ischaemic stroke patients.1 Up to 80% of patients with an acute ischaemic stroke present with systolic BP in excess of 140 mmHg on hospital arrival,2,3 and elevated systolic and/or diastolic BP is commonly observed after an acute ischaemic stroke even in previously normotensive patients.4
A U-shaped relationship between systolic BP on hospital arrival and functional outcome has been observed in acute ischaemic stroke, such that both high and low systolic BP have been associated with poor outcome.3 In stroke patients treated with intravenous thrombolysis, elevated pretreatment systolic BP was associated with a lower likelihood of benefit from thrombolysis.5 While BP on hospital arrival is a prognostic factor that cannot be influenced by treating physicians, intervention to modify BP can be applied over the first hours after hospitalisation. Clinical trials and registries report that not only increased systolic BP on hospital arrival, but also BP up to 24 hours after thrombolysis was associated with neurological impairment, poor functional outcome, mortality, and increased risk of haemorrhagic transformation in stroke patients.6–8
In addition, BP fluctuation over time was suggested to impact stroke outcome and, therefore, be of prognostic value. Usually measured as standard deviation or successive variation, a higher range of within-patient blood pressure variability (BPV) was reported to be associated with higher rates of poor functional outcome, mortality, haemorrhagic transformation, and symptomatic intracerebral haemorrhage (SICH) in stroke patients after thrombolysis.7,9,10 Whether BPV also modifies the treatment effect of thrombolysis, has not yet been studied.
The aim of the present study was to investigate the relationship between BPV within the first 24 hours and treatment effect of intravenous thrombolysis with alteplase in the WAKE-UP trial (Efficacy and Safety of magnetic resonance imaging-based Thrombolysis in Wake-Up Stroke).
Patients and methods
Study design
For this secondary analysis, individual BP values of all patients randomised in the WAKE-UP trial were studied. WAKE-UP was a multicentre-randomised, double blind, placebo-controlled trial to study magnetic resonance imaging (MRI)-based intravenous thrombolysis in acute stroke patients with unknown time of symptom onset (ClinicalTrials.gov identifier NCT01525290). The mandatory imaging criterion for randomisation to treatment with alteplase or placebo was a mismatch between an acute ischaemic lesion on diffusion weighted imaging (DWI) with no corresponding marked parenchymal hyperintensity on fluid-attenuated inversion recovery (FLAIR).11 The detailed trial protocol and the results of the original paper have been published previously.11 Patients or their legal representatives provided written informed consent according to national and local regulations, with an exception from explicit informed consent in emergency circumstances in some countries. The trial was approved for each study site by the competent authorities and the corresponding ethics committee. In line with licensing criteria for intravenous alteplase, patients presenting with severe uncontrolled hypertension before study entry (systolic BP >185 mmHg or diastolic BP >110 mmHg, or requiring aggressive medication to maintain blood pressure within these limits) were not considered eligible.
Medical history, including vascular risk factors, and medication history were recorded. Neurological deficits on hospital arrival were assessed using the National Institutes of Health Stroke Scale (NIHSS). The primary outcome measure was for this analysis, as for the WAKE-UP trial, favourable outcome, defined by a modified Rankin scale (mRS) score 0–1 at 90 days after stroke, indicating no or clinically not significant disability. Safety outcome measures were the incidence of any SICH according to the SITS-MOST criteria and radiologically assessed incidence of parenchymal haemorrhage type 2 (PH-2) according to the Heidelberg Bleeding Classification on follow-up MRI 22–36 hours after randomisation and treatment.12,13
Blood pressure
Blood pressure was measured once on hospital arrival (screening before randomisation), and after administration of alteplase or placebo every 15 minutes during the first hour, and thereafter at 1-hour intervals up to 24 hours. In total, up to 28 BP measurements within the first 24 hours were obtained for each patient. From individual BP profiles, within-subject mean systolic and diastolic BP and BP variability (BPV), measured by coefficient of variation (CV) of all BP readings during the first 24 hours, were calculated.
Statistical analysis
Baseline clinical parameters were described by mean, median and interquartile ranges for continuous variables and with frequency and percentages for categorical variables. Values of mean systolic and diastolic intra-patient BP and BPV as measured by CV were divided into quintiles. Quintiles were used to discretise the distribution, while keeping enough patients in each quintile to preserve enough precision of the estimates. Baseline clinical data were compared between groups of quintiles of mean BP and BPV using the Cochran Mantel-Haenszel chi-square test for categorical variables, and the Kruskal-Wallis test for continuous variables. Relationship between quintiles of BPV and treatment effect was analysed on the primary efficacy endpoint of the WAKE-UP trial (favourable outcome at 90 days after stroke as defined by mRS score 0–1) using an unconditional logistic regression analysis, fitted to estimate the odds ratio and its 95% CI in each quintile. In addition, a logistic regression model was applied based on a continuous linear trend of BPV. We tested for a significant interaction between mean BP and BPV and treatment (alteplase or placebo). All models were adjusted for baseline NIHSS, age, and baseline blood pressure measured on hospital arrival. Odds ratios (OR) and 95% Wald confidence intervals were calculated. Statistical analyses were performed with SAS version 9.4 (SAS Institute).
Results
Patient characteristics
Of 503 patients randomised in WAKE-UP, 498 patients had available BP recordings within the first 24 hours after hospital arrival. Of these, 177 (35.5%) patients were women. Mean age was 65.2 (standard deviation [SD], 11.5) years. Median NIHSS on hospital arrival was 6 (interquartile range [IQR] 4–9). Median systolic BP on hospital arrival was 154 mmHg (IQR, 139–169 mmHg). Median diastolic BP was 83 mmHg (IQR, 74–92 mmHg). Systolic BP ≥140 mmHg and/or diastolic BP ≥90 mmHg on hospital arrival was detected in 383 (76.9%) patients, while 103 (20.7%) patients had systolic BP 90–140 mmHg and/or diastolic BP 60–90 mmHg, and 12 (2.4%) patients had systolic BP <90 mmHg and/or diastolic BP <60 mmHg). 263 (52.8%) patients had a medical history of arterial hypertension, and 243 (48.8%) patients were on antihypertensive medication according to their medical history.
Association of systolic blood pressure variability with outcome and treatment effect
To elucidate whether indices of systolic BPV after thrombolysis were associated with functional outcome, patients were divided into quintiles. Higher systolic BPV was associated with higher age (p = 0.015), history of hypertension (p = 0.023), and hypercholesterolemia (p = 0.02). An overview of baseline characteristics according to the quintiles of systolic BPV is presented in Table 1 of the supplementary material. Favourable outcome (mRS score 0–1) at 90 days after stroke was observed in 232 of 488 patients (47.5%) with available information on all covariates used in the models. In continuous analysis systolic BPV did not interact with the treatment effect of thrombolysis (interaction systolic BPV * treatment, p = 0.46, see Figure 1(b)). The adjusted odds ratio (aOR) for favourable outcome, adjusted for age, stroke severity and baseline BP on admission, did not show a specific distribution across the quintiles of increasing systolic BPV with an aOR 1.89 (95% confidence interval [CI], 0.76–4.70) in the lowest quintile to aOR 1.05 (95% CI, 0.43–2.56) in the highest quintile.
Table 1.
Clinical characteristics according to the quintiles of mean systolic blood pressure during the first 24 hours.
| Variable | Q1 | Q2 | Q3 | Q4 | Q5 |
|---|---|---|---|---|---|
| 97.3–123.9 mmHg | 124.1–134.5 mmHg | 134.5–143.8 mmHg | 143.8–154.1 mmHg | 154.2-184.7 mmHg | |
| Age, mean (SD), y | 58 (16) | 65 (11) | 67 (10) | 67 (8) | 69 (7) |
| Male sex, No. (%) | 62 (62.0) (75.8) | 53 (53.5) | 66 (66.0) | 67 (67.0) | 73 (73.7) |
| Reason for unknown time of symptom onset, No. (%) | |||||
| Night-sleep | 84 (84.0) | 90 (90.9) | 92 (92.0) | 88 (88.0) | 90 (90.9) |
| Day-sleep | 8 (8.0) | 1 (1.00) | 5 (5.0) | 4 (4.0) | 5 (5.1) |
| Aphasia, confusion, or other | 8 (8.0) | 8 (8.0) | 3 (3.0) | 8 (8.0) | 4 (4.0) |
| Time between last seen well and symptom recognition, median (IQR), hours | 7.08 (4.67–9.00) | 7.50 (5.00–8.67) | 7.00 (5.50–8.50) | 7.17 (5.75–9.33) | 7.00 (4.50–8.83) |
| Medical history/risk factors, No. (%) | |||||
| Arterial hypertension | 23 (23.0) | 45 (45.5) | 63 (63.0) | 67 (67.0) | 65 (65.7) |
| Diabetes mellitus | 8 (8.0) | 14 (14.1) | 18 (18.0) | 17 (17.0) | 24 (24.2) |
| Hypercholesterolemia | 25 (25.0) | 37 (37.4) | 48 (48.0) | 42 (42.0) | 26 (26.3) |
| Atrial fibrillation | 12 (12.0) | 14 (14.1) | 13 (13.0) | 10 (10.0) | 9 (9.1) |
| History of ischaemic stroke | 13 (13.0) | 13 (13.1) | 19 (19.0) | 15 (15.0) | 8 (8.08) |
| Current antihypertensive medication, No. (%) | 25 (25.0) | 47 (47.5) | 59 (59.0) | 60 (60.0) | 52 (52.53) |
| NIHSS score, median (IQR) | 5 (3–9) | 5 (3-9) | 6 (4-9) | 6 (4-10) | 6 (4-11) |
| Systolic blood pressure, mean (SD), mmHg | 132.5 (18.0) | 142.9 (16.2) | 156.5 (16.1) | 161.6 (15.0) | 168.0 (15.7) |
| Diastolic blood pressure, mean (SD), mmHg | 77.0 (12.2) | 81.1 (11.4) | 83.9 (11.3) | 86.3 (13.1) | 88.5 (12.4) |
| DWI lesion volume at baseline, median (IQR), ml | 2.32 (0.85–10.40) | 1.94 (0.80-10.66) | 3.06 (0.91-8.85) | 2.06 (0.69-7.78) | 2.17 (0.73-6.00) |
| Symptomatic intracranial heamorrhage (SICH) as defined in SITS-MOST – No. (%) | 0 (0) | 2 (2.00) | 0 (0) | 0 (0) | 4 (4.04) |
| Parenchymal heamorrhage type 2 (PH-2) | 1 (1.00) | 1 (1.00) | 2 (2.00) | 0 (0) | 6 (6.06) |
NIHSS: National Institute of Health Stroke Scale; DWI: diffusion weighted imaging; SITS-MOST: Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST).
Figure 1.
Relationship between systolic blood pressure and treatment effect of alteplase. Increasing mean systolic blood pressure (BP, a) is inversely related to the odds ratio for favourable outcome (related to age, stroke severity and baseline BP on admission) and significantly modifies the treatment effect of alteplase (test for interaction of mean systolic BP*treatment, p = 0.033). The treatment effect of thrombolysis is not modified by systolic BPV (systolic BPV * treatment, p = 0.46, b).
Increased mean systolic BP was significantly associated with baseline systolic (p < 0.001) and diastolic BP on admission (p < 0.001), age (p < 0.001), history of hypertension (p < 0.001) as well as diabetes mellitus type II (p = 0.009). For a detailed overview of baseline characteristics according to the quintiles of mean systolic BP see Table 1. Higher mean systolic BP was associated with smaller treatment effects of thrombolysis with a significant interaction (p = 0.033, see Figure 1(a)). The aOR for favourable outcome with alteplase, adjusted for age, stroke severity and baseline blood pressure on admission, decreased with quintiles of increasing mean systolic BP over the first 24 hours after treatment initiation from aOR 3.16 (95% CI, 1.26–7.93) in the lowest quintile to aOR 0.84 (95% CI, 0.34–2.10) in the highest quintile.
SICH according to the criteria of SITS-MOST was observed in six patients, PH-2 in ten patients with no significant association with mean systolic BP nor systolic BPV. Low number of safety outcomes precluded further statistical analysis.
Diastolic blood pressure variability
Increased diastolic BPV, divided into quintiles was associated with age (p = 0.009). Mean diastolic BP, divided into quintiles was significantly associated with baseline diastolic BP (p < 0.001), baseline systolic BP (p < 0.001) and age (p < 0.001). All other clinical characteristics were comparable between the groups according to quintiles of BPV or mean BP.
Favourable outcome (mRS score 0–1) at 90 days after stroke was observed in 232 of 488 patients (47.5%) with available information on all covariates used in the models. The treatment effect of thrombolysis was also not modified by diastolic BPV (interaction diastolic BPV * treatment, p = 0.790) nor by mean diastolic BP (interaction mean diastolic BP*treatment, p = 0.496). Analysis by quintiles of diastolic BPV as well as mean diastolic BP, did not show an association of diastolic BPV/mean BP and treatment effect.
The low incidence of SICH and PH-2 did not show any significant distribution across the quintiles of diastolic BPV nor mean diastolic BP.
Discussion
In this secondary post-hoc analysis of the WAKE-UP trial, we studied the association of systolic and diastolic BPV with the treatment effect of intravenous alteplase. As a main finding, we observed no association between BPV and outcome after thrombolysis nor an interaction between the treatment effect of thrombolysis and BPV. Further findings revealed an association of higher mean systolic BP with a less pronounced treatment effect of thrombolysis.
Elevated BP is a common phenomenon in acute ischaemic stroke patients and was observed in 77% of all patients, of which up to one third had no known history of hypertension.3,4 As a dynamic parameter, BP can fluctuate over the first hours after stroke onset, and is assumed to result from multifactorial conditions after acute stroke such as an impaired cardiac baroreflex, reduced arterial compliance and changes in the neuroendocrine systems.14,15 Higher BPV was found associated with poor functional outcome, mortality and haemorrhagic transformation in stroke patients after thrombolysis.7,9,10
If the observed association between BPV and outcome after acute stroke is assumed to represent a causal one, then a proposed mechanism relates to impaired cerebral autoregulation within the acute ischaemic brain region.16 The dysfunctional, particularly dynamic, autoregulation results in a linear correlation between cerebral perfusion and systemic arterial BP.16–18 Consequently, BP increases in a compensatory way to maintain cerebral bloodflow in the ischaemic penumbra. Thus, the brain becomes vulnerable to fluctuations of BP that can result in instability of cerebral perfusion such as hypo- or hyperperfusion of ischaemic brain, potentially leading to lesion growth, increased intracranial pressure and bleeding.19,20
Previous studies have reported an association between different parameters of BPV and favourable outcome,9,21 but it remains challenging for researchers and clinicians how to best measure fluctuations of BP. In our analysis, BPV was measured by the coefficient of variation, and we did not observe an association of this measure with stroke outcome or treatment effect. In contrast, in previous studies BPV measured by the standard deviation (SD) showed such an association.7,22 This discrepancy illustrates the importance of the parameter chosen for measurement of BPV. Findings of an association of SD with outcome of stroke thrombolysis need to be interpreted with caution, as SD is strongly correlated with the mean BP, which was associated with outcome after thrombolysis in our study as well as in previous reports.
BP management has been the subject of multiple clinical trials in acute stroke patients, but there is to date no evidence that intervention to modify BP in the acute phase of stroke improves outcome. The assumed causal relationship may not be correct. Management of BP in ischaemic stroke patients is mainly based on baseline values or average BP levels, and guidelines recommend tolerating systolic BP values up to 185 mmHg or diastolic values up to 110 mmHg in patients eligible for thrombolysis and up to 180 or 105 mmHg or for the first 24 hours after thrombolysis because of the most feared complication of SICH. Guidelines for BP management in thrombolysis are derived from small studies and expert opinion rather than specific evidence. In patients not eligible for thrombolysis, it is not recommended to intervene unless for extreme BP values (≥220/120 mmHg) or in cases of specific comorbid conditions.23 Although the BP profile is usually highly variable in the early phase of acute ischaemic stroke, the general message in guidelines is not to intervene unless for extreme BP values. Even though our data show a relationship between mean systolic BP and treatment effect of thrombolysis, we cannot conclude a causal relationship. Whether a mean BP reducing intervention improves the treatment effect, or whether our results show an epiphenomenon of other physiological parameters, putting patients with higher mean BP at risk of worse outcome, only an interventional trial can reveal.
Increased diastolic mean BP and BPV was not associated with favourable outcome and it did not modify the treatment effect of thrombolysis in our study. Although DBP is assumed an independent predictor of favourable outcome at 90 days,24 diastolic BP values show less variability after acute stroke and are not considered a prognostic value to the extent of systolic BP.21
Symptomatic intracranial haemorrhage is the most feared complication in management of acute stroke patients eligible for thrombolysis, because it can dramatically impact the prognosis.25 In a previous study, increased BP fluctuation was significantly associated with haemorrhagic transformation and SICH after ischaemic stroke, irrespective of whether the patients were treated with thrombolysis or not.20 Haemorrhagic transformation is linked to impaired cerebral autoregulation in acute ischaemic brain, which consecutively relate on systemic BP.26 Because the incidence of SICH and PH-2 in our study population was too low to allow for reliable statistical analysis, we cannot draw any clear conclusions to the association of BP and intracranial haemorrhage after thrombolysis.
There are limitations to our study. This is a post-hoc analysis of a randomised, controlled trial, hence, all findings have to be considered hypothesis-generating. Moreover, no causality can be assumed from the observed association of mean systolic BP during the first 24 hours after treatment initiation with treatment effect of thrombolysis. Furthermore, our results do not allow a firm conclusion on management of BP in acute stroke patients, but might inform potential interventional studies targeting 24 h mean BP in stroke thrombolysis, taking into consideration further covariates such as BP on admission, age, hypertension in medical history, current intake of antihypertensive medication and administration of antihypertensive medication during the acute phase of stroke treatment. WAKE-UP randomised patients with unknown time of stroke onset, who, according to brain imaging findings, were highly likely to be within the time window for effective thrombolysis, i.e., within 4.5 hours of symptom onset. There is no reason to assume that these patients differ from patients within 4.5 hours of known symptom onset with regards to the biological and clinical effects of intravenous alteplase.
Conclusion
Our study revealed an association of increased mean systolic blood pressure within the first 24 hours of stroke with decreasing treatment effect of intravenous alteplase in acute stroke. Mechanisms underlying this association warrant further research and whether this identifies mean BP as a target for intervention needs to be tested.
Acknowledgements
None.
Declaration of conflicting interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: EB, BC, ME, MEn, JBF, AN, VT, KWM, PR, SP, CG and GT report grants from European Union 7th Framework Program during the conduct of the study. FB reports grants from University Medical Center Hamburg-Eppendorf during the conduct of the study. MEn reports grants from Bayer and fees paid to the Charité from Bayer, Boehringer Ingelheim, BMS/Pfizer, Daiichi Sankyo, Amgen, GlaxoSmithKlineGSK, Sanofi, Covidien, Novartis, all outside the submitted work. JBF reports personal fees from Bioclinica, Artemida, Cerevast, and Nicolab outside the submitted work. RL reports fees paid to VIB/KU Leuven from Bayer, Boehringer Ingelheim, Medtronic, Ischemiaview and Genentec all outside the submitted work. VT reports personal fees and non-financial support from Boehringer Ingelheim, Pfizer/BMS, Bayer, Sygnis, Amgen and Allergan outside the submitted work. KWM reports personal fees and non-financial support from Boehringer Ingelheim outside the submitted work. CZS reports grants from Novo Nordisk Foundation and personal fees from Bayer outside the submitted work. CG reports personal fees from AMGEN, Bayer Vital, BMS, Boehringer Ingelheim, Sanofi Aventis, Abbott, and Prediction Biosciences outside the submitted work. GT reports personal fees from Acandis, Boehringer Ingelheim, BMS/Pfizer, Stryker, Daiichi Sankyo, grants and personal fees from Bayer, grants from Corona Foundation, German Innovation Fonds and Else Kroener Fresenius Foundation outside the submitted work. All remaining authors declare no competing interests.
Funding: The author(s) disclosed receipt of the following financial support for the research, authorship and/or publication of this article: WAKE-UP received funding from the European Union Seventh Framework Program [FP7/2007–2013] under grant agreement n°2,78,276 (WAKE-UP). RL is a senior clinical investigator of FWO Flanders.
Ethical approval: The WAKE-UP trial was approved for each study site by the competent authorities and the corresponding ethics committee.
Informed consent: Patients or their legal representatives provided written informed consent according to national and local regulations, with an exception from explicit informed consent in emergency circumstances in some countries.
Guarantor: GT.
Contributorship: EB and GT conceived and designed the study, analysed and interpreted the data. EB wrote the first draft of the manuscript. FB conducted the statistical analysis. BC, AK, T-HC, JF, JP, PR, RL and SP acquired data. FB, MEb, MEn, JBF, VT, KWM, NN, CZS and CG acquired data and critically revised the manuscript. GT acquired the data and critically revised the manuscript.
ORCID iD: Ewgenia Barow https://orcid.org/0000-0003-2318-0959
Supplemental Material: Supplemental material for this article is available online.
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