Association of Characteristics of Blood Pressure Profiles and Stroke Outcomes in the ECASS-II Trial
Background and Purpose— Certain characteristics of early blood pressure (BP) profiles were reported to be independent predictors of long-term outcome in the first European Cooperative Acute Stroke Study (ECASS-I) trial. The aim of the study was to find out the association of BP profiles with functional outcome, mortality, and hemorrhagic complications in the ECASS-II database.
Methods— We studied 793 patients with acute ischemic hemispheric stroke in the ECASS-II. After randomization, BP was measured every 15 minutes during the first 2 hours, then every 30 minutes during the first 8 hours, and thereafter at 1-hour intervals up to 24 hours. Individual 0- to 24-hour BP profiles were characterized by baseline, maximum, minimum, and mean BP and successive variation of the profile. The end points were favorable outcome (modified Rankin Scale score of 0 or 1) at day 90, all-cause mortality at day 90, and hemorrhagic transformation within the first 7 days.
Results— High baseline, maximum, mean level, and variability of systolic BP profiles were each inversely associated with favorable outcome (OR=0.84, 95% CI: 0.74 to 0.94; OR=0.82, 95% CI: 0.73 to 0.91; OR=0.81, 95% CI: 0.71 to 0.93; OR=0.57, 95% CI: 0.35 to 0.92, respectively) and associated with an increased risk of parenchymal hemorrhage within the first 7 days (OR=1.27, 95% CI: 1.07 to 1.51; OR=1.49, 95% CI: 1.27 to 1.75; OR=1.52, 95% CI: 1.23 to 1.87; OR=2.62, 95% CI: 1.40 to 4.87; respectively) in recombinant tissue plasminogen activator-treated patients. In placebo-treated patients, high maximum, mean level, and successive variation of systolic BP profiles were inversely associated with favorable outcome (OR=0.76, 95% CI: 0.66 to 0.86; OR=0.76, 95% CI: 0.65 to 0.89; OR=0.41, 95% CI: 0.22 to 0.76; respectively), although the association of baseline systolic BP and favorable outcome was not significant (OR=0.91, 95% CI: 0.80 to 1.03). No association with hemorrhagic transformation was found, even after the adjustment.
Conclusions— The hemorrhagic transformation within the first 7 days and favorable outcome were independently associated with dynamics of BP within the first 24 hours after an acute ischemic stroke in patients treated with thrombolysis, but in placebo-treated patients, only with favorable outcome. Continuous BP monitoring is hence important for the prognosis and gives implications to optimize BP management, particularly regarding a reasonable BP level and stability.
Elevated systolic and/or diastolic blood pressure (BP) is commonly observed in patients after acute ischemic stroke, even in previously normotensive patients.1 The elevated BP often returns to normal spontaneously within a few days after stroke or after recanalization of the occluded artery with thrombolysis.2 Despite controversial findings in observational studies, a meta-analysis summarized that high BP in acute ischemic stroke or primary intracerebral hemorrhage is associated independently with adverse outcomes, long-term dependency, death, and/or deterioration.3 In a pooled analysis of clinical trials of thrombolysis, higher levels of initial systolic BP were associated with lower likelihood of benefit from recombinant tissue plasminogen activator (rtPA).4
Although BP profile is usually highly variable in the early phase of acute ischemic stroke, clinical management of BP is mainly based on only the baseline or average levels; within-patient BP variability is not considered in management guidance and its prognostic value for stroke outcome is rarely addressed. The course of BP was suggested to be related to stroke type and stroke severity.5 BP fluctuation and its prognostic value was studied earlier,6,7 in which 20% to 30% BP drop in mean arterial pressure almost tripled the chance of a complete recovery. A wider maximal range of fluctuation within a BP profile has recently been reported to be associated with increased 90-day mortality for both systolic BP and diastolic BP.8 The higher variability of beat-to-beat mean arterial pressure measured with standard deviation indicated higher risk of death before or dependency after 30 days.9 Characteristics of BP profiles and their associations with stroke outcome had been studied comprehensively in a recent report: Smaller successive variation (SV), which quantifies the serial variability of successive BP measurements, and lower mean BP within the first 72 hours were associated with a better outcome in the patients of the first European Cooperative Acute Stroke Study (ECASS), which had randomized patients to either the experimental dose of 1.1 mg/kg body weight rtPA or placebo.10
The aim of the present study was to further explore the relationship of these characteristics of BP profiles with the occurrence of hemorrhagic transformation within the first 7 days in particular, and with 90 days stroke outcome in general, in the second European Cooperative Acute Stroke Study (ECASS-II) that had randomized patients to either the currently approved dose of 0.9 mg/kg body weight rtPA or placebo.
Materials and Methods
The patient sample is from the ECASS-II. ECASS-II was a multicenter, randomized, double-blind, placebo-controlled trial to test the efficacy and safety of rtPA in acute hemispheric stroke. Eight hundred eligible patients were randomly assigned to either 0.9 mg/kg rtPA or placebo. Seven of the randomized patients did not receive trial medication. Intravenous administration of trial medication was started within 6 hours after the onset of symptoms. Among the 793 treated patients, 407 received rtPA and 386 placebo. Nine patients who were lost to follow-up did not have the 90-day assessment.
Aims, methodology, and patient inclusion and exclusion criteria of ECASS-II have been described previously in more detail.11 Patients already receiving sufficient heparin to elevate the activated partial thromboplastin time or warfarin to increase international normalized ratio to therapeutic level were excluded from the study. Administration of oral anticoagulants, antiplatelet agents, hemorrhagic agents, and brain-protective drugs was not permitted during the first 24 hours after completion of the study drug administration. Patients with systolic BP (SBP) >185 mm Hg or diastolic BP (DBP) >110 mm Hg on repeated measurements before study entry were excluded.
According to the baseline BP, almost 80% of patients had elevated BP (SBP ≥140 or DBP ≥90 mm Hg) and 20% patients did not. The distributions of demographic and clinical factors, disease and medication histories, and the CT signs of the 2 post hoc groups according to their baseline BP measurement were compared, and homogeneity in treatment assignment, gender, time from onset to treatment, disease, and medication histories are shown (Table 1).
Supine BP was measured in the hemiparetic arm using a standard mercury sphygmometer. BP was measured on admission, every 15 minutes during the first 2 hours, then every 30 minutes during the first 8 hours, and thereafter at 1-hour intervals up to 24 hours. Thirty-seven BP measurements within the first 24 hours were thus obtained.
Summary parameters used to describe individual patient BP profiles were baseline BP, 0- to 24-hour maximum, 0- to 24-hour minimum, 0- to 24-hour average level (mean), 0- to 24-hour SBP change=SBPbaseline−SBP24 hour, and SV12 to represent variability of an individual 0- to 24-hour BP profile that consists of 37 readings X1, X2, …, X37, accordingly to protocol such that equation . SV of a patient’s BP profile is the square root of average squared difference between the 2 successive BP measurements. In contrast with the widely known sample SD, the SV addresses the time sequence of measurements.
Functional outcome was assessed on the modified Rankin Scale (mRS) score at 90±7 days after the treatment. It was dichotomized into favorable outcome (mRS 0 to 1) or unfavorable outcome (mRS 2 to 6, death was graded 6). The case fatality included all-cause mortality within 90 days. Hemorrhagic transformations on CT within 7 days were chosen as the secondary end points. Hemorrhagic transformation13 was classified into hemorrhagic infarction (HI) and parenchymal hemorrhage (PH). Hemorrhagic infarction was defined as petechiae without space-occupying effect that ranged from small petechiae along the margins of the infarct (HI1) to confluent petechiae within the infarct area (HI2). Parenchymal hemorrhage was then defined as blood clots with space-occupying effect, ranging from ≤30% (PH1) to >30% (PH2).
Chi square tests were used for the categorical variables and 2-sided nonparametric Wilcoxon U tests for the continuous variables in the univariate analyses. Binomial logistic regression models for the prediction of favorable 90-day outcome (mRS score ≤1), death, and hemorrhagic transformation were considered. At first, the characteristics of SBP and DBP profiles were included respectively in a single model, and the crude OR was obtained. Second, the known baseline predictors were included in the model to obtain adjusted estimates of the effects of the characteristics of BP profiles on the respective stroke outcomes. The enrolled known predictors are age and gender of the patients, time from stroke onset to treatment, the initial stroke severity assessed by Scandinavian Stroke Scale score, history of hypertension and medication of acetylsalicylic acid before stroke onset, and the extent of hypodensity on baseline CT. Results were presented as ORs with 95% CIs in 10-mm Hg increase as unit for each characteristic of BP profiles. Probability values are not adjusted for multiple testing because the present analysis is exploratory by its post hoc nature and the trial had not been powered for the present comparisons.
The analyses were performed with S-Plus14 version 5.1 release for AIX 4.3.1.
Among the total of 793 patients of the intent-to-treat cohort, 2 (0.25%) patients died within the first 24 hours leaving only 791 patients with complete BP measurements according to trial protocol; 630 (79.5%) had elevated initial BP. Hemorrhagic infarctions were observed in 141 (36.5%) placebo-treated patients and in 142 (35%) rtPA-treated patients, and PH was observed in 12 (3%) placebo-treated patients and in 48 (11.8%) rtPA-treated patients.
Sample Mean Profiles of Systolic Blood Pressure and Association With Outcome
The 0- to 24-hour profiles of sample means of SBP in patients assigned to 0.9 mg/kg rtPA intravenously or to placebo were presented in subgroups according to favorable outcomes at day 90 (mRS 0 to 1), mortality until day 90 and hemorrhagic transformation (PH and HI) within the first 7 days, respectively (Figures 1 and 2⇓). The sample means of SBP decreased gradually with time in all subgroups. The sample means are overall numerically lower in those patients who had favorable outcome (mRS 0 to 1), irrespective of treatment (Figure 1). In contrast, those patients who had PH events had apparently higher sample mean of SBP than those free of hemorrhagic transformation in rtPA-treated patients, whereas the difference was not noticeable in the placebo group (Figure 2).
Association of Systolic Blood Pressure Profiles and Favorable Outcomes
After adjustment for the known baseline predictors, within-patient maximum, minimum, and successive variation of SBP were inversely associated with favorable outcome at day 90 both in placebo- and rtPA-treated patients (see Table 2). Death within 90 days was not associated with BP profiles either in placebo- or in rtPA-treated patients (see Table 2).
Association of Systolic Blood Pressure Profiles and Hemorrhagic Transformations Within 7 Days
After adjustment for the known baseline predictors, high baseline SBP, within-patient maximum, mean level, and successive variation of SBP are associated with increased risk of PH within the first 7 days only in rtPA-treated patients (see Table 3). Hemorrhagic infarction was not associated with SBP profiles either in placebo- or in rtPA-treated patients except for 0 to 24 SBP change in rtPA-treated patients (see Table 3).
It was demonstrated that 90-day favorable outcome was associated inversely with several characteristics of within-patient BP profiles, the profile’s maximum, its mean, and its SV among both the rtPA- and placebo-treated patients, whereas an association with baseline SBP was only seen among the rtPA-treated patients. No association between mortality and any of these BP profile characteristics was revealed. Parenchymal hemorrhage is a major concern with thrombolytic treatments and BP management is considered to be a key issue in the acute care of those patients. We found that higher baseline SBP, maximum and average levels of SBP, and its SV within the first 24 hours after acute ischemic stroke each increased the risk of PH among rtPA-treated patients, even after adjustment for other baseline confounders. Petechial hemorrhage in infarction is clinically benign phenomenon, although no association of HI with characteristics of BP profile have been suggested.
Higher 72-hour BP variability, measured either with SD9 or SV10 has been suggested to increase the risk of death or dependent outcome. BP oscillation indicates reduced elastics of arteries. Stiffness of the large arterial wall, which is common in patients with hypertension, attenuates the baroreflex, which results in larger BP variability,15 which may further worsen the perfusion in the penumbra area after acute ischemic stroke. A matched case–control study gave hints that dynamic but not static cerebral autoregulation is impaired in acute ischemic stroke.16 This finding supports our postulation that changes, especially the successive changes of systemic BP, may cause a swirl and worsen the perfusion furthermore in the penumbra area. Sudden rise of BP may then increase the risk of hemorrhagic transformation.
Another possible cause of BP variability could be the BP management. In the study protocol of ECASS-II, comedication of antihypertensive agents was permitted during the first 24 hours after the completion of the study drug to keep the BP under 180/105 mm Hg. Therefore, BP management may be involved in the higher BP variability of patients with unfavorable outcome.
Previous analysis of the relationship between the characteristics of the first 72-hour BP profiles and functional outcome and mortality in ECASS-I database suggested that lower 72-hour mean SBP/DBP and smaller SBP/DBP variability were associated with favorable 90-day outcome,10 which is corroborated with the present findings. The impact of the baseline BP on 90-day independency is controversial in these 2 studies. The baseline BP in the ECASS-II was lower than that in the ECASS-I. This can be attributed to stricter patient selection according to baseline BP level in the ECASS-II after the negative ECASS-I.
The present study differs from earlier studies in several aspects. First, we consider the whole course of BP within 24 hours and its prognostic value on outcome rather than baseline BP17–20 or change between 2 measurements.6,21 Second, we use the summary characteristic parameters of BP profiles one by one to estimate their impact on outcome adjusting for baseline covariates individually instead of selecting the most significant among them like in the previous study.8 Third, in the ECASS-II data, maximal SBP within the first 24 hours resulted in being an independent predictor for favorable outcome and risk of PHs in the rtPA-treated patients. This gives new clues for BP management in connection of thrombolysis. Fourth, we have extended our work to study the relationship among PHs, HIs, and BP profiles. To our knowledge, this is the first report about this.
We have studied all associations separately in placebo- and rtPA-treated patients rather than adjusting for an averaged treatment effect. This has the advantage that the different patterns of risk profiles with and without thrombolysis can be revealed independently, because interactions among rtPA, BP, and other factors may be more complicated than mathematical predictive modeling can provide.
The present study used the data from a randomized, controlled trial and therefore has limitations attributable to its post hoc nature. Patients who had minor stroke symptoms and showed rapid improvement of the symptoms at the time of enrollment were not randomized to ECASS-II; hence, the study sample may not represent all patients with ischemic stroke. Patients with repeated measurements of SBP >185 and DBP >110 mm Hg were excluded; hence, the impact of higher BP profiles on outcomes may potentially be underestimated in the present analysis. Despite a standardized study examination protocol, variation in BP measurements between the 108 centers has to be considered.22 However, we consider that the intraindividual BP profile measurement error within-patient is probably minimal. The regular measurements of BP make it possible to assess the BP variability. However, the different frequencies of measurements may lead to bias in clinical routine. Although intermittent BP measurements less than 30 or 60 minutes apart are good surrogates of continuous BP measurements in estimating 24-hour average BP,23 we are aware that accurate estimates of BP variability by means of beat-to-beat BP measurements instead of sporadic measurements would be more appropriate.
Furthermore, the present study treated ECASS-II data in which the patients were not randomly assigned according to the BP as an observational study. The heterogeneities regarding the baseline BP are indicated in Table 1. Even after the adjustment for these known confounders, residual confounding from unobserved factors is still possible.
Our data do not allow a firm conclusion on how to manage BP in rtPA-treated patients, although it suggests that higher SBP is associated with worse functional outcome and an increased risk of PH.
In conclusion, our present analysis suggests that increased BP variability, mean, and maximal BP within the first 24 hours have impacts on functional recovery in both placebo- and rtPA-treated patients and on PHs in rtPA-treated patients. This underlines again the importance of BP monitoring in the early phase of ischemic stroke to warrant reasonable BP level and stability. Future research is required to elaborate clinical recommendations for BP management.
- Received April 26, 2007.
- Revision received June 28, 2007.
- Accepted July 18, 2007.
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