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Current Smoking Does Not Modify the Treatment Effect of Intravenous Thrombolysis in Acute Ischemic Stroke Patients-A Post-hoc Analysis of the WAKE-UP Trial.

ABSTRACT: Background: The "smoking paradox" indicates that patients with acute ischemic stroke (AIS) who smoke at the time of their stroke may have a better prognosis after intravenous thrombolysis than non-smokers. However, findings are inconsistent and data analyzing the effect of smoking on treatment efficacy of intravenous thrombolysis are scarce. Methods: We performed a pre-specified post-hoc subgroup analysis of the Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke (WAKE-UP) trial that randomized AIS patients with unknown time of symptom onset who had diffusion-weighted imaging-fluid attenuation inversion recovery (DWI-FLAIR) mismatch to either alteplase or placebo. Patients were categorized as current smokers or non-smokers (including former smokers and never-smokers). Baseline demographic and clinical characteristics, as well as clinical and imaging follow-up data were analyzed according to smoking status. Results: Four hundred and eighty six patients were included in the analysis. Current smokers (133, 27.4%) were younger (60.1 ± 13.0 vs. 67.2 ± 10.3 years; p < 0.001) and less often had arterial hypertension (45.0% vs. 56.8%; p = 0.02) or atrial fibrillation (3.8% vs. 15.3%; p < 0.001). The acute stroke presentation was more often due to large vessel occlusion among current smokers (27.1 vs. 16.2%; p = 0.01), and smokers had a trend towards more severe strokes (National Institutes of Health Stroke Scale score>10 in 27.1% vs. 19.5%; p = 0.08). The treatment effect of alteplase, quantified as odds ratio for a favorable outcome (modified Rankin Scale [mRS] score at 90 days of 0 or 1), did not differ between current smokers and non-smokers (p-value for interaction: 0.59). After adjustment for age and stroke severity, neither the proportion of patients with favorable outcome, nor the median mRS score at 90 days differed between current smokers and non-smokers. When additional potential confounders were included in the model, the median mRS score was higher in current smokers than in non-smokers (cOR of better outcome for current smokers vs. non-smokers: 0.664 [0.451-0.978], p = 0.04). Conclusions: In patients with mild to moderate MRI-proven AIS and unknown time of symptom onset with DWI-FLAIR mismatch, current smokers had worse functional outcome as compared to non-smokers. Current smoking did not modify the treatment effect of alteplase. Clinical Trial registration: Main trial (WAKE-UP): ClinicalTrials.gov, NCT01525290; and EudraCT, 2011-005906-32. Registered 02 February 2012.

SUBMITTER: Schlemm L

PROVIDER: S-EPMC6883001 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Current Smoking Does Not Modify the Treatment Effect of Intravenous Thrombolysis in Acute Ischemic Stroke Patients-A Post-hoc Analysis of the WAKE-UP Trial.

Schlemm Ludwig L Kufner Anna A Boutitie Florent F Nave Alexander Heinrich AH Gerloff Christian C Thomalla Götz G Simonsen Claus Z CZ Ford Ian I Lemmens Robin R Muir Keith W KW Nighoghossian Norbert N Pedraza Salvador S Ebinger Martin M Endres Matthias M

Frontiers in neurology 20191122

Background: The "smoking paradox" indicates that patients with acute ischemic stroke (AIS) who smoke at the time of their stroke may have a better prognosis after intravenous thrombolysis than non-smokers. However, findings are inconsistent and data analyzing the effect of smoking on treatment efficacy of intravenous thrombolysis are scarce. Methods: We performed a pre-specified post-hoc subgroup analysis of the Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke ...[more]

PMID: 31824412

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Project description:Background and Aims: Fluid-attenuated inversion recovery (FLAIR) hyperintense vessels (FHVs) on MRI are a radiological marker of vessel occlusion and indirect sign of collateral circulation. However, the clinical relevance is uncertain. We explored whether the extent of FHVs is associated with outcome and how FHVs modify treatment effect of thrombolysis in a subgroup of patients with confirmed unilateral vessel occlusion from the randomized controlled WAKE-UP trial. Methods: One hundred sixty-five patients were analyzed. Two blinded raters independently assessed the presence and extent of FHVs (defined as the number of slices with visible FHV multiplied by FLAIR slice thickness). Patients were then separated into two groups to distinguish between few and extensive FHVs (dichotomization at the median <30 or ?30). Results: Here, 85% of all patients (n = 140) and 95% of middle cerebral artery (MCA) occlusion patients (n = 127) showed FHVs at baseline. Between MCA occlusion patients with few and extensive FHVs, no differences were identified in relative lesion growth (p = 0.971) and short-term [follow-up National Institutes of Health Stroke Scale (NIHSS) score; p = 0.342] or long-term functional recovery [modified Rankin Scale (mRS) <2 at 90 days poststroke; p = 0.607]. In linear regression analysis, baseline extent of FHV (defined as a continuous variable) was highly associated with volume of hypoperfused tissue (? = 2.161; 95% CI 0.96-3.36; p = 0.001). In multivariable regression analysis adjusted for treatment group, stroke severity, lesion volume, occlusion site, and recanalization, FHV did not modify functional recovery. However, in patients with few FHVs, the odds for good functional outcome (mRS) were increased in recombinant tissue plasminogen activator (rtPA) patients compared to those who received placebo [odds ratio (OR) = 5.3; 95% CI 1.2-24.0], whereas no apparent benefit was observed in patients with extensive FHVs (OR = 1.1; 95% CI 0.3-3.8), p-value for interaction was 0.11. Conclusion: While the extent of FHVs on baseline did not alter the evolution of stroke in terms of lesion progression or functional recovery, it may modify treatment effect and should therefore be considered relevant additional information in those patients who are eligible for intravenous thrombolysis. Clinical Trial Registration: Main trial (WAKE-UP): ClinicalTrials.gov, NCT01525290; and EudraCT, 2011-005906-32. Registered February 2, 2012.

Project description:Background and objectivesCerebral microbleeds (CMBs) are common in patients with acute ischemic stroke and are associated with increased risk of intracerebral hemorrhage (ICH) after intravenous thrombolysis. Whether CMBs modify the treatment effect of thrombolysis is unknown.MethodsWe performed a prespecified analysis of the prospective randomized controlled multicenter Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke (WAKE-UP) trial including patients with acute ischemic stroke with unknown time of symptom onset and diffusion-weighted imaging-fluid-attenuated inversion recovery mismatch on MRI receiving alteplase or placebo. Patients were screened and enrolled between September 2012 and June 2017 (with final follow-up in September 2017). Patients were randomized to treatment with IV thrombolysis with alteplase at 0.9 mg/kg body weight or placebo. CMB status (presence, number, and distribution) was assessed after study completion by 3 raters blinded to clinical information following a standardized protocol. Outcome measures were excellent functional outcome at 90 days, defined by modified Rankin Scale (mRS) score ≤1, and symptomatic ICH according to National Institutes of Neurological Disease and Stroke trial criteria 22 to 36 hours after treatment.ResultsOf 503 patients enrolled in the WAKE-UP trial, 459 (91.3%; 288 [63%] men) were available for analysis. Ninety-eight (21.4%) had at least 1 CMB on baseline imaging; 45 (9.8%) had exactly 1 CMB; 37 (8.1%) had 2 to 4 CMBs; and 16 (3.5%) had ≥5 CMBs. Presence of CMBs was associated with a nonsignificant increased risk of symptomatic ICH (11.2% vs 4.2%; adjusted odds ratio [OR] 2.32, 95% confidence interval [CI] 0.99-5.43, p = 0.052) but had no effect on functional outcome at 90 days (mRS score ≤1: 45.8% vs 50.7%; adjusted OR 0.99, 95% CI 0.59-1.64, p = 0.955). Patients receiving alteplase had better functional outcome (mRS score ≤1: 54.6% vs 44.6%, adjusted OR 1.61, 95% CI 1.07-2.43, p = 0.022) without evidence of heterogeneity in relation to CMB presence (p of the interactive term = 0.546). Results were similar for subpopulations with strictly lobar (presumed cerebral amyloid angiopathy related) or not strictly lobar CMB distribution.DiscussionIn the randomized-controlled WAKE-UP trial, we saw no evidence of reduced treatment effect of alteplase in patients with acute ischemic stroke with ≥1 CMBs. Additional studies are needed to determine the treatment effect of alteplase and its benefit-harm ratio in patients with a larger number of CMBs.Trial registration informationClinicalTrials.gov identifier NCT01525290; ClinicalTrialsRegister.EU identifier 2011-005906-32.Classification of evidenceThis study provides Class II evidence that for patients with acute ischemic stroke with unknown time of onset and diffusion-weighted imaging-fluid-attenuated inversion recovery mismatch who received IV alteplase, CMBs are not significantly associated with functional outcome at 90 days.

Project description:Importance:The rationale for intravenous thrombolysis in patients with lacunar infarcts is debated, since it is hypothesized that the microvascular occlusion underlying lacunar infarcts might not be susceptible to pharmacological reperfusion treatment. Objective:To study the efficacy and safety of intravenous thrombolysis among patients with lacunar infarcts. Design, Setting, and Participants:This exploratory secondary post hoc analysis of the WAKE-UP trial included patients who were screened and enrolled between September 2012 and June 2017 (with final follow-up in September 2017). The WAKE-UP trial was a multicenter, double-blind, placebo-controlled randomized clinical trial to study the efficacy and safety of intravenous thrombolysis with alteplase in patients with an acute stroke of unknown onset time, guided by magnetic resonance imaging. All 503 patients randomized in the WAKE-UP trial were reviewed for lacunar infarcts. Diagnosis of lacunar infarcts was based on magnetic resonance imaging and made by consensus of 2 independent investigators blinded to clinical information. Main Outcomes and Measures:The primary efficacy variable was favorable outcome defined by a score of 0 to 1 on the modified Rankin Scale at 90 days after stroke, adjusted for age and severity of symptoms. Results:Of the 503 patients randomized in the WAKE-UP trial, 108 patients (including 74 men [68.5%]) had imaging-defined lacunar infarcts, whereas 395 patients (including 251 men [63.5%]) had nonlacunar infarcts. Patients with lacunar infarcts were younger than patients with nonlacunar infarcts (mean age [SD], 63 [12] years vs 66 [12] years; P = .003). Of patients with lacunar infarcts, 55 (50.9%) were assigned to treatment with alteplase and 53 (49.1%) to receive placebo. Treatment with alteplase was associated with higher odds of favorable outcome, with no heterogeneity of treatment outcome between lacunar and nonlacunar stroke subtypes. In patients with lacunar strokes, a favorable outcome was observed in 31 of 53 patients (59%) in the alteplase group compared with 24 of 52 patients (46%) in the placebo group (adjusted odds ratio [aOR], 1.67 [95% CI, 0.77-3.64]). There was 1 death and 1 symptomatic intracranial hemorrhage according to Safe Implementation of Thrombolysis in Stroke-Monitoring Study criteria in the alteplase group, while no death and no symptomatic intracranial hemorrhage occurred in the placebo group. The distribution of the modified Rankin Scale scores 90 days after stroke also showed a nonsignificant shift toward better outcomes in patients with lacunar infarcts treated with alteplase, with an adjusted common odds ratio of 1.94 (95% CI, 0.95-3.93). Conclusions and Relevance:While the WAKE-UP trial was not powered to demonstrate the efficacy of treatment in subgroups of patients, the results indicate that the association of intravenous alteplase with functional outcome does not differ in patients with imaging-defined lacunar infarcts compared with those experiencing other stroke subtypes.

Project description:ImportanceIntravenous thrombolysis (IVT) followed by mechanical thrombectomy (MT) is recommended to treat acute ischemic stroke (AIS) with a large vessel occlusion (LVO). Most hospitals do not have on-site MT facilities, and most patients need to be transferred secondarily after IVT (drip and ship), which may have an effect on the neurologic outcome.ObjectiveTo compare the functional independence at 3 months between patients treated under the drip-and-ship paradigm and those treated on site (mothership).Design, setting, and participantsThis study used a prospectively gathered registry of patients with AIS to select patients admitted through the Saint-Antoine and Tenon (drip and ship) or the Fondation Rothschild (mothership) hospitals from January 1, 2013, through April 30, 2016. The study included patients older than 18 years treated with bridging therapy for AIS with LVO of the anterior circulation. Among the 159 patients who received MT at the mothership, 100 had been transferred after IVT from the drip-and-ship hospitals and 59 had received IVT on site.Main outcomes and measuresThe main outcome was 3-month functional independence (modified Rankin scale score ≤2). Both groups were compared using a multivariate linear model, including variables that were significantly different in the 2 groups.ResultsDuring the study period, 497 patients were hospitalized at the drip-and-ship and mothership hospitals for an AIS eligible to reperfusion therapy; 11 patients had a basilar artery occlusion and were excluded, leaving 100 patients in the drip-and-ship group (mean age, 73 years; age range, 60-81 years; 57 men [57.0%]) and 59 in the mothership group (mean age, 70 years; age range, 58-82 years; 29 men [49.2%]). The proportion of patients with a favorable neurologic outcome at 3 months was similar in both groups (drip and ship, 61 [61.0%]; mothership, 30 [50.8%]; P = .26), even after adjusting the analysis for the baseline National Institutes of Health Stroke Scale score, diffusion-weighted imaging Alberta Stroke Program Early Computed Tomography Score, and general anesthesia (P = .82). Patients had less severe conditions in the drip-and-ship group (median baseline National Institutes of Health Stroke Scale score, 15 vs 17 [P = .03]; median diffusion-weighted imaging Alberta Stroke Program Early Computed Tomography Score, 7.5 vs 7 [P = .05]). Process times were longer in the drip-and-ship group (onset-to-needle time, 150 vs 135 minutes; onset-to-puncture time, 248 vs 189 minutes; and onset-to-recanalization time, 297 vs 240 minutes; P < .001). Both groups were similar in terms of substantial recanalization (Thrombolysis in Cerebral Ischemia scores 2B to 3; drip and ship, 84 [84.0%]; mothership, 47 [79.7%]; P = .49) and symptomatic hemorrhagic transformation (drip and ship, 2 [2.0%]; mothership, 2 [3.4%]; P = .63).Conclusions and relevanceThis study found that patients treated under the drip-and-ship paradigm also benefit from bridging therapy, with no statistically significant difference compared with those treated directly in a comprehensive stroke center.

Dataset Information

Current Smoking Does Not Modify the Treatment Effect of Intravenous Thrombolysis in Acute Ischemic Stroke Patients-A Post-hoc Analysis of the WAKE-UP Trial.

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Current Smoking Does Not Modify the Treatment Effect of Intravenous Thrombolysis in Acute Ischemic Stroke Patients-A <i>Post-hoc</i> Analysis of the WAKE-UP Trial.

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