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

Background: Though obesity is a well-known risk factor for vascular disease, the impact of obesity on stroke outcome has been disputed. Several studies have shown that obesity is associated with better functional outcome after stroke. Whether obesity influences the benefit of endovascular treatment (EVT) in stroke patients is unknown. We evaluated the association between body mass index (BMI) and outcome in acute ischemic stroke patients with large vessel occlusion (LVO), and assessed whether BMI affects the benefit of EVT. Methods: This is a post hoc analysis of the Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands trial (ISRCTN10888758). BMI was used as a continuous and categorical variable, distinguishing underweight and normal weight (BMI <25), overweight (BMI 25–30), and obesity (BMI ≥30). We used multivariable ordinal logistic regression analysis to estimate the association of BMI with functional outcome (shift analysis), assessed with modified Rankin Scale (mRs) at 90 days. The impact of BMI on EVT effect was tested by the use of a multiplicative interaction term. Results: Of 366 patients, 160 (44%) were underweight or normal weight, 145 (40%) overweight, and 61 (17%) were obese. In multivariable analysis with BMI as a continuous variable, we found a shift toward better functional outcome with higher BMI (mRS adjusted common OR 1.04; 95% CI 1.0–1.09), and mortality was inversely related to BMI (aOR 0.92; 95% CI 0.85–0.99). Safety analysis showed that higher BMI was associated with lower risk of stroke progression (aOR 0.92, 95% CI 0.87–0.99). Additional analysis showed no interaction between BMI and EVT effect on functional outcome, mortality, and other safety outcomes. Conclusion: Our study confirms the effect of obesity on outcome in acute ischemic stroke patients with LVO, meaning better functional outcome, lower mortality, and lower risk of stroke progression for patients with higher BMI. As we found no interaction between BMI and EVT effect, all BMI classes may expect the same benefit from EVT.

Download Full-text

Cerebral Microbleeds and Treatment Effect of Intravenous Thrombolysis in Acute Stroke: An Analysis of the WAKE-UP Randomized Clinical Trial

Neurology ◽

10.1212/wnl.0000000000013055 ◽

2021 ◽

pp. 10.1212/WNL.0000000000013055

Author(s):

Ludwig Schlemm ◽

Tim Bastian Braemswig ◽

Florent Boutitie ◽

Jan Vynckier ◽

Märit Jensen ◽

...

Keyword(s):

Ischemic Stroke ◽

Acute Ischemic Stroke ◽

Functional Outcome ◽

Treatment Effect ◽

Intravenous Thrombolysis ◽

Stroke Patients ◽

Randomized Controlled ◽

Link Type ◽

Increased Risk ◽

Search Trial

Background and ObjectivesCerebral microbleeds (CMBs) are common in acute ischemic stroke patients 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 pre-specified analysis of the prospective randomized controlled multicenter WAKE-UP trial including patients with acute ischemic stroke with unknown time of symptom onset and DWI-FLAIR 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 intravenous thrombolysis with alteplase at 0.9 mg / kg body weight or placebo. CMB status (presence, number, and distribution) was assessed after study completion by three raters blinded to clinical information following a standardized protocol. Outcome measures were excellent functional outcome at 90 days, defined by modified Rankin Scale score (mRS)≤1, and symptomatic intracerebral hemorrhage (ICH) according to NINDS 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; 98 (21.4%) had at least 1 CMB on baseline imaging; 45 (9.8%) had exactly 1 CMB, 37 (8.1%) had 2-4 CMBs, and 16 (3.5%) had ≥5 CMBs. Presence of CMBs was associated with a non-significant increased risk of symptomatic ICH (11.2% versus 4.2%; adjusted odds ratio 2.32 [95% CI 0.99-5.43]; P=.052), but had no effect on functional outcome at 90 days (mRS≤1: 45.8% versus 50.7%; adj. OR 0.99 [0.59-1.64]; P=.955). Patients receiving alteplase had better functional outcome (mRS≤1: 54.6% versus 44.6%, adj. OR 1.61 [1.07-2.43], P=.022) without evidence of heterogeneity in relation to CMB presence (P value of the interactive term .546). Results were similar for subpopulations with strictly lobar (presumed cerebral amyloid angiopathy-related) or non-strictly-lobar CMB distribution.DiscussionIn the randomized-controlled WAKE-UP trial, we saw no evidence of reduced treatment effect of alteplase in acute ischemic stroke patients with one or more 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 registrationClinicalTrials.gov number, NCT01525290 (https://clinicaltrials.gov/ct2/show/NCT01525290); EudraCT number, 2011-005906-32 (https://www.clinicaltrialsregister.eu/ctr-search/trial/2011-005906-32/GB).Classification of EvidenceThis study provides Class II evidence that for patients with acute ischemic stroke with unknown time of onset and DWI-FLAIR mismatch who received IV alteplase, CMBs are not significantly associated with functional outcome at 90 days.

Download Full-text

Is Differential Activity of Enoxaparin and Unfractionated Heparin According to the Location of Deep-Vein Thrombosis in Acute Ischemic Stroke Patients Driven by Different Pathogenic Mechanisms?.

Blood ◽

10.1182/blood.v110.11.303.303 ◽

2007 ◽

Vol 110 (11) ◽

pp. 303-303

Author(s):

Ludovic Drouet ◽

David G. Sherman ◽

Gregory W. Albers ◽

Christopher Bladin ◽

Cesare Fieschi ◽

...

Keyword(s):

Ischemic Stroke ◽

Relative Risk ◽

Ct Scan ◽

Acute Ischemic Stroke ◽

Motor Impairment ◽

The Body ◽

Stroke Patients ◽

Post Hoc Analysis ◽

Post Hoc ◽

Deep Vein

Abstract Introduction Studies of patients undergoing hip surgery have shown that approximately two-thirds of subsequent deep-vein thromboses (DVT) were ipsilateral to the surgery and that not all thromboprophylactic agents were equally effective in reducing DVT on both sides of the body. This suggests a possible difference in the mechanisms of action of these agents. In PREVAIL, a study of VTE prophylaxis in acute ischemic stroke patients, we assessed the relationship between the side of the body affected by motor impairment, the side on which a DVT occurred, and the comparative effects of enoxaparin and UFH on the incidence of ipsilateral and contralateral DVT. Methods Patients with acute ischemic stroke (confirmed by CT scan or MRI) and unable to walk unassisted due to motor impairment of the leg were randomized, within 48h of symptom onset, to receive enoxaparin 40mg subcutaneously once-daily or UFH 5000 IU subcutaneously every 12h for 10±4 days. DVT was confirmed by venography, or ultrasonography when venography was not practical. Pulmonary embolism (PE) was confirmed by VQ or CT scan, or angiography. We conducted a post hoc analysis to test: the correlation between side of motor impairment and side of subsequent DVT; the relative risk reduction for DVT, associated with enoxaparin versus UFH when DVT and motor impairment were ipsilateral or contralateral. Differences between the sides of motor impairment and VTE were tested using the McNemar test. Results The PREVAIL study reported a 43% relative reduction in the risk of symptomatic or asymptomatic DVT, symptomatic PE, or fatal PE with enoxaparin compared with UFH in acute ischemic stroke patients (10.2% versus 18.1%, p=0.0001), with no increase in clinically important bleeding. The current analyses, investigating the incidence of unilateral DVT, demonstrated a good concordance between the side of the motor impairment and subsequent DVT (McNemar test, p=0.47 suggesting strong correlation). The benefit of enoxaparin compared with UFH for reducing the risk of DVT was significant for ipsilateral DVT, but not contralateral DVT (see Table). Table: DVT incidence in acute ischemic stroke patients relative to the side of motor impairment Side of DVT relative to motor impairment Enoxaparin (N=613) UFH (N=609) Relative Risk [95% CI] P value* *Chi-squared test Ipsilateral, n (%) 33 (5.4) 60 (9.9) 0.55 [0.36–0.82] 0.003 Contralateral, n (%) 21 (3.4) 26 (4.3) 0.80 [0.46–1.41] 0.44 Conclusion Our observations in this post hoc analysis of PREVAIL study data are consistent with the hypothesis that the relative effectiveness of enoxaparin compared with UFH may be more important for flow-dependent thrombogenic factors (ipsilateral side of DVT) than for inflammation (hypercoagulability)-dependent thrombogenic factors (contralateral side of DVT). Further research is warranted to confirm this hypothesis.

Download Full-text

Benefit of Intravenous Thrombolysis in Acute Ischemic Stroke Patients With High Cerebral Microbleed Burden

Stroke ◽

10.1161/strokeaha.119.027633 ◽

2020 ◽

Vol 51 (1) ◽

pp. 232-239 ◽

Cited By ~ 1

Author(s):

Ludwig Schlemm ◽

Matthias Endres ◽

David J. Werring ◽

Christian H. Nolte

Keyword(s):

Ischemic Stroke ◽

Acute Ischemic Stroke ◽

Treatment Effect ◽

Older Patients ◽

Intravenous Thrombolysis ◽

Modified Rankin Scale ◽

Resonance Imaging ◽

Stroke Patients ◽

Treatment Delays ◽

Point Estimates

Background and Purpose— Cerebral microbleeds (CMBs) are a risk factor for intracranial hemorrhage. Whether intravenous thrombolysis (IVT) improves functional outcome in acute ischemic stroke patients with CMBs is unknown. We aimed to estimate the treatment effect of IVT in patients with acute ischemic stroke and a high burden (>10) of CMBs. Methods— We devised a multistep algorithm to model 90-day modified Rankin Scale scores in patients with ≤10 versus >10 CMBs who do or do not receive IVT. Parameters were extracted from recently published meta-analyses and included pairwise relationships between CMBs, IVT, 3-month functional outcome, and intracranial hemorrhage. Uncertainty was quantified in probabilistic sensitivity analyses. Results— In patients with >10 CMBs as compared with ≤10 CMBs, point estimates of the odds ratios for favorable outcome (modified Rankin Scale ≤2) associated with IVT were 7% to 10% lower but still >1 (range, 1.03–1.51). On the other hand, IVT in patients with >10 CMBs significantly increased the odds of mortality. The point estimates for the net treatment effect of IVT (change in the utility-weighted modified Rankin Scale score) in patients with >10 CMBs were in favor of withholding IVT in older patients with more severe strokes and longer treatment delays. However, because the general pretest probability of >10 CMBs is low (0.6%–2.7%), pretreatment magnetic resonance imaging to quantify CMB burden would be justified only if it delayed IVT by <10 minutes. Conclusions— High CMB burden modifies the treatment effect of IVT. In patients with >10 CMBs, IVT is associated with higher mortality and, in older patients with severe strokes and longer treatment delays, a net utility loss. Patients with higher-than-average pretest probability of >10 CMB might profit from magnetic resonance imaging screening if it does not increase the treatment time.

Download Full-text

Management of acute ischemic stroke in patients with COVID-19 infection: Report of an international panel

International Journal of Stroke ◽

10.1177/1747493020923234 ◽

2020 ◽

Vol 15 (5) ◽

pp. 540-554 ◽

Cited By ~ 39

Author(s):

Adnan I Qureshi ◽

Foad Abd-Allah ◽

Fahmi Al-Senani ◽

Emrah Aytac ◽

Afshin Borhani-Haghighi ◽

...

Keyword(s):

Ischemic Stroke ◽

Acute Ischemic Stroke ◽

Current Knowledge ◽

Intravenous Thrombolysis ◽

Adult Patients ◽

World Health ◽

Stroke Patients ◽

International Panel ◽

Health Organization ◽

Tract Infections

Background and purpose On 11 March 2020, World Health Organization (WHO) declared the COVID-19 infection a pandemic. The risk of ischemic stroke may be higher in patients with COVID-19 infection similar to those with other respiratory tract infections. We present a comprehensive set of practice implications in a single document for clinicians caring for adult patients with acute ischemic stroke with confirmed or suspected COVID-19 infection. Methods The practice implications were prepared after review of data to reach the consensus among stroke experts from 18 countries. The writers used systematic literature reviews, reference to previously published stroke guidelines, personal files, and expert opinion to summarize existing evidence, indicate gaps in current knowledge, and when appropriate, formulate practice implications. All members of the writing group had opportunities to comment in writing on the practice implications and approved the final version of this document. Results This document with consensus is divided into 18 sections. A total of 41 conclusions and practice implications have been developed. The document includes practice implications for evaluation of stroke patients with caution for stroke team members to avoid COVID-19 exposure, during clinical evaluation and performance of imaging and laboratory procedures with special considerations of intravenous thrombolysis and mechanical thrombectomy in stroke patients with suspected or confirmed COVID-19 infection. Conclusions These practice implications with consensus based on the currently available evidence aim to guide clinicians caring for adult patients with acute ischemic stroke who are suspected of, or confirmed, with COVID-19 infection. Under certain circumstances, however, only limited evidence is available to support these practice implications, suggesting an urgent need for establishing procedures for the management of stroke patients with suspected or confirmed COVID-19 infection.

Download Full-text

Acute reperfusion therapies for acute ischemic stroke patients with unknown time of symptom onset or in extended time windows: an individualized approach

Therapeutic Advances in Neurological Disorders ◽

10.1177/17562864211021182 ◽

2021 ◽

Vol 14 ◽

pp. 175628642110211

Author(s):

Georgios Magoufis ◽

Apostolos Safouris ◽

Guy Raphaeli ◽

Odysseas Kargiotis ◽

Klearchos Psychogios ◽

...

Keyword(s):

Ischemic Stroke ◽

Endovascular Treatment ◽

Acute Ischemic Stroke ◽

Symptom Onset ◽

Time Windows ◽

Intravenous Thrombolysis ◽

Inclusion Criteria ◽

Stroke Patients ◽

Treatment Algorithms ◽

Late Presenters

Recent randomized controlled clinical trials (RCTs) have revolutionized acute ischemic stroke care by extending the use of intravenous thrombolysis and endovascular reperfusion therapies in time windows that have been originally considered futile or even unsafe. Both systemic and endovascular reperfusion therapies have been shown to improve outcome in patients with wake-up strokes or symptom onset beyond 4.5 h for intravenous thrombolysis and beyond 6 h for endovascular treatment; however, they require advanced neuroimaging to select stroke patients safely. Experts have proposed simpler imaging algorithms but high-quality data on safety and efficacy are currently missing. RCTs used diverse imaging and clinical inclusion criteria for patient selection during the dawn of this novel stroke treatment paradigm. After taking into consideration the dismal prognosis of nonrecanalized ischemic stroke patients and the substantial clinical benefit of reperfusion therapies in selected late presenters, we propose rescue reperfusion therapies for acute ischemic stroke patients not fulfilling all clinical and imaging inclusion criteria as an option in a subgroup of patients with clinical and radiological profiles suggesting low risk for complications, notably hemorrhagic transformation as well as local or remote parenchymal hemorrhage. Incorporating new data to treatment algorithms may seem perplexing to stroke physicians, since treatment and imaging capabilities of each stroke center may dictate diverse treatment pathways. This narrative review will summarize current data that will assist clinicians in the selection of those late presenters that will most likely benefit from acute reperfusion therapies. Different treatment algorithms are provided according to available neuroimaging and endovascular treatment capabilities.

Download Full-text

Incorporation of α2-Plasmin Inhibitor into Fibrin Clots and Its Association with the Clinical Outcome of Acute Ischemic Stroke Patients

Biomolecules ◽

10.3390/biom11030347 ◽

2021 ◽

Vol 11 (3) ◽

pp. 347

Author(s):

Zsuzsa Bagoly ◽

Barbara Baráth ◽

Rita Orbán-Kálmándi ◽

István Szegedi ◽

Réka Bogáti ◽

...

Keyword(s):

Ischemic Stroke ◽

Acute Ischemic Stroke ◽

Intracranial Hemorrhage ◽

Intravenous Thrombolysis ◽

Fibrin Clot ◽

Clot Lysis ◽

Stroke Patients ◽

Plasmin Inhibitor ◽

Fibrin Clots

Cross-linking of α2-plasmin inhibitor (α2-PI) to fibrin by activated factor XIII (FXIIIa) is essential for the inhibition of fibrinolysis. Little is known about the factors modifying α2-PI incorporation into the fibrin clot and whether the extent of incorporation has clinical consequences. Herein we calculated the extent of α2-PI incorporation by measuring α2-PI antigen levels from plasma and serum obtained after clotting the plasma by thrombin and Ca2+. The modifying effect of FXIII was studied by spiking of FXIII-A-deficient plasma with purified plasma FXIII. Fibrinogen, FXIII, α2-PI incorporation, in vitro clot-lysis, soluble fibroblast activation protein and α2-PI p.Arg6Trp polymorphism were measured from samples of 57 acute ischemic stroke patients obtained before thrombolysis and of 26 healthy controls. Increasing FXIII levels even at levels above the upper limit of normal increased α2-PI incorporation into the fibrin clot. α2-PI incorporation of controls and patients with good outcomes did not differ significantly (49.4 ± 4.6% vs. 47.4 ± 6.7%, p = 1.000), however it was significantly lower in patients suffering post-lysis intracranial hemorrhage (37.3 ± 14.0%, p = 0.004). In conclusion, increased FXIII levels resulted in elevated incorporation of α2-PI into fibrin clots. In stroke patients undergoing intravenous thrombolysis treatment, α2-PI incorporation shows an association with the outcome of therapy, particularly with thrombolysis-associated intracranial hemorrhage.

Download Full-text