The smoking paradox in ischemic stroke patients treated with intra-arterial thrombolysis in combination with mechanical thrombectomy–VISTA-Endovascular

Abstract

Background The smoking-paradox of a better outcome in ischemic stroke patients who smoke may be due to increased efficacy of thrombolysis. We investigated the effect of smoking on outcome following endovascular therapy (EVT) with mechanical thrombectomy alone versus in combination with intra-arterial (IA-) thrombolysis. Methods The primary endpoint was defined by three-month modified Rankin Scale (mRS). We performed a generalized linear model and reported relative risks (RR) for smoking (adjustment for age, sex, hypertension, atrial fibrillation, stroke severity, time to EVT) in patient data stemming from the Virtual International Stroke Trials Archive—Endovascular database. Results Among 1,497 patients, 740(49.4%) were randomized to EVT; among EVT patients, 524(35.0%) received mechanical thrombectomy alone and 216(14.4%) received it in combination with IA-thrombolysis. Smokers (N = 396) had lower mRS scores (mean 2.9 vs. 3.2; p = 0.02) and mortality rates (10% vs. 17.3%; p<0.001) in univariate analysis. In all patients and in patients treated with mechanical thrombectomy alone, smoking had no effect on outcome in regression analyses. In patients who received IA-thrombolysis (N = 216;14%), smoking had an adjusted RR of 1.65 for an mRS≤1 (95%CI 0.77–3.55). Treatment with IA-thrombolysis itself led to reduced RR for favorable outcome (adjusted RR 0.30); interaction analysis of IA-thrombolysis and smoking revealed that non-smokers with IA-thrombolysis had mRS≤2 in 47 cases (30%, adjusted RR 0.53 [0.41–0.69]) while smokers with IA-thrombolysis had mRS≤2 in 23 cases (38%, adjusted RR 0.61 [0.42–0.87]). Conclusions Smokers had no clear clinical benefit from EVT that incorporates IA-thrombolysis.

Relation of Pre‐Stroke Aspirin Use With Cerebral Infarct Volume and Functional Outcomes

“…In the analysis of the relationship between pre‐stroke aspirin use and infarct volume, WMH volume was included as a covariate in the augmented IPW analysis to explore the association between pre‐stroke aspirin use and infarct volume independently of WMH burden, which has been shown to associate with larger infarct volume 35 and more frequent infarct growth 36 . For hemorrhagic transformation, early neurological deterioration, and favorable 3‐month outcome, adjusted odds ratios (95% confidence interval [CI]) of pre‐stroke aspirin use (vs nonuse) were also estimated by using multivariable logistic regression analysis in the inverse probability weighted data with adjustment for the covariates that were used for the augmented IPW 28–34 . As a priori subgroup analyses, effect modification by stroke subtypes was assessed using multiple linear regression analysis (for infarct volume) or multivariable logistic regression analysis (for hemorrhagic transformation, early neurological deterioration, and favorable 3‐month outcome) in the inverse probability weighted data, with adjustment for the covariates that were used for the IPW.…”

“…In the inverse probability weighted data, potential outcome means 27 of aspirin users and nonusers and subsequently intergroup differences were estimated for (1) infarct volume, (2) the incidence of hemorrhagic transformation, (3) the incidence of early neurological deterioration, and (4) the proportion of favorable functional outcome at 3 months (mRS scores 0–2) by using the teffects aipw function in STATA software to perform augmented IPW: a “doubly robust” method 27 combining IPW with outcome regression. In the outcome regression of the augmented IPW, predefined variables that have been reported to be associated with infarct volume or stroke outcomes 28 , 29 , 30 , 31 , 32 , 33 , 34 were used. In the analysis of the relationship between pre‐stroke aspirin use and infarct volume, WMH volume was included as a covariate in the augmented IPW analysis to explore the association between pre‐stroke aspirin use and infarct volume independently of WMH burden, which has been shown to associate with larger infarct volume 35 and more frequent infarct growth.…”

“… 36 For hemorrhagic transformation, early neurological deterioration, and favorable 3‐month outcome, adjusted odds ratios (95% confidence interval [CI]) of pre‐stroke aspirin use (vs nonuse) were also estimated by using multivariable logistic regression analysis in the inverse probability weighted data with adjustment for the covariates that were used for the augmented IPW. 28 , 29 , 30 , 31 , 32 , 33 , 34 As a priori subgroup analyses, effect modification by stroke subtypes was assessed using multiple linear regression analysis (for infarct volume) or multivariable logistic regression analysis (for hemorrhagic transformation, early neurological deterioration, and favorable 3‐month outcome) in the inverse probability weighted data, with adjustment for the covariates that were used for the IPW. Moreover, a sensitivity analysis of the relationship between aspirin use and infarct volume was performed using augmented IPW in patients who underwent MRI within 24 hours of stroke onset.…”

No Paradoxical Effect of Smoking Status on Recurrent Cardiovascular Events in Patients Following Percutaneous Coronary Intervention: Thai PCI Registry

“…This data suggests that a pharmacoinvasive strategy is suitable for the treatment of current smokers who develop STEMI in rural areas and cannot be transferred to primary PCI centers within 120 min, as recommended in the guidelines. This aggressive beneficial approach was supported by the recent publication of the smoking paradox in patients with ischemic stroke who were treated with intra-arterial thrombolysis in combination with mechanical thrombectomy ( 29 ).…”

Effects of Nicotine Exposure From Tobacco Products and Electronic Cigarettes on the Pathogenesis of Neurological Diseases: Impact on CNS Drug Delivery

“…Although tobacco use increases the risk of ischemic stroke, some studies have demonstrated a paradoxical association between current smoking and favorable stroke outcome following intravenous thrombolysis with r-tPA or endovascular treatment (Ovbiagele and Saver 2005;Ali et al, 2013;Kufner et al, 2013;Kvistad et al, 2014;Hussein et al, 2017;Kufner et al, 2021). Studies of this smoking-thrombolysis paradox have shown that TS use is associated with reduced infarct growth, as well as a higher rate of recanalization and reperfusion in TS users treated with IV r-tPA, following ischemic stroke (Kufner et al, 2013).…”