Study design
This study included stroke patients registered in the Fukuoka Stroke Registry (FSR), a multicenter, hospital-based registry of acute stroke (Appendix in Supplementary Information).25,26 The registry enrolled stroke patients who were admitted to seven participating hospitals within 7 days of stroke onset (University Hospital Medical Information Clinical Trial Registry: UMIN-CTR, Unique ID: UMIN000000800, 2007/9/1). This study was performed in accordance with the Declaration of Helsinki. The study design was approved by the Institutional Review Boards of all the participating hospitals: Kyushu University Institutional Review Board for Clinical Research, 22086-00; Kyushu Medical Center Institutional Review Board, R06-03; Clinical Research Review Board of Fukuoka-Higashi Medical Center, 29-C-38; Fukuoka Red Cross Hospital Institutional Review Board, 629; St. Mary’s Hospital Research Ethics Review Committee, S13-0110; Steel Memorial Yawata Hospital Ethics Committee, 06-04-13; and Kyushu Rosai Hospital Institutional Review Board, 21-8. Written informed consent was obtained from all the participants. If the patients could not provide consent, permission was obtained from their family members.
Stroke was defined as the sudden onset of nonconvulsive and focal neurological deficits. Ischemic stroke was diagnosed using brain computed tomography, magnetic resonance imaging, or both. Reperfusion therapy included intravenous thrombolysis using recombinant tissue plasminogen activator (tPA) and endovascular therapies, such as mechanical thrombectomy and intra-arterial thrombolysis.
Patient selection
A total of 14,501 patients with acute ischemic stroke were registered in the FSR between July 2007 and November 2018; of these, 13,005 patients who did not receive acute reperfusion therapy were excluded. Patients excluded among the 1,496 who received acute reperfusion therapy included (i) 321 patients with impaired activities of daily living before stroke onset, defined as a modified Rankin Scale (mRS) score ≥2 and (ii) 27 patients who could not be followed up at 3 months poststroke. Finally, this study analyzed the data of 1,148 patients with acute ischemic stroke who were independent before stroke onset and received acute reperfusion therapy (Supplementary Fig. S1).
Smoking status
On admission or during hospitalization, stroke patients or their family members were asked about the pre-stroke smoking status of patients using the questionnaire developed in Specific Health Checkups and Guidance in Japan.27 The patients were divided into two groups based on their smoking status: (i) current and (ii) noncurrent smokers. A current smoker was defined as a patient with a smoking history within 6 months preceding the index stroke. A noncurrent smoker was defined as a patient who had previously smoked (former smoker) but had stopped smoking for 6 months before the index stroke or a patient who had never smoked (never smoker).5,19,28
Clinical assessment
Background characteristics, including cardiovascular risk factors (hypertension, diabetes mellitus, dyslipidemia, and atrial fibrillation) and history of any stroke, were assessed based on previously described definitions.25,26 Ischemic stroke was classified into four subtypes according to the TOAST criteria29: cardioembolism, large artery atherosclerosis, small vessel occlusion, and others. Stroke severity was assessed using the National Institutes of Health Stroke Scale (NIHSS) and categorized into minor or non-minor stroke according to the NIHSS score on admission, 1–9 or ≥10, respectively. The NIHSS score was evaluated at admission and discharge. Functional outcomes were assessed using the mRS. Trained stroke neurologists assessed the NIHSS and mRS scores during hospitalization. Trained and certified research nurses evaluated the mRS score at 3 months poststroke through telephonic assessment using a standardized structured questionnaire validated in a previous study aimed at minimizing the inter-rater variability.30 We also collected information on acute reperfusion therapy during hospitalization, including thrombolytic therapy with intravenous recombinant tPA and endovascular therapy with intra-arterial thrombolysis, endovascular thrombectomy, thromboaspiration, or angioplasty.
Study outcomes
The study outcomes were neurological improvement during hospitalization and good functional outcomes at 3 months after stroke onset. Neurological improvement was defined as a ≥4-point decrease in the NIHSS score during hospitalization or 0 point at discharge.31 A good functional outcome was defined as an mRS score of 0–2 at 3 months poststroke.32
Statistical analysis
Baseline characteristics according to smoking status were compared using the chi-square test, unpaired t-test, or Wilcoxon signed-rank sum test, as appropriate. Logistic regression analysis was used to estimate multivariate-adjusted odds ratios and 95% confidence intervals of the study outcomes. The multivariate model included age and the baseline NIHSS score as continuous variables and sex, hypertension, diabetes mellitus, dyslipidemia, atrial fibrillation, alcohol consumption, coronary artery disease, chronic kidney disease, previous stroke, stroke subtype, intravenous thrombolysis, and endovascular therapy as categorical variables.33 In the subgroup analyses, patients were divided into two subgroups according to age (<75 or ≥75 years), sex, stroke subtype (cardioembolism or non-cardioembolism), and stroke severity (minor stroke or non-minor stroke). P-values for heterogeneity were calculated by adding the interaction term of smoking status and the variable of interest to the model.
Propensity score-matched analysis was performed to rule out selection bias by controlling baseline differences between current and noncurrent smokers. For propensity score matching, logistic regression modeling was used to calculate propensity scores incorporating the following variables: age, sex, hypertension, diabetes mellitus, dyslipidemia, atrial fibrillation, alcohol consumption, coronary artery disease, chronic kidney disease, previous stroke, stroke subtype, NIHSS score on admission, intravenous thrombolysis, and endovascular therapy. Patients with and without current smoking underwent one-to-one nearest neighbor (greedy type) matching of the standard deviation of the propensity score logit with a caliper width of 0.25. Matching was performed without replacement and unpaired cases and controls that did not meet the matching criteria were excluded. Each propensity score-derived matched pair was assigned a unique pair identification number and 201 matched-pair identification numbers were selected.
The sensitivity analyses examined the associations after categorizing smoking status into three groups: current, former, and never smokers. In addition, this study evaluated the association between current smoking status and clinical outcomes after restricting the study to patients treated with intravenous thrombolysis.
Statistical analyses were performed using Stata 15 software (StataCorp LP, College Station, TX, USA). Two-tailed P-values <0.05 were considered statistically significant.