| BackgroundStroke is the leading cause of long-term disability and mortality in China and increasingly prevalent. Ischemic stroke, accounting for two thirds of stroke, is becoming an ever-increasing public health burden in China. Therefore, it’s becoming emergent to improve outcomes of ischemic stroke. Better understanding ischemic stroke prognostic predictors would improve ischemic stroke outcomes. To literature, previous stroke, neurological impairment, diabetes, hypertension, hyperlipidemia, myocardial infarction, and heart failure are potential indicators for ischemic stroke mortality, recurrence and dependency. Although modifications against these risk factors have improved the outcomes, some unfavorable outcomes remained unexplained by these well documented risk factors, which has led to a search for new risk factors for ischemic stroke prognosis. Recently, antiphospholipid antibodies(a PLs), a heterogeneous family of antibodies to phospholipids and phospholipid-binding proteins, have been found to lead to blood-brain barrier dysfunction, which may allow the influx of a PLs and cytokines into the brain that have toxicity to neurons and glial cells, resulted in aggravation of neurological dificit after ischemic stroke. In addition, a PLs have been linked to thrombosis and associated with incident stroke. Therefore, we hypothesized that a PLs may have a role in prognosis of ischemic stroke, including death, major disability, and subsequent cardiovascular diseases. To examine the prognostic effect of a PLs on the global outcomes of ischemic stroke, we examined three types of a PLs at the time of the onset of ischemic stroke and then prospectively obtained the data on mortality, major disability, and cardiovascular events, within a large, randomized, single-blind clinical trial(the China Antihypertensive Trial in Acute Ischemic Stroke, CATIS) testing whether moderate lowering blood pressure within 48 hours after the onset of ischemic stroke would reduce death or major disability.MethodsOur participants were selected from the CATIS study. It was a multicenter, singleblind, blinded end-points randomized clinical trial conducted in 26 hospitals across China between August 2009 and May 2013. The CATIS recruited 4071 patients aged over 22 years who had ischemic stroke, confirmed by computed tomography or magnetic resonance imaging of the brain within 48 hours of symptom onset. Among the 4071 enrolled patients, 3013 patients received a PLs measurements and included in current analysis. Information was recorded by means of a structured questionnaire about demographic characteristics, lifestyle risk factors, medical history, and time from symptom onset to hospitalization at the time of enrollment. Blood samples were collected immediately after hospitalization prior to any medications. a PLs were quantified by enzyme-linked immunosorbent assays according to the manufacture’s guidelines in the Central Laboratory of School of Public Health in Soochow University. The staff in the laboratory were blind to the characteristics of the stroke patients. We measured three types of a PLs: anticardiolipin antibody, beta(2)-glycoprotein I-dependent anticardiolipin antibody, and antiphosphatidylserine antibody. Patients were considered a PLs positive if one or more of the 3 antibodies excessed the cutoff values.We obtained the outcomes at 14 days or discharge, and 3 months after onset of stroke. The primary outcomes were defined as death or disability. Disability was defined as a score of 3 to 5 on the modified Rankin Scale(m RS) at the follow-up visits. Death or disability was defined as a m RS ≥ 3. The secondary outcomes included death and subsequent cardiovascular events. Cardiovacular events included fatal and nonfatal recurrent stroke, myocardial infarction, pulmonary embolism, heart failure, and peripheral arterial disease. In addition, all adverse events comprising both the primary and secondary outcomes were also used as an outcome in data analysis.Logistic regression analysis was used to estimate odds ratios(ORs) and 95% confidence intervals(CIs) of the study outcomes associated with a PLs positivity compared with a PLs negativity. To evaluate the independent effect of a PLs positivity on outcomes, ORs were adjusted for age, gender, hours from onset to hospitalization, NIHSS score at admission, cigarette smoking, alcohol consumption, history of hypertension, history of hyperlipidemia, history of coronary heart disease, history of diabetes, and ischemic stroke subtypes. These covariates were included in the multivariate model due to an imbalance between a PLs status groups or were reported to be associated with the primary outcome. In addition, Cox proportional hazards model was used to estimate the cumulative incidence of death or subsequent cardiovascular diseases within 3 months after onset associated with a PLs positivity compared with a PLs negativity. To examine the potential influence of coronary heart disease, subtypes of ischemic stroke, and anticoagulation on the results, a series of sensitivity analysis were conducted. ResultsAmong the 3013 ischemic stroke patients, there were 693 patients who demonstrated a PLs positivity. The prevalence of a PLs positivity was 23.00%.At 14 days after stroke or hospital discharge, 1022 patients suffered from death or disability and the incidence rate of the primary outcome was 33.92%. During the follow-up period, we observed 28 deaths(0.93%), 18 cardiovscular events(0.60%), 43 death or cardiovascular events(1.43%), 7 heart failures(0.23%), 9 pulmonary embolisms(0.30%), and 3 myocardial infarctions(0.10%). Collectively, 1030 patients suffered from adverse outcomes and the incidence rate was 34.19%. We failed to find a significant difference in risks for adverse outcomes, and death or disability between a PLs positive and negative patients in either univariate or multivariate analysis(all P > 0.05). We did not find a significant difference in m RS score at 14 days after onset or hospital discharge between the two groups(P = 0.352). In contrast, before multivariate adjustment we found a significantly increased risk for death(OR, 95%CI: 2.94, 1.40-6.21), death or cardiovascular events(OR, 95%CI: 2.45, 1.33-4.52), and pulmonary embolism(OR, 95%CI: 4.10, 1.10-15.29) in patients with a PLs positivity compared with those with a PLs negativity. After multivariate adjustment, a PLs positive patients had a significantly higher risk for death or cardiovascular events(OR = 2.15, P = 0.024) and pulmonary embolism(OR = 4.97, P = 0.019) than a PLs negative patients. Sensitivity analysis showed that among the ischemic stroke patients receiving anticoagulation treatment, a PLs positive patients had a 9 times higher risk for death or cardiovascular events(OR, 95%CI: 10.01, 2.49-40.13) and a 6 times higher risk for pulmonary embolism(OR, 95%CI: 7.20, 1.08-48.01) compared with a PLs negative patients. In stark contrast, among ischemic stroke patients not receiving anticoagulation treatment, no significant difference in risks for any outcomes was observed between a PLs positive and negative patients(all P > 0.05).At the 3 months follow-up visit, 15 patients were lost of follow-up. The follow-up rate was 99.5%. The remained 2998 patients were successfully followed and included in the analysis of the association of a PLs with outcomes within 3 months after onset of stroke. At 3 months after onset 751 patients suffered from death or disability. The incidence rate of primary outcome is 25.04%. During the follow-up period, we observed 83 deaths(2.77%), 102 cardiovascular events(3.40%), 145 death or cardiovascular events(4.83%). Collectively, at 3 months after onset of stroke, 778 patients suffered from adverse outcomes. The incidence rate of adverse outcome was 25.94%. We observed 54 stroke recurrences(1.80%), 35 heart failures(1.17%), 9 pulmonary embolisms(0.33%), and 5 myocardial infarctions(0.17%). a PLs positivity significantly increased the risks for death or disability and adverse outcomes at 3 months after onset of stroke. After multivariate adjustment, a PLs positive patients had a 1.28 times risk for death or disability(P = 0.035) and a 1.29 times risk for adverse outcomes(P = 0.026) as a PLs negative patients. We failed to observe a significant difference in cardiovascular events between a PLs positive and negative patients after multivariate adjustment(P = 0.248), however, we found a significantly increased risk for pulmonary embolism(OR = 4.44, P = 0.028) and heart failure(OR = 2.00, P = 0.050) in a PLs positive patients compared with a PLs negative patients. In addition, the COX proportional hazard model found a significantly higher risk for follow-up days to death or cardiovascular events within 3 months after onset of stroke in a PLs positive patients than a PLs negative patients(Log-rank test, P = 0.015). Sensitivity analysis showed that among ischemic stroke patients receiving anticoagulation treatment, a PLs positive patients had a significantly higher risk for heart failure(OR, 95%CI: 4.62, 1.26-16.96) and pulmonary embolism(OR, 95%CI: 7.19, 1.08-47.96) within 3 months after onset of stroke than a PLs negative patients. In stark contrast, among ischemic stroke patients not receiving anticoagulation treatment, no significant difference in risks for any outcomes was observed between a PLs positive and negative patients(all P > 0.05). ConclusionsOur study found that, compared with a PLs negative patients, a PLs positive patients had significantly increased risks for death or cardiovascular events and pulmonary embolism within 14 days after onset of ischemic stroke or in hospital, and death or disability, heart failure, pulmonary embolism and adverse outcomes within 3 months after onset of ischemic stroke. Our findings suggested that a PLs measurement should be routinely performed for ischemic stroke patients in clinical practice. Those with a PLs positivity should be intensively followed and treated to improve their clinical outcomes. |
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