Association Of Blood Pressure Reduction And Immune-related Factors With Clinical Outcomes In Patients With Ischemic Stroke

Stroke is characterized with high morbidity and mortality,and high disability rate.In China,stroke is the leading cause of death and long-term disability.The present study was drawn from the China Antihypertensive Trial in Acute Ischemic Stroke(CATIS),a randomized clinical trial conducted in 26 hospitals across China from August 2009 to May 2013.In Part I,we aimed to assess whether disease severity modifies the effect of early antihypertensive treatment on death and disability among patients with acute ischemic stroke;and whether antihypertensive treatment would reduce cognitive impairment in patients with acute ischemic stroke.In part II,we aimed to test whether rheumatoid factor(RF),complement C3 and anti phosphatidylserine antibodies(a PS)will influence clinical outcomes in patients with acute ischemic stroke.Part IObjectiveTo test whether disease severity would modify the effect of early antihypertensive treatment on death and disability among patients with acute ischemic stroke;and whether antihypertensive treatment would reduce cognitive impairment in patients with acute ischemic stroke.Subjects and MethodsThis study was drawn from the China Antihypertensive Trial in Acute Ischemic Stroke(CATIS).Antihypertensive treatment aimed at lowering systolic BP by 10% to 25% within the first 24 hours after randomization,achieving a systolic BP <140 mm Hg and diastolic BP <90 mm Hg within 7 days,and maintaining this level of BP control during the remainder of a patient’s hospitalization.Demographic characteristics and medical histories were collected at enrollment.Stroke severity was assessed by trained neurologists using NIHSS(scores range from 0 to 42,with higher scores indicating more severe neurologic deficits: 0=no stroke symptoms;1-4=minor stroke;5-15=moderate stroke;16-20=moderate to severe stroke;and 21-42=severe stroke)at baseline.BP was measured every two hours for the first 24 hours,every four hours during the second and third days,and three times a day thereafter until hospital discharge or death.The primary outcome was a combination of death and major disability(modified Rankin Scale 3 to 6).Secondary outcomes included an ordered 7-level categorical score of the modified Rankin Scale,major disability,death,stroke recurrence and vascular events.Homogeneity of treatment effect on all clinical outcomes in subgroups by baseline stroke severity was assessed by adding an interaction term(subgroup × treatment)in logistic regression models.In a pre-planned ancillary study,660 CATIS trial participants were systemically selected prior to randomization from seven participating hospitals for cognitive function assessment at their 3-month follow-up visit.Cognitive function was measured by the Mini-Mental State Examination(MMSE)and Montreal Cognitive Assessment(MOCA).Logistic regression analysis was used to estimate odds ratios(ORs)and 95% confidence intervals(CIs)for cognitive impairment associated with antihypertensive treatment compared with control.ResultsAt 24 hours after randomization,mean systolic BP differences(95% CI)were-8.5(-10.0 to-7.1),-9.8(-11.4 to-8.3),and-9.1(-14.4 to-3.8)mm Hg between the treatment and control groups(all P<0.001)for patients with a baseline NIHSS score of 0-4,5-15,and ≥16,respectively.At day 7 after randomization,the corresponding mean systolic BP differences were-9.3(-10.5 to-8.2),-9.1(-10.3 to-7.8),and-10.1(-15.1 to-5.1)mm Hg between the treatment and control groups(all P<0.001).The primary outcome was not significantly different between the treatment and control groups at day 14 or hospital discharge among all NIHSS subgroups(P for homogeneity=0.66).Odds ratios(95% CI)associated with treatment were 1.14(0.87-1.49,P=0.33),1.04(0.86-1.25,P=0.70),and 0.67(0.18-2.44,P=0.54)for patients with a baseline NIHSS score of 0-4,5-15,and ≥16,respectively.The composite outcome of death and major disability at 3-month follow-up did not differ between the two comparison groups for all NIHSS subgroups.In addition,vascular events and recurrent stroke were not significantly different between the two comparison groups at the 3-month follow-up visit among all NIHSS subgroups except that there was a suggestive risk reduction for recurrent stroke among those with a NIHSS score of 5-15(OR=0.45,95% CI,0.20-0.99,P=0.05).Mean systolic blood pressure was reduced by 21.5 mm Hg in the antihypertensive treatment group and 13.9mm Hg in the control group within 24 h after randomization(P<0.001).Mean systolic blood pressure was 134.9 mm Hg in the antihypertensive treatment group and 141.6 mm Hg in the control group at day 14 after randomization(P<0.001).MMSE score was 26 and MOCA score was 22 in both the antihypertensive treatment and control groups at 3 months.A MMSE<24 was present in 22.8% of patients in the antihypertensive treatment group compared with 22.3% in the control group(OR=1.01;95% CI,0.69–1.48;P=0.97).Likewise,proportions of patients with MOCA<26 were similar between the antihypertensive treatment(70.6%)and control(70.7%)groups(OR=0.99;95% CI,0.70–1.40;P=0.96).Subgroup analyses showed that BP lowering was associated with a significant risk of cognitive impairment defined by Mo CA<26 in patients aged ≥65 years(OR=1.95;95% CI,1.00–3.81;P for homogeneity=0.02).ConclusionEarly BP reduction with antihypertensive medications did not reduce or increase death,major disability,recurrent stroke,and vascular events in acute ischemic stroke patients with a variety of disease severities.Early blood pressure reduction with antihypertensive medication in patients with acute ischemic stroke had no effect on cognitive impairment at 3 months,but subgroup analyses suggested that early antihypertensive treatment might increase cognitive impairment in patients aged ≥65 years but reduce risk among patients <65 years.Part IIObjectiveTo test whether RF,complement C3 and a PS will influence clinical outcomes in patients with acute ischemic stroke.Subjects and MethodsThis study was drawn from the China Antihypertensive Trial in Acute Ischemic Stroke(CATIS).A total of 4071 patients aged ≥22 years who had first-ever ischemic stroke confirmed by computed tomography or magnetic resonance imaging of the brain within 48 hours of symptom onset,and with a systolic BP between 140 and <220 mm Hg were recruited.For present study,597 participants were excluded because they did not offer blood samples,or collected samples were hemolyzed in storage or transport,or failed to measure RF,complement C3 or a PS.Finally,3474 participants were included in analysis.RF and complement C3 were measured using a turbidimetric immunoassay on Roche cobas c systems;a PS was measure using an enzyme-linked immunosorbent assay(ELISA)kits.Cutoff value for positive was RF≥14 IU/m L;Ig G-a PS ≥11 GPS.The primary outcome was a combination of death and major disability(modified Rankin Scale score 3-6)at 14 days or hospital discharge and at 3-month follow-up.Secondary outcomes include death,major disability,recurrent stroke,and vascular events.Logistic regression models were used to analyze the association between RF,complement C3,and a PS with study outcomes.Net reclassification index(NRI)and integrated discrimination improvement(IDI)were calculated to evaluate the predictive value of adding RF,complement C3,and a PS to conventional risk factors.ResultsAt 14 days or hospital discharge,1169 patients had a composite outcome of death or major disability(33.6%).We did not find a significant association of RF,complement C3,and a PS with risks of death or major disability,death,and major disability at 14 days or hospital discharge.Within 3 months,69 patients were lost to follow-up,866 had a composite outcome of death or major disability(99 died),61 developed a recurrent stroke,and 91 experienced vascular events.Patients with positive RF had a higher risk of composite outcome of death or major disability(adjusted OR=1.46,95% CI,1.03-2.07;P=0.03).There was no association between RF and risks of stroke recurrence and vascular events.Adding RF positive to a model containing conventional risk factors slightly improved risk prediction for composite outcome of death or major disability(NRI=0.07,P=0.005;IDI=0.002,P=0.07).Compared to patients with complement C3 <1.33g/L,those patients with complement C3 >1.59g/L had higher risks of composite outcome of death or major disability(OR=1.32,95% CI,1.02-1.71;P=0.04).For one standard deviation increase of complement C3,risks of composite outcome of death or major disability increased by 12%.Adding complement C3 to a model containing conventional risk factors improved risk prediction for composite outcome of death or major disability(NRI=0.08,P=0.04;IDI=0.002,P=0.06).There was no significant association between complement C3 and risks of recurrent stroke and vascular events.Compared to a PS-negative,adjusted ORs(95% CI)associated with a PS-positive were 1.35(1.07-1.71)for composite outcome of death or major disability.For one interquartile range increase of a PS,the adjusted ORs were 1.10(1.01-1.21).Adding a PS status to a model containing conventional risk factors improved risk prediction for composite outcome of death or major disability(NRI=0.11,P=0.006;IDI=0.002,P=0.04).There was no significant association between a PS and risks of recurrent stroke and vascular events.ConclusionIn conclusion,we found that positive RF,elevated complement C3 and positive a PS increased risks of death or major disability at 3 months after an acute ischemic stroke.Adding RF,complement C3 and a PS to conventional risk factors slightly improved risk prediction for death or major disability in patients with acute ischemic stroke.