ischemic stroke is a disease with substantial etiologic heterogeneity , including large artery atherothrombotic disease , small artery atherothrombotic disease , cardioembolism , and other subtypes . hmg - coa reductase inhibitors , or  statins ,  are established therapeutic agents for the prevention of atherosclerotic - based large or small vessel vascular events . indeed , in a randomized trial assessing the impact of statin use on recurrent vascular events of atherosclerotic origin , the stroke prevention by aggressive reduction in cholesterol levels ( sparcl ) study , high dose atorvastatin significantly reduced the risk of recurrent stroke as well as recurrent major vascular events . however , in order to target recent stroke patients with atherosclerotic disease , sparcl excluded patients with atrial fibrillation . based on published data , it remains unclear as to whether statin therapy should be applied to the substantial numbers of ischemic stroke patients who have atrial fibrillation as an identified potential mechanism of their event , including patients with and without hypercholesterolemia and patients with and without evidence of tandem large or small vessel atherosclerotic disease . as far as we are aware , there are no ongoing clinical trials designed to address this issue . clarifying whether statins are beneficial in atrial fibrillation patients with ischemic stroke would assist with a common management dilemma . among ischemic stroke patients in the taiwan stroke registry , 16.5% had atrial fibrillation , and 49.4% had dyslipidemia , with 8% of these patients having both atrial fibrillation and hypercholesteremia . beside their effect of lowering cholesterol to mitigate symptomatic atherosclerosis , statins have pleiotropic antithrombotic , anti - inflammatory , and additional actions that also may be beneficial in lowering vascular risk in patients with atrial fibrillation . for instance , atrial fibrillation upregulates cd40 expression and platelet adhesion to the endocardium , and simvastatin is effective in modulating this expression , potentially reducing the risk of intra - atrial thrombus formation . also , a randomized controlled trial enrolling 34 elderly patients with atrial fibrillation showed that intensive cholesterol lowering with atorvastatin significantly reduced inflammation and was accompanied by reduced thrombin generation . to investigate whether statin therapy can influence the prognosis , such as recurrent stroke and mortality , in recent ischemic stroke patients with atrial fibrillation , we conducted a retrospective cohort study in taiwan using the national health insurance research database ( nhird ) . taiwan implemented a single - payer , compulsory national health insurance program in 1995 , which includes reimbursement of outpatient visits , hospital admissions , and prescriptions for 99% of the taiwanese population . all contracted institutions must file claims according to standard formats , which later are archived in the nhird . we identified all hospitalized patients ( 18 years ) who were admitted with a primary diagnosis of ischemic stroke ( international classification of diseases , ninth revision ( icd-9 ) codes 433 , 434 , 436 ) for the first time between 2001 and 2011 . only patients who had atrial fibrillation ( icd-9 code 427.31 ) documented prior to the index stroke or in a list of hospitalization diagnoses during the index stroke admission were included in our analysis . in order to show the effect of statin therapy , patients were excluded if they had a recurrent stroke 90 days after the index stroke or follow - up 90 days . we also excluded patients who undergo hemodialysis because it is still unclear whether statin is benefit for these patients . patients receiving at least 30 days of statin therapy within 90 days after the index stroke were categorized in the statin group , whereas patients not receiving any statin therapy within 90 days were categorized in a comparison group . patients receiving some statin therapy , but less than 30 days , within 90 days after index stroke were excluded . during the study period , the national reimbursement policy for statin prescriptions supported statin prescriptions for patients with total cholesterol 200  mg / dl or low - density lipoprotein cholesterol 130  mg / dl . comorbidities were identified using icd-9 codes based on coding of concomitant diagnoses during the index stroke admission and on coding for outpatient visit before the index stroke . heart failure was diagnosed solely from the hospitalization diagnoses since coding for this diagnosis is less reliable in the outpatient setting in taiwan . the stroke severity index , which was developed specifically to evaluate the severity of strokes in taiwan nhird , was used to generate an estimated national institutes of health stroke scale ( e - nihss ) score for the index stroke . the pearson correlation coefficient between the e - nihss and the nihss real scores was 0.742 ( 95% ci : 0.736 , 0.747 ) . patients not treated with statins in the first 90 days after the index stroke were matched to patients treated with statins in the first 90 days in a 2:1 ratio on the basis of age , sex , hypertension , diabetes mellitus , ischemic heart disease , heart failure , e - nihss , use of anticoagulant ( warfarin , dabigatran , and rivaroxaban ) in the first 90 days after index stroke , and year of their entry into the cohort . the study protocol was approved by the institutional review boards of chang gung memorial hospital . the primary outcome of this study was the first event of recurrent stroke ( combined endpoint of ischemic and hemorrhagic stroke ) , validated by the use of brain computed tomography or magnetic resonance imaging . the requirement for imaging served to exclude stroke patients who were hospitalized solely for rehabilitation during chronic stage . the leading secondary outcome was in - hospital death , defined as any death during a hospitalization during the follow - up period . additional outcomes were hemorrhagic stroke ( icd-9 codes 430432 ) , ischemic stroke ( icd-9 codes 433434 , 436 ) , fatal stroke , myocardial infarction ( icd-9 code 410 ) , and major adverse cardiovascular events ( comprised of any ischemic or hemorrhagic stroke , and myocardial infarction ) . causes of death were defined according to the primary diagnosis of the hospitalization during which the death occurred . fatal stroke was defined as in - hospital death during the first recurrent ischemic or hemorrhagic stroke . cardiovascular death was defined as in - hospital death caused by stroke ( icd-9 codes 430438 ) , ischemic heart disease ( icd-9 codes 410414 ) , cardiac arrhythmia ( icd-9 codes 425427 ) , or heart failure ( icd-9 code 428 ) . noncardiovascular death was defined as in - hospital death with primary diagnosis other than cardiovascular death . we also analyzed the subgroup of patients not having diabetes mellitus at baseline to see whether statin therapy was associated with increased incident diabetes mellitus . the follow - up period for outcome events started from the date of index stroke to the date of last medical claim , stroke recurrence , death during any hospitalization , or the end of 2012 , whichever came first . the association between statin therapy and recurrent stroke in stroke patients with atrial fibrillation was analyzed using the cox proportional hazards model and presented as hazard ratios ( hr ) with 95% confidence intervals ( 95% ci ) , and so did subgroups and interactions . all statistics analyses were performed with sas statistical software , version 9.2 ( sas institute inc . , cary , nc ) . a 2-sided p value  <  0.05 was considered to be statistically significant . taiwan implemented a single - payer , compulsory national health insurance program in 1995 , which includes reimbursement of outpatient visits , hospital admissions , and prescriptions for 99% of the taiwanese population . all contracted institutions must file claims according to standard formats , which later are archived in the nhird . we identified all hospitalized patients ( 18 years ) who were admitted with a primary diagnosis of ischemic stroke ( international classification of diseases , ninth revision ( icd-9 ) codes 433 , 434 , 436 ) for the first time between 2001 and 2011 . only patients who had atrial fibrillation ( icd-9 code 427.31 ) documented prior to the index stroke or in a list of hospitalization diagnoses during the index stroke admission were included in our analysis . in order to show the effect of statin therapy , patients were excluded if they had a recurrent stroke 90 days after the index stroke or follow - up 90 days . we also excluded patients who undergo hemodialysis because it is still unclear whether statin is benefit for these patients . patients receiving at least 30 days of statin therapy within 90 days after the index stroke were categorized in the statin group , whereas patients not receiving any statin therapy within 90 days were categorized in a comparison group . patients receiving some statin therapy , but less than 30 days , within 90 days after index stroke were excluded . during the study period , the national reimbursement policy for statin prescriptions supported statin prescriptions for patients with total cholesterol 200  mg / dl or low - density lipoprotein cholesterol 130  mg / dl . comorbidities were identified using icd-9 codes based on coding of concomitant diagnoses during the index stroke admission and on coding for outpatient visit before the index stroke . heart failure was diagnosed solely from the hospitalization diagnoses since coding for this diagnosis is less reliable in the outpatient setting in taiwan . the stroke severity index , which was developed specifically to evaluate the severity of strokes in taiwan nhird , was used to generate an estimated national institutes of health stroke scale ( e - nihss ) score for the index stroke . the pearson correlation coefficient between the e - nihss and the nihss real scores was 0.742 ( 95% ci : 0.736 , 0.747 ) . patients not treated with statins in the first 90 days after the index stroke were matched to patients treated with statins in the first 90 days in a 2:1 ratio on the basis of age , sex , hypertension , diabetes mellitus , ischemic heart disease , heart failure , e - nihss , use of anticoagulant ( warfarin , dabigatran , and rivaroxaban ) in the first 90 days after index stroke , and year of their entry into the cohort . the study protocol was approved by the institutional review boards of chang gung memorial hospital . the primary outcome of this study was the first event of recurrent stroke ( combined endpoint of ischemic and hemorrhagic stroke ) , validated by the use of brain computed tomography or magnetic resonance imaging . the requirement for imaging served to exclude stroke patients who were hospitalized solely for rehabilitation during chronic stage . the leading secondary outcome was in - hospital death , defined as any death during a hospitalization during the follow - up period . additional outcomes were hemorrhagic stroke ( icd-9 codes 430432 ) , ischemic stroke ( icd-9 codes 433434 , 436 ) , fatal stroke , myocardial infarction ( icd-9 code 410 ) , and major adverse cardiovascular events ( comprised of any ischemic or hemorrhagic stroke , and myocardial infarction ) . causes of death were defined according to the primary diagnosis of the hospitalization during which the death occurred . fatal stroke was defined as in - hospital death during the first recurrent ischemic or hemorrhagic stroke . cardiovascular death was defined as in - hospital death caused by stroke ( icd-9 codes 430438 ) , ischemic heart disease ( icd-9 codes 410414 ) , cardiac arrhythmia ( icd-9 codes 425427 ) , or heart failure ( icd-9 code 428 ) . noncardiovascular death was defined as in - hospital death with primary diagnosis other than cardiovascular death . we also analyzed the subgroup of patients not having diabetes mellitus at baseline to see whether statin therapy was associated with increased incident diabetes mellitus . the follow - up period for outcome events started from the date of index stroke to the date of last medical claim , stroke recurrence , death during any hospitalization , or the end of 2012 , whichever came first . the association between statin therapy and recurrent stroke in stroke patients with atrial fibrillation was analyzed using the cox proportional hazards model and presented as hazard ratios ( hr ) with 95% confidence intervals ( 95% ci ) , and so did subgroups and interactions . all statistics analyses were performed with sas statistical software , version 9.2 ( sas institute inc . , cary , nc ) . a 2-sided p value  <  0.05 was considered to be statistically significant . a total of 1546 patients with statin therapy in the first 90 days poststroke and 3092 matched controls were enrolled for this analysis . the mean age was 75.6    7.4 years , and approximately 49% of them were male ( table 1 ) . overall , the index ischemic stroke hospitalization occurred from 2001 to 2006 in 31% of patients and from 2007 to 2011 in 69% . ( there were twice as many patients from the later 5-year period than from the earlier 4-year period because statin was much more widely used after the publication of the sparcl trial in 2006 ) . index ischemic stroke severity was minor ( e - nihss 05 ) in half of the subjects , moderate ( e - nihss 610 ) in 14% , moderate to severe ( e - nihss 1115 ) in 7% , and severe ( e - nihss > 15 ) in 28% . the baseline characteristics were not different between the 2 groups as the result of matching . in the early statin group , 3.8% of subjects had received 2 or more statins during the first 90 poststroke days . the follow - up period was from 0.3 year to 12 year ( median 2.4 years ; interquartile range 1.34.1 years ) . during this period the results revealed no difference in stroke recurrence between early as far as statin - users and early nonusers ( hr  =  1.01 , 95% ci 0.881.15 , p  =  0.92 ) . for the secondary endpoint , early statin use was associated with lower frequency of death during any hospitalization throughout the long - term follow - up period ( hr  =  0.74 , 95% ci 0.610.89 , p  <  0.01 ) ( table 2 ) . this difference was due to a reduced rate of noncardiovascular death ( hr  =  0.70 , 95% ci 0.560.86 , p  <  0.01 ) causes of noncardiovascular death in the 2 groups are shown in table 3 . the effects of statin therapy were similar across the additional endpoints , including ischemic stroke , intracerebral hemorrhage , fatal stroke , myocardial infarction , and major adverse cardiovascular events . among patients not having diabetes mellitus at baseline , early post - stroke statin therapy cox proportional hazard models for primary and secondary end points by statin group vs comparison group . the effects of early statin therapy were consistent across subgroups of age , sex , calendar year , chads2 score , and presenting stroke severity ( fig . no subgroup was identified that either differentially benefitted from statins in preventing recurrent stroke or differentially failed to benefit from statins in preventing in - hospital death . subgroup analysis for recurrent stroke ( a ) and in - hospital death ( b ) between statin and comparison groups . in this analysis of a nationwide cohort study of stroke patients with atrial fibrillation , we found that statin therapy within 3 months of index stroke failed to reduce recurrent stroke risk in the average 3-year follow - up period . however , statin therapy was associated with reduced risk of future in - hospital death , especially of noncardiovascular death . prior randomized trials and observational studies that have shown a benefit of statin therapy in reducing recurrent stroke have focused upon patients whose index ischemic stroke was due to large or small artery atherosclerosis . in sparcl , statin therapy was associated with a reduction in recurrent stroke risk among patients with index ischemic stroke presumed to have occurred  owing to atherosclerotic causes . meta - analyses of statin therapy have also confirmed a beneficial effect of statin therapy in atherosclerotic ischemic stroke patients with regard to stroke recurrence . however , these studies generally excluded patient with atrial fibrillation . in this study , we focused on ischemic stroke patient with atrial fibrillation and found no significant difference between the early statin and nonstatin groups in stroke recurrence . in patients with previous stroke or transient ischemic attack , 2.4% annual recurrent stroke or systemic embolism occurred in the apixaban group , whereas 9.2% annual recurrent stroke or systemic embolism occurred in the aspirin group in a randomized controlled trial . about 40% patients in this study received anticoagulant therapy , mostly warfarin , at baseline and the annual recurrent stroke risk was 8.0% . it was not unreasonable that the annual recurrent stroke risk in this study was higher than patients receiving apixaben in a randomized controlled trial . our findings of an association of statin use with reduced mortality are consonant with some prior studies . several observational studies found that statin treatment is associated with reduced overall mortality in patients with ischemic stroke . also , a cohort study indicated that statins were associated with lower mortality among patients with atrial fibrillation with or without stroke who were less than 80 years old . recently , the results of 2 hospital - based studies showed that statin treatment was independently associated with reduced mortality specifically in patients with atrial fibrillation - related stroke . the mechanisms by which statins may reduce all - cause mortality have not been investigated in detail . prior studies reporting reduced mortality in atrial fibrillation patients with initial ischemic stroke did not explore whether the effect was mediated by reductions in cardiovascular death , noncardiovascular death , or both . choi and colleagues reported that statins did not reduce the rate of recurrent stroke among atrial fibrillation patients , suggesting that the reduced mortality was not due to reduction in fatal recurrent strokes . we found that lower in - hospital death in the statin therapy group was largely driven by lower noncardiovascular death ( e.g. , respiratory complication ) . one prior study has found a reduced risk of pneumonia in thrombolyzed stroke patients when statins are administered . studies have suggested a link between statin use and diabetes in the general population . also , a prior study suggested that statin therapy may increase hemorrhagic stroke risk among ischemic stroke patients . in this study , however , statin therapy was not associated with an increased incidence of future diabetes or hemorrhagic stroke for ischemic stroke patients with atrial fibrillation . one caveat is that the exposure time and cumulative dosage of statin in this study were lower than that in the above clinical trials . a limitation of the current study is that the reasons for use or nonuse of statins early after the ischemic stroke were not directly available from the analyzed administrative data . based on a reimbursement regulation in taiwan , patients were covered to receive statins if they had documented hypercholesterolemia . however , the taiwan national health insurance administration also suggested that physicians stop or reduce statin dosage when the nation goal cholesterol was reached ( total cholesterol<160  mg / dl or low - density lipoprotein cholesterol < 100  mg / dl ) . patients in the statin group had higher baseline cholesterol levels and only 52% continued statin therapy for more than 1 year . the cholesterol levels of patients with statin discontinuation may return to higher levels , thus increasing the risk of recurrent stroke and showing no benefit of statin therapy in stroke prevention . several established stroke risk factors , such as smoking , lifestyle , and laboratory results , such as cholesterol level , were not available in the claims database . the diagnosis of acute ischemic stroke using the administrative data has high , but not perfect , reliability . in one study of the nhird administrative database against the gold standard of the taiwan stroke registry another study , comparing the nhird to detailed diagnoses from review of original hospital medical records , found that 94.5% of acute ischemic stroke patients were assigned we could only use in - hospital mortality in the analysis because encrypted nhird were not linked to the national death registry . furthermore , the accuracy of the recorded primary cause of in - hospital death in nhird is not well validated ; thus , this result should be cautiously interpreted . the effect of different statins in preventing recurrent stroke was not analyzed . in conclusion , statin therapy initiated during the acute to subacute stage of ischemic stroke was not associated with a reduced risk of stroke recurrence in stroke patients with atrial fibrillation . however , statin use was associated with a decreased risk of in - hospital death during follow - up period .