a retrospective longitudinal observational cohort study was conducted considering multiple antithrombotic treatments for each individual . patients may have had multiple treatment and nontreatment times during the entire follow - up period ( eg , stop therapy , switch therapy , and restart therapy ) . the dynamics of treatment patterns and outcomes associated with them were captured in a longitudinal analysis . kpsc is a nonprofit , integrated healthcare delivery organization with a membership of over 3.6 million people in southern california . kpsc provides integrated , comprehensive medical services through its own facilities , which include 14 hospitals , > 200 outpatient facilities , and a centralized laboratory . all aspects of care and interaction with the healthcare delivery system are captured in a continuously updated electronic medical record ( emr ) system . over 95% of the patients receiving warfarin treatment in kpsc each encounter ( mostly telephone counseling ) at an anticoagulation clinic is stored in the emr system . patients newly diagnosed with atrial fibrillation ( 2 serial international classification of diseases , ninth revision clinical modification [ icd-9-cm ] of 427.31 30  days apart ) in outpatient visit or hospital records were identified between january 1 , 2006 and december 31 , 2011 . the first diagnosis date was defined as the index date and patients were followed until the first outcomes of interest , end of enrollment , death , or december 31 , 2012 , whichever occurred first . individuals who had a history of atrial fibrillation diagnosis , ablation , cardioversion , warfarin prescription , or an anticoagulation clinic visit during 12  months prior to the index date were excluded to ensure that only newly diagnosed nvaf patients were captured . patients < 18  years old at index , without continuous health - plan membership or drug benefit during the 12  months prior to the index date ( gaps of 30  days were treated as continuous membership ) , evidence of pregnancy at any point during the entire follow - up period , and individuals who had valvular diseases , valvular repair , or replacement 12  months prior to the index date were also excluded . in the final study cohort , we excluded patients on novel oral anticoagulation agents ( dabigatran and rivaroxaban : n=101 ) due to small sample size , and patients who only had 1 warfarin prescription but were not followed by an anticoagulation clinic ( n=133 ) , since it would be difficult to confirm these patients were taking warfarin due to lack of monitoring . the analyses were conducted for patients with at least 1 or more major risk factors for stroke ( chads2 1 ) . the current study was reviewed and approved by the kpsc institutional review board . we defined warfarin treatment episodes using prescriptions , inr lab measurements , and anticoagulation clinic data . the start date of a warfarin episode was defined as the first warfarin prescription date , and the end date of the episode was defined as the earliest date with one for the following : ( 1 ) date of discharge from the anticoagulation clinic ; or ( 2 ) the most recent covered date ( last refill date plus days supply ) plus additional 80  days of grace period to incorporate interpersonal variability of warfarin dosage use ; or ( 3 ) inr measurement date plus 80  days of grace period ( regular inr measurement intervals at kpsc [ 8  weeks ] and around 4  weeks of additional period20 ) from the date of discharge . previous literature9,20 applied 30  days of grace period at the end of a prescription because patients may be instructed to take half - doses of warfarin.20 applying a similar concept , we determined 80  days of grace period since this is a mean warfarin days supply at kpsc . ttr was calculated using the linear interpolation method by rosendaal et  al21 expressed as a percentage of observation time , which in our study we defined as each warfarin treatment episode . inr tests performed during hospitalization or inr gaps > 80  days were not interpolated . based on ttr , we stratified patients into 2 different groups ( warfarin ttr 55% , warfarin ttr < 55% ) . the 55% threshold was selected a priori since this level is the lower bound of reported means from previous clinical trials and large observational studies.22,23 the 55% threshold may be understood as the initial cutoff for poor control . stratified analyses were conducted to investigate the outcomes at the different ttr levels based on the distribution of the data . low - dose aspirin ( 75 to 325  mg ) use in the emr , chart notes , and prescription data were searched for the entire nonwarfarin time . we built a natural language processing algorithm2426 to search for low - dose aspirin use information , and 1 evidence of aspirin use was considered as being on aspirin . chart  notes ( 5339 ) from 100 patients records were randomly selected and manually reviewed to validate the algorithm . the algorithm achieved 95.5% sensitivity and 98.9% specificity . we applied 180  days criteria for the first and the last evidence of aspirin use and assumed patients were on aspirin during this period . the nontreatment time after aspirin use was considered as  off aspirin  period . thus , the entire follow - up time for this patient group was considered as  never on therapy  episode . there was another group of patients who started warfarin or aspirin therapy after their index date . the time between the index date to the first use of warfarin or aspirin was considered as a  never on therapy the outcomes of interest were stroke and/or se ( stroke / se ) and major bleed . primary hospital discharge diagnoses of stroke ( icd-9-cm of 430 , 431 , 433.xx , 434.xx , 436.xx ) and/or se ( 444.0 , 444.1 , 444.2x , 444.8x , 444.9 , 557.x , 593.81 ) was defined as an outcome . major bleed was defined as an intracranial bleed or any other bleed ( gastrointestinal , intraspinal , intraocular , pericardial , intra - articular , intramuscular bleed ) that was associated with an inpatient care visit ; blood transfusion of 2 or more units of whole blood or red blood cells ; decreased hemoglobin 2  g / dl or more ; physician - guided medical or surgical treatment ;  or death ( table1 ) . decreased hemoglobin was identified by searching 7  days before and 7  days after the bleed diagnosis codes and determining nadir hemoglobin level . the highest hemoglobin level before the nadir level was considered as a baseline value and was compared with the nadir level . a decrease in 2 g / dl or more was considered a major hemorrhage according to the definition published by the international society on thrombosis and hemostatis.27 definition of outcomes cpt indicates current procedural terminology ; icd-9-cm , international classification of diseases , ninth revision clinical modification . death information may not be complete since there is a 1-year delay in receiving death information from california state death records , and federal sources . patient - level baseline characteristics were investigated and  descriptive statistics were reported to examine differences among each treatment option ( warfarin use , aspirin only , and no therapy ) . the crude rate of stroke / se and major bleeding ( number of events per 100 person - years [ py ] ) were evaluated for each treatment episode . longitudinal multivariable analyses using generalized estimating equations ( logit link , poisson distribution ) were conducted  considering interindividual correlations . patient demographics ( age , gender , race / ethnicity ) , body mass index , baseline comorbidities ( peripheral vascular disease , cirrhosis , cardiac myopathy , dementia ) , history of bleed , myocardial infarction , or fall , and baseline medication use  ( periprocedural anticoagulation , antiarrhythmic medications , clopidogrel , ticlopidine , prasugrel , ticagrelor , heart rate control medications , statin , angiotensin - converting enzyme inhibitors , angiotensin receptor blockers ) were considered as covariates . p - value < 0.2 in the univariate analysis , and other clinically relevant covariates were  included in the multivariable regression model . the final multivariable model was created by applying a backward model selection procedure that retained those covariates with p<0.05 . other clinically relevant covariates that were not significant were forced into the final model as needed . we used key risk factors such as age , congestive heart failure , hypertension , diabetes , stroke / transient ischemic attack , and major bleed as time - varying covariates . relative risks ( rr ) with 95% ci were reported  from the multivariable analyses . subgroup analyses were conducted based on the baseline chads2 scores ( 1 ,  2 , 3 ) . a retrospective longitudinal observational cohort study was conducted considering multiple antithrombotic treatments for each individual . patients may have had multiple treatment and nontreatment times during the entire follow - up period ( eg , stop therapy , switch therapy , and restart therapy ) . the dynamics of treatment patterns and outcomes associated with them were captured in a longitudinal analysis . kpsc is a nonprofit , integrated healthcare delivery organization with a membership of over 3.6 million people in southern california . kpsc provides integrated , comprehensive medical services through its own facilities , which include 14 hospitals , > 200 outpatient facilities , and a centralized laboratory . all aspects of care and interaction with the healthcare delivery system are captured in a continuously updated electronic medical record ( emr ) system . over 95% of the patients receiving warfarin treatment in kpsc each encounter ( mostly telephone counseling ) at an anticoagulation clinic is stored in the emr system . patients newly diagnosed with atrial fibrillation ( 2 serial international classification of diseases , ninth revision clinical modification [ icd-9-cm ] of 427.31 30  days apart ) in outpatient visit or hospital records were identified between january 1 , 2006 and december 31 , 2011 . the first diagnosis date was defined as the index date and patients were followed until the first outcomes of interest , end of enrollment , death , or december 31 , 2012 , whichever occurred first . individuals who had a history of atrial fibrillation diagnosis , ablation , cardioversion , warfarin prescription , or an anticoagulation clinic visit during 12  months prior to the index date were excluded to ensure that only newly diagnosed nvaf patients were captured . patients < 18  years old at index , without continuous health - plan membership or drug benefit during the 12  months prior to the index date ( gaps of 30  days were treated as continuous membership ) , evidence of pregnancy at any point during the entire follow - up period , and individuals who had valvular diseases , valvular repair , or replacement 12  months prior to the index date were also excluded . in the final study cohort , we excluded patients on novel oral anticoagulation agents ( dabigatran and rivaroxaban : n=101 ) due to small sample size , and patients who only had 1 warfarin prescription but were not followed by an anticoagulation clinic ( n=133 ) , since it would be difficult to confirm these patients were taking warfarin due to lack of monitoring . the analyses were conducted for patients with at least 1 or more major risk factors for stroke ( chads2 1 ) . the current study was reviewed and approved by the kpsc institutional review board . we defined warfarin treatment episodes using prescriptions , inr lab measurements , and anticoagulation clinic data . the start date of a warfarin episode was defined as the first warfarin prescription date , and the end date of the episode was defined as the earliest date with one for the following : ( 1 ) date of discharge from the anticoagulation clinic ; or ( 2 ) the most recent covered date ( last refill date plus days supply ) plus additional 80  days of grace period to incorporate interpersonal variability of warfarin dosage use ; or ( 3 ) inr measurement date plus 80  days of grace period ( regular inr measurement intervals at kpsc [ 8  weeks ] and around 4  weeks of additional period20 ) from the date of discharge . previous literature9,20 applied 30  days of grace period at the end of a prescription because patients may be instructed to take half - doses of warfarin.20 applying a similar concept , we determined 80  days of grace period since this is a mean warfarin days supply at kpsc . ttr was calculated using the linear interpolation method by rosendaal et  al21 expressed as a percentage of observation time , which in our study we defined as each warfarin treatment episode . inr tests performed during hospitalization or inr gaps > 80  days were not interpolated . based on ttr , we stratified patients into 2 different groups ( warfarin ttr 55% , warfarin ttr < 55% ) . there is no consensus in terms of appropriate ttr cutoff . the 55% threshold was selected a priori since this level is the lower bound of reported means from previous clinical trials and large observational studies.22,23 the 55% threshold may be understood as the initial cutoff for poor control . stratified analyses were conducted to investigate the outcomes at the different ttr levels based on the distribution of the data . low - dose aspirin ( 75 to 325  mg ) use in the emr , chart notes , and prescription data were searched for the entire nonwarfarin time . we built a natural language processing algorithm2426 to search for low - dose aspirin use information , and 1 evidence of aspirin use was considered as being on aspirin . chart  notes ( 5339 ) from 100 patients records were randomly selected and manually reviewed to validate the algorithm . the algorithm achieved 95.5% sensitivity and 98.9% specificity . we applied 180  days criteria for the first and the last evidence of aspirin use and assumed patients were on aspirin during this period . the nontreatment time after aspirin use was considered as  off aspirin  period . thus , the entire follow - up time for this patient group was considered as  never on therapy  episode . there was another group of patients who started warfarin or aspirin therapy after their index date . the time between the index date to the first use of warfarin or aspirin was considered as a  never on therapy we defined warfarin treatment episodes using prescriptions , inr lab measurements , and anticoagulation clinic data . the start date of a warfarin episode was defined as the first warfarin prescription date , and the end date of the episode was defined as the earliest date with one for the following : ( 1 ) date of discharge from the anticoagulation clinic ; or ( 2 ) the most recent covered date ( last refill date plus days supply ) plus additional 80  days of grace period to incorporate interpersonal variability of warfarin dosage use ; or ( 3 ) inr measurement date plus 80  days of grace period ( regular inr measurement intervals at kpsc [ 8  weeks ] and around 4  weeks of additional period20 ) from the date of discharge . previous literature9,20 applied 30  days of grace period at the end of a prescription because patients may be instructed to take half - doses of warfarin.20 applying a similar concept , we determined 80  days of grace period since this is a mean warfarin days supply at kpsc . ttr was calculated using the linear interpolation method by rosendaal et  al21 expressed as a percentage of observation time , which in our study we defined as each warfarin treatment episode . inr tests performed during hospitalization or inr gaps > 80  days were not interpolated . based on ttr , we stratified patients into 2 different groups ( warfarin ttr 55% , warfarin ttr < 55% ) . there is no consensus in terms of appropriate ttr cutoff . the 55% threshold was selected a priori since this level is the lower bound of reported means from previous clinical trials and large observational studies.22,23 the 55% threshold may be understood as the initial cutoff for poor control . stratified analyses were conducted to investigate the outcomes at the different ttr levels based on the distribution of the data . low - dose aspirin ( 75 to 325  mg ) use in the emr , chart notes , and prescription data were searched for the entire nonwarfarin time . we built a natural language processing algorithm2426 to search for low - dose aspirin use information , and 1 evidence of aspirin use was considered as being on aspirin . chart  notes ( 5339 ) from 100 patients records were randomly selected and manually reviewed to validate the algorithm . the algorithm achieved 95.5% sensitivity and 98.9% specificity . we applied 180  days criteria for the first and the last evidence of aspirin use and assumed patients were on aspirin during this period . the nontreatment time after aspirin use was considered as  off aspirin  period . some patients were never on warfarin or aspirin therapy . thus , the entire follow - up time for this patient group was considered as  never on therapy  episode . there was another group of patients who started warfarin or aspirin therapy after their index date . the time between the index date to the first use of warfarin or aspirin was considered as a  never on therapy the outcomes of interest were stroke and/or se ( stroke / se ) and major bleed . primary hospital discharge diagnoses of stroke ( icd-9-cm of 430 , 431 , 433.xx , 434.xx , 436.xx ) and/or se ( 444.0 , 444.1 , 444.2x , 444.8x , 444.9 , 557.x , 593.81 ) was defined as an outcome . major bleed was defined as an intracranial bleed or any other bleed ( gastrointestinal , intraspinal , intraocular , pericardial , intra - articular , intramuscular bleed ) that was associated with an inpatient care visit ; blood transfusion of 2 or more units of whole blood or red blood cells ; decreased hemoglobin 2  g / dl or more ; physician - guided medical or surgical treatment ;  or death ( table1 ) . decreased hemoglobin was identified by searching 7  days before and 7  days after the bleed diagnosis codes and determining nadir hemoglobin level . the highest hemoglobin level before the nadir level was considered as a baseline value and was compared with the nadir level . a decrease in 2 g / dl or more was considered a major hemorrhage according to the definition published by the international society on thrombosis and hemostatis.27 definition of outcomes cpt indicates current procedural terminology ; icd-9-cm , international classification of diseases , ninth revision clinical modification . death information may not be complete since there is a 1-year delay in receiving death information from california state death records , and federal sources . patient - level baseline characteristics were investigated and  descriptive statistics were reported to examine differences among each treatment option ( warfarin use , aspirin only , and no therapy ) . the crude rate of stroke / se and major bleeding ( number of events per 100 person - years [ py ] ) were evaluated for each treatment episode . longitudinal multivariable analyses using generalized estimating equations ( logit link , poisson distribution ) were conducted  considering interindividual correlations . patient demographics ( age , gender , race / ethnicity ) , body mass index , baseline comorbidities ( peripheral vascular disease , cirrhosis , cardiac myopathy , dementia ) , history of bleed , myocardial infarction , or fall , and baseline medication use  ( periprocedural anticoagulation , antiarrhythmic medications , clopidogrel , ticlopidine , prasugrel , ticagrelor , heart rate control medications , statin , angiotensin - converting enzyme inhibitors , angiotensin receptor blockers ) were considered as covariates . p - value < 0.2 in the univariate analysis , and other clinically relevant covariates were  included in the multivariable regression model . the final multivariable model was created by applying a backward model selection procedure that retained those covariates with p<0.05 . other clinically relevant covariates that were not significant were forced into the final model as needed . we used key risk factors such as age , congestive heart failure , hypertension , diabetes , stroke / transient ischemic attack , and major bleed as time - varying covariates . relative risks ( rr ) with 95% ci were reported  from the multivariable analyses . subgroup analyses were conducted based on the baseline chads2 scores ( 1 ,  2 , 3 ) . a total of 23  297 patients with chads2 1 were included in the study . data were censored at the first occurrence of each outcome of interest ; a total of 60  021  py for stroke / se outcomes , and 56  760  py for major bleed outcomes were identified in this study . among the population , 47.5% had at least 1 warfarin prescription , 29.0% had evidence of aspirin use only , and 23.5% did not receive any antithrombotic therapy . mean ( sd ) age of the population was 74.9 ( 11.1 ) years , and 47.7% were female . baseline differences were found among 3 different treatment groups ( warfarin , aspirin only , and no therapy ) . mean ( sd ) age of the aspirin - only group was higher compared to warfarin users ( 77.6 [ 10.8 ] for aspirin versus 73.1 [ 10.3 ] for warfarin ) and a higher percentage of patients age 85 was found in the aspirin - only group . warfarin users had higher rates of comorbidities : hypertension , diabetes , and stroke / transient ischemic attack compared to the aspirin - only group , whereas the aspirin - only and no - therapy groups had higher rates of congestive heart failure , myocardial infarction , and bleeding . a higher percentage of patients with chads2 2 was found in the aspirin group compared to the warfarin or no - therapy groups . a total of 1782 stroke / se events occurred during the follow - up period . the lowest stroke / se rates ( 95% ci ) were observed in the warfarin ttr 55% episodes ( 0.87 [ 0.71 to 1.04 ] per 100  py ) ( table3 ) . the stroke / se event rates from the warfarin ttr < 55% episodes were similar ( 3.23 [ 2.76 to 3.70 ] per 100  py ) compared to the event rates during episodes of aspirin use ( 3.11 [ 2.83 to 3.39 ] per 100  py ) . higher occurrences of stroke / se were observed during periods of no treatment ( off warfarin , off aspirin , and never on therapy ) . the highest stroke / se rates were found during the off - warfarin therapy episodes ( 4.38 [ 3.70 to 5.05 ] per 100  py ) . the majority of the total stroke / se events were from ischemic stroke ( 79.9% ) and 8.7% were from hemorrhagic stroke . crude rate of stroke / systemic embolism and major bleed events gi indicates gastrointestinal ; ich , intracranial hemorrhage ; se , systemic embolism ; ttr , time in therapeutic range . the lowest major bleed rates ( 95% ci ) were also found during warfarin ttr 55% episodes ( 4.91 [ 4.53 to 5.28 ] per 100  py ) , and these were similar to the rates observed during episodes of aspirin use ( 4.95 [ 4.58 to 5.32 ] per 100  py ) ( table3 ) . bleeding rates were the highest in warfarin ttr < 55% episodes ( 12.33 [ 11.41 to 13.24 ] per 100  py ) , followed by off - warfarin episodes ( 9.56 [ 8.39 to 10.73 ] per 100  py ) . a large proportion ( 69.8% ) of major bleeds was gastrointestinal bleeds and 5.5% were from intracranial hemorrhages . when controlling for other factors and individual correlations due to an individual patient having multiple episodes , warfarin ttr 55% episodes were associated with a 77% lower risk of stroke / se ( adjusted rr [ 95% ci]=0.23 [ 0.18 to 0.28 ] ) compared to never on therapy episodes , whereas warfarin ttr < 55% and on - aspirin episodes were associated with a 20% lower risk and with a 26% lower risk of stroke / se compared to never on therapy episodes , respectively ( table4 and figure2 ) . the stroke / se risks from off - aspirin episodes were not statistically different from never on therapy episodes ; however , a 22% higher risk of stroke / se was found from off - warfarin episodes compared to never on therapy episodes ( rr=1.22 [ 1.01 to 1.48 ] ) . other significant factors associated with stroke / se included older age , female gender , black or hispanic race , having diabetes , hypertension , previous stroke / transient ischemic attack , peripheral vascular events , higher comorbidity score , and no experiences of recent major bleed . cci indicates charlson comorbidity index ; se , systemic embolism ; ttr , time in therapeutic range . statistically significant . adjusted relative risks ( 95% ci ) of stroke / systemic embolism for antithrombotic treatment ( vs never on therapy ) . controlling for other factors , warfarin ttr < 55% was associated with nearly twice the risk of a major bleed compared to never being on therapy ( adjusted rr=1.93 [ 1.74 to 2.14 ] ) ( table5 , figure3 ) . however , warfarin ttr 55% episodes were associated with a reduced risk of major bleed compared to never on therapy episodes ( rr=0.84 [ 0.76 to 0.93 ] ) . increased risk of bleed was observed in the off - warfarin compared to never on therapy episodes ( rr=1.54 [ 1.33 to 1.79 ] ) . many factors associated with a major bleed were the same as those associated with stroke / se including older age , black or hispanic race , and higher comorbidity score ( tables4 and 5 ) . being male , having congestive heart failure , baseline bleed , and no experience of recent stroke / se were also associated with an increased risk of major bleed . cci indicates charlson comorbidity index ; se , systemic embolism ; ttr , time in therapeutic range . statistically significant . adjusted relative risks ( 95% ci ) of major bleed for antithrombotic treatment ( vs never on therapy ) . subgroup analyses showed that stroke / se as well as major bleeding events were increased in higher chads2 risk categories ( stroke / se event rates=1.62 per 100  py for chads2=1 , 3.15 for chads2=2 , 4.85 for chads2 3 ; major bleed event rates=4.39 for chads2=1 , 6.41 for chads2=2 , 8.53 for chads2 3 ) ( table3 ) . the antithrombotic treatment effect was relatively consistent among different chads2 risk groups ( figures2 and 3 ) . a greater impact on reduction of stroke / se was observed for warfarin ttr 55% or warfarin ttr < 55% episodes compared to never on therapy ( figure2 ) . the outcomes from the lowest 25th warfarin ttr quartile ( warfarin ttr < 43.9% ) were poor . this group reported the highest stroke / se rates ( 5.37 per 100  py ) with the highest major bleed rates ( 17.32 per 100  py ) , whereas stroke / se rates from the highest 25th warfarin ttr quartile ( warfarin ttr > 71.3% ) were only 0.93 per 100  py with major bleed events of 4.59 per 100  py ( figure4 ) . stroke / systemic embolism and major bleed events by time in therapeutic range ( ttr ) quartiles . it is crucial for nvaf patients to continue antithrombotic therapy as well as maintain an adequate level of ttr for warfarin users to prevent strokes . this study shows that warfarin therapy with higher ttr range was associated with a reduction in stroke / se for nvaf patients in a us managed - care setting . this finding is consistent with previous findings from other secondary analyses of clinical trial cohorts1216 and a retrospective observational study,17 which emphasizes the importance of achieving and maintaining an adequate level of ttr . a significantly higher proportion of stroke / se events occurred when the inrs were subtherapeutic ( inr < 2 ) as opposed to supratherapeutic ( inr > 3 ) ( 45.0% versus 13.8% , respectively ) . the absolute stroke / se rates in the warfarin ttr 55% episodes were even lower than the event rates from the highest quartiles in some clinical trials;12,13 therefore , more distinct differences between high versus low warfarin ttr were observed from our study . this may be due to treatment selection bias ; physicians might prescribe warfarin for individuals with greater perceived benefits , or this could be explained by the continuous anticoagulation management efforts from pharmacist - led clinics in kpsc . these findings were consistent across chads2 stratification ; the stroke / se rates remained very low even for higher - risk patients . our study found that bleeding rates in the higher - warfarin ttr episodes were comparable to the rates observed among aspirin therapy episodes ; however , much greater bleeding rates were found in the low - warfarin ttr episodes . some ad - hoc analyses reported similar findings,13,14 and a systematic review article also found a negative correlation between warfarin ttr and hemorrhagic events.28 however , it is not clear whether the higher bleeding events observed during the low - warfarin ttr episodes were associated with inrs that were supratherapeutic or subtherapeutic , as a similar proportion of bleeding events occurred when inrs were supratherapeutic and subtherapeutic ( 21.0% versus 24.8% , respectively ) . other factors such as concomitant antiplatelet use , alcohol intake , comorbidities , or other patient behaviors may be associated with these findings . our study showed much greater bleeding differences between high- versus low - warfarin ttr episodes compared to the results from clinical trials , which may have been due to the relatively tight control of inr in clinical trial settings . bleeding rates in the never on therapy episodes were higher than the warfarin ttr 55% episodes . older age , higher baseline bleed , and previous fall may explain part of these findings . while this finding may seem counterintuitive , 92% of these patients in the study were defined as a warfarin discontinuation due to being discharged from the anticoagulation clinic . the potential reasons for discharge from the anticoagulation clinic are often associated with the high risk of bleeds , adverse side effects , patient refusal , and nonadherence . future studies should consider investigating reasons for high bleeding rates in these groups to better understand the population . this study revealed that 52.4% of nvaf patients with chads2 1 did not receive any antithrombotic therapy or were only on aspirin therapy . interestingly , these percentages were consistent with higher chads2 groups ( 52.6% for chads2 2 , 55.3% for chads2 3 ) , which has also been suggested by other observational studies.6 however , an increasing trend of warfarin use was observed over the study period ; 28.2% of the incident nvaf patients initiated warfarin during 20062008 and 36.0% in 20092011 . this trend may be associated with the introduction of new guidelines calling for use of the chads2 score to determine warfarin use.29 for warfarin users , 59.3% of person - time were either warfarin ttr < 55% or off warfarin , which may represent care gaps . moreover , this study also found a median ttr of 59% in the nvaf population . this ttr range was slightly higher than the mean ttr ( 53.7% ) in office - based community practices in the united states,30 and the differences may be larger given the fact that this study only included incident nvaf patients and ttr was calculated including the inception warfarin period . however , this study shows that a substantial portion of patients were not able to achieve a high ttr . outcomes based on the ttr quartiles showed that the lowest quartile ( ttr < 44% ) may have driven the worse outcomes observed in the low ttr episodes ( ie , given that no linear relationship between ttr and outcomes was found : stroke / se in the upper 2 ttr quartiles were similar : 4.59 per 100  py for ttr > 71.3% versus 4.99 per 100  py for ttr 59.1% to 71.3% ) . while this information might be helpful for healthcare providers and policy - makers designing interventions to improve outcomes , it is important to note that this study does not provide solid evidence regarding an appropriate ttr threshold . the primary strength of this study was the unique data source with the availability of emr in a large cohort . over 20  000 of the new nvaf patients information were analyzed with maximum 6  years of follow - up considering longitudinal treatment patterns . in addition , we were able to separate aspirin use from the no - therapy group , and found notable differences in outcomes . also , off - warfarin episodes were rigorously defined using actual anticoagulation pharmacist intervention data as well as lab and pharmacy records . this study depended on the availability and accuracy of the medical and pharmacy records provided . accuracy or completeness of kpsc emr data in terms of warfarin treatment has not been validated . arbitrary grace periods ( eg , 80  days for warfarin treatment and 180  days for aspirin treatment ) to determine antithrombotic therapy episodes also have not been validated . death information may not have been complete , since there is a delay in receiving death information from state and federal sources and then loading it into data systems . icd-9-cm code of 430 , 431 , and 432.x are interchangeably used to define hemorrhagic strokes and intracranial hemorrhages in retrospective observational studies.3133 there is likely to be a selection bias due to any lack of randomization . patients with high risk of bleeding may be less likely to receive antithrombotic therapy , and treatment effect estimates are likely to be biased when these factors are unobserved and not controlled . novel oral anticoagulation agents were not considered in this study due to a small sample size , which might influence treatment patterns . generalizability of the study results may also be an issue since this study only evaluated patients in kpsc . most of the warfarin patients in kpsc are managed by anticoagulation clinics , which may lead to higher warfarin ttr or lower event rates compared to usual care . to our knowledge , the association between real - world antithrombotic treatment patterns and clinical outcomes has not been widely studied . episodes of warfarin ttr 55% were associated with a substantial reduction in stroke / se events in patients with nvaf , while bleeding rates were similar to the rates of the aspirin use . in contrast , warfarin ttr < 55% or aspirin - only therapy was associated with a moderate stroke / se reduction , and warfarin ttr < 55% episodes were also associated with a highly increased risk of bleed . future studies should examine modifiable factors to improve outcomes for patients with suboptimal warfarin or for those who are off antithrombotic therapy . an : grant / research support from bristol - myers squibb / pfizer , genentech . niu , rashid : grant from bristol - myers squibb / pfizer to the institution for salary reimbursement .
backgroundthe quality of antithrombotic therapy for patients with nonvalvular atrial fibrillation during routine medical care is often suboptimal . 
 evidence linking stroke and bleeding risk with antithrombotic treatment is limited . 
 the purpose of this study was to evaluate the associations between antithrombotic treatment episodes and outcomes.methods and resultsa retrospective longitudinal observational cohort study was conducted using patients newly diagnosed with nonvalvular atrial fibrillation with 1 or more stroke risk factors ( chads2 1 ) in kaiser permanente southern california between january 1 , 2006 and december 31 , 2011 . 
 a total of 1782 stroke and systemic embolism ( se ) and 3528 major bleed events were identified from 23  297 patients during the 60  021 person - years of follow - up . 
 the lowest stroke / se rates and major bleed rates were observed in warfarin time in therapeutic range ( ttr ) 55% episodes ( stroke / se : 0.87 [ 0.71 to 1.04 ] ; major bleed : 4.91 [ 4.53 to 5.28 ] per 100  person - years ) , which was similar to the bleed rate in aspirin episodes ( 4.95 [ 4.58 to 5.32 ] per 100  person - years ) . 
 the warfarin ttr 55% episodes were associated with a 77% lower risk of stroke / se ( relative risk=0.23 [ 0.18 to 0.28 ] ) compared to never on therapy ; and the warfarin ttr < 55% and on - aspirin episodes were associated with a 20% lower and with a 26% lower risk of stroke / se compared to never on therapy , respectively . 
 the warfarin ttr < 55% episodes were associated with nearly double the risk of a major bleed compared to never on therapy ( relative risk=1.93 [ 1.74 to 2.14]).conclusionscontinuation of antithrombotic therapy as well as maintaining an adequate level of ttr is beneficial to prevent strokes while minimizing bleeding events .