patients with af have a five - fold greater risk of stroke compared with patients in sinus rhythm . further , af - associated strokes have been shown to be more severe than strokes not due to af . it is estimated that af - associated stroke costs the european union 10 billion euros annually . due to the increased risk of stroke , while antithrombotic therapy with vitamin k antagonists , such as warfarin , has been shown to be efficacious in reducing the risk of stroke , it also increases the risk of bleeding events , including intracranial haemorrhage and haemorrhagic stroke . because of these associated bleed risks , as many as 40% of patients clinically indicated for warfarin do not receive the therapy . for these patients , treatment with aspirin has often been recommended , although its efficacy is much lower than that of warfarin . novel oral anticoagulants ( noac ) are associated with less bleeding than warfarin , but only apixaban has been evaluated in warfarin - intolerant patients . percutaneous left atrial appendage closure ( laac ) is a device - based alternative to chronic pharmacologic therapy for stroke prophylaxis in non - valvular af . autopsy and echocardiographic studies have implicated the left atrial appendage to be the source of thrombus in > 90% of strokes in patients with af . while this device - based approach to stroke prevention is a potentially life - saving innovation for patients with contraindications to warfarin therapy , evidence of cost effectiveness in this clinical setting is sparse . this analysis sought to understand the economic and clinical consequences of long - term stroke prevention with laac using the watchman device when compared with aspirin or apixaban in patients with contraindications to warfarin therapy . a markov cost - effectiveness model was developed to assess incremental costs and quality - adjusted life years ( qalys ) of laac compared with aspirin or apixaban in non - valvular af patients with contraindications to warfarin . the analysis was conducted from the perspective of the german healthcare system and included costs related to treatment and associated clinical events , including ischaemic stroke , systemic embolism , transient ischaemic attack ( tia ) , haemorrhagic stroke , intracranial haemorrhage ( ich ) , extracranial haemorrhage , minor bleeding , and acute myocardial infarction . the recent approval of three noacs has resulted in multiple publications on cost - effectiveness analyses of stroke prevention in af . the model structure and model assumptions used here are based on a model submitted to the national institute for clinical excellence ( nice ) in the uk . our model included three treatment strategies : laac with the watchman device ( boston scientific , marlborough , massachusetts , usa ) ; aspirin , the conventional therapy often used in patients unable to take warfarin ; and apixaban ( eliquis , bristol - myers squibb , new york , usa ) , the only noac evaluated in warfarin unsuitable patients . both of the two new stroke prevention strategies , laac and apixaban , were evaluated against aspirin and each other . the model was constructed using 3-month cycles and investigated cost effectiveness annually up to 20 years to determine time to cost effectiveness . within each cycle , patients could experience clinical events leading to death , disability , and/or primary therapy discontinuation and incur associated costs and quality of life ( qol ) adjustments ( figure  1 ) . figure  1patient flow upon entering laac arm of the markov model . within each model cycle , patients could remain well or experience acute events that may lead to a worse health state . , patients could remain well or experience acute events that may lead to a worse health state . patients cycled through until death or 20 years . within the model , ich and stroke could lead to death or disability . patients experiencing an embolic event were at increased risk for a second embolic event , which could worsen their disability level . in addition to death from acute events , patients also faced a risk of death from unrelated causes . in the case of laac , patients faced one - time procedure - related risk , including pericardial effusion ( 2.0% ) , major bleeding ( 2.7% ) , femoral pseudoaneurysm ( 0.7% ) , and device embolization ( 1.3% ) . these patients could also experience a successful or failed procedure . following a failed procedure , one in which the watchman device was not implanted , aspirin therapy for stroke prevention was assumed . patients in the aspirin or apixaban arms could discontinue therapy following either a bleeding event or for other patient or physician recommended reasons . aspirin patients who discontinued therapy were assumed to receive no further therapy ; apixaban patients were assumed to transition to aspirin therapy . clinical inputs for these events were drawn from several sources ( table  1 ) . for laac , event probabilities were taken from the asap study ( asa plavix feasibility study with watchman left atrial appendage closure technology ) in which 150 non - valvular af patients with absolute contraindications to warfarin were treated with the watchman device . therefore , the probabilities for bleeding events in patients with laac were estimated to be comparable with those of concomitant drug therapy ( aspirin and clopidogrel for 6 months following the procedure and aspirin thereafter ) and were taken from active a and active w. 
 table  1clinical inputseventlaacaspirinapixabanrelative risk of ischaemic stroke0.23 ( relative to no therapy)0.78 ( relative to no therapy)0.37 ( relative to aspirin)annual risk of systemic embolism0.12% ( assumption based on stroke risk vs. aspirin)0.4%0.1%relative risk of haemorrhage1.10.651.16per cent of haemorrhage that are ich21.2%17.8%25%per cent of haemorrhage that are gastrointestinal bleeds52%41.7%27.3%per cent of haemorrhage that are non - gastrointestinal extracranial bleeds26.8%40.5%47.7%annual risk of acute myocardial infarction0.86%0.9%0.8%for 6 months then equal to aspirin . for 6 months then equal to aspirin . for the aspirin arm of the model , the relative risk of stroke was taken from a meta - analysis of multiple trials of stroke prevention in af . all other event probabilities were taken from active a , the results of which have been described elsewhere . while many trials have assessed the effectiveness of aspirin in patients with af , only the active trials have explicitly investigated the effectiveness of aspirin in patients who could not tolerate warfarin therapy . the apixaban arm of the model took clinical event probabilities from the averroes trial which investigated patients unsuitable for warfarin therapy . baseline stroke risk was assigned based on chads2 scores and bleeding risk based on hasbled scores . hasbled score was estimated from the weighted clinical risk factors described in the asap study . in the base case analysis , it was assumed that patients were 70 years old , with a chads2 score of 3 ( annual stroke risk 8.6% ) and a hasbled score of 3 ( annual haemorrhage risk 3.74% ) , which reflects the typical patient in the watchman asap study . to account for increasing risk with age , rates of embolic events increased 1.4 times per decade and rates of ich increased 1.97 times per decade , based on rates reported in the literature . patients who experienced an ischaemic event had a 2.6 times increase in the probability of experiencing a second ischaemic event . stroke disability outcomes were not captured in the asap study . therefore , modified rankin scale ( mrs ) disability data for laac patients were taken from the protect af trial of the watchman device . analysis of protect af showed 71% of strokes resulted in mrs scores of 02 , 5% resulted in mrs score of 3 , 5% resulted in mrs scores of 45 , and 19% resulted in mrs score of 6 ( death ) . these data were used to assign patients to disability states following a stroke , which impacted both qol and costs for disability - related care . quality of life was captured in the model as utility values , which reflect decrements to life quality based on health states . as is conventional , utilities used within the model were rated on a scale of 01 , with 0 representing death and 1 a state of perfect health . the model incorporated qol adjustments for each disability state , as derived from the literature . a utility value for  well with laac of 1.0 was developed using sf-12 data collected during the watchman asap study . the study found that laac patients experienced qol improvements across 11 of 12 domains , with only general health remaining the same following implantation . a utility value for  well on apixaban of 0.994 was taken from published cost - effectiveness analyses of apixaban . utility values reported in the literature for patients with af have ranged from 0.774 to 1 . in this analysis , well utility values were used as multipliers against a baseline utility of 0.82 for well patients with af at age 70 years . this value was taken from the literature , as it captured the decremented qol due to age and burden of af . utility was reduced by 22% per decade to account for general age - related decline based on data from euroqol . disutilities , one - time deductions to qol to account for an acute event , were applied for the laac procedure and all acute events . quality - adjusted life years were calculated by multiplying the length of time in a given state by the utility for that state . the analysis considered direct medical costs as well as costs associated with long - term disability care in a facility . data on costs were collected from multiple sources including the german diagnosis related group ( g - drg ) system for 2014 , german pharmaceutical price lists and published literature on stroke and disability costs in germany ( table  2 ) . table  2cost inputseventcostg - drgsourcelaac device and procedure9136f95aminor ischaemic stroke8249b39cmajor ischaemic stroke31 829b39a , b42aminor haemorrhagic stroke4357b70d , b70emajor haemorrhagic stroke16 802b70a , b70b , b44csystemic embolism2226b69dtia3999b69a , b69b , b69c , b69dmajor gastrointestinal bleeding2096g69a , g67b , g67c , g73zmajor extra cranial bleeding outside of the gastrointestinal1301d62zmyocardial infarction5331f60a , f60b , f41a , f41bquarterly cost of functional independence post - stroke875naquarterly cost of moderate disability post - stroke2745naquarterly cost of severe disability post - stroke4285naquarterly cost of aspirin11naestimatequarterly cost of apixaban292na the laac procedure received a unique g - drg in 2012 which was the basis for its cost . additional costs related to procedural adverse events including pericardial effusion , femoral pseudoaneurysm , and bleeding complications were factored into the total costs of the procedure . uncertainty of model parameters was assessed using one - way and probabilistic sensitivity analyses ( psa ) . for treatment - specific inputs , all event rates , costs , and health utilities the one - way sensitivity analysis explored the impact on model outcomes from a variation in input parameters of 20% unless otherwise noted , which includes available 95% confidence intervals . adherence is an important consideration when comparing a device - based therapy to a lifelong pharmacologic therapy . the impact of different rates of non - clinical discontinuation for aspirin and apixaban were explored in sensitivity analyses with the lower bound for discontinuation set to zero for complete adherence . the one - way sensitivity analysis also quantified the impact of changing patient characteristics , including baseline stroke and bleeding risks and utility score . model parameters were fitted to a distribution with the mean equivalent to the base case and an interval of 20% around the mean . exceptions were the same as those noted above with the additional exception of procedure and pharmaceutical costs , whose upper bounds were set equal to the base case , with the assumption that costs were likely to decrease over time . all cost parameters were assumed to follow a normal distribution , event probabilities and health utilities were fitted to a beta distribution , and relative risks assumed a log normal distribution . the dirichlet distribution was selected for mutually exclusive events such as the severity of stroke . the psa was based on a monte carlo approach with 5000 iterations of the model over a 10-year time frame . as germany does not use a cost per qaly threshold in its decision - making process , the threshold was set in accordance with nice guidelines at  30 000/qaly . a markov cost - effectiveness model was developed to assess incremental costs and quality - adjusted life years ( qalys ) of laac compared with aspirin or apixaban in non - valvular af patients with contraindications to warfarin . the analysis was conducted from the perspective of the german healthcare system and included costs related to treatment and associated clinical events , including ischaemic stroke , systemic embolism , transient ischaemic attack ( tia ) , haemorrhagic stroke , intracranial haemorrhage ( ich ) , extracranial haemorrhage , minor bleeding , and acute myocardial infarction . the recent approval of three noacs has resulted in multiple publications on cost - effectiveness analyses of stroke prevention in af . the model structure and model assumptions used here are based on a model submitted to the national institute for clinical excellence ( nice ) in the uk . our model included three treatment strategies : laac with the watchman device ( boston scientific , marlborough , massachusetts , usa ) ; aspirin , the conventional therapy often used in patients unable to take warfarin ; and apixaban ( eliquis , bristol - myers squibb , new york , usa ) , the only noac evaluated in warfarin unsuitable patients . both of the two new stroke prevention strategies , laac and apixaban , were evaluated against aspirin and each other . the model was constructed using 3-month cycles and investigated cost effectiveness annually up to 20 years to determine time to cost effectiveness . within each cycle , patients could experience clinical events leading to death , disability , and/or primary therapy discontinuation and incur associated costs and quality of life ( qol ) adjustments ( figure  1 ) . figure  1patient flow upon entering laac arm of the markov model . within each model cycle , patients could remain well or experience acute events that may lead to a worse health state . , patients could remain well or experience acute events that may lead to a worse health state . patients cycled through until death or 20 years . within the model , ich and stroke could lead to death or disability . patients experiencing an embolic event were at increased risk for a second embolic event , which could worsen their disability level . in addition to death from acute events , patients also faced a risk of death from unrelated causes . in the case of laac , patients faced one - time procedure - related risk , including pericardial effusion ( 2.0% ) , major bleeding ( 2.7% ) , femoral pseudoaneurysm ( 0.7% ) , and device embolization ( 1.3% ) . these patients could also experience a successful or failed procedure . following a failed procedure , one in which the watchman device was not implanted , aspirin therapy for stroke prevention was assumed . patients in the aspirin or apixaban arms could discontinue therapy following either a bleeding event or for other patient or physician recommended reasons . aspirin patients who discontinued therapy were assumed to receive no further therapy ; apixaban patients were assumed to transition to aspirin therapy . clinical inputs for these events were drawn from several sources ( table  1 ) . for laac , event probabilities were taken from the asap study ( asa plavix feasibility study with watchman left atrial appendage closure technology ) in which 150 non - valvular af patients with absolute contraindications to warfarin were treated with the watchman device . therefore , the probabilities for bleeding events in patients with laac were estimated to be comparable with those of concomitant drug therapy ( aspirin and clopidogrel for 6 months following the procedure and aspirin thereafter ) and were taken from active a and active w. 
 table  1clinical inputseventlaacaspirinapixabanrelative risk of ischaemic stroke0.23 ( relative to no therapy)0.78 ( relative to no therapy)0.37 ( relative to aspirin)annual risk of systemic embolism0.12% ( assumption based on stroke risk vs. aspirin)0.4%0.1%relative risk of haemorrhage1.10.651.16per cent of haemorrhage that are ich21.2%17.8%25%per cent of haemorrhage that are gastrointestinal bleeds52%41.7%27.3%per cent of haemorrhage that are non - gastrointestinal extracranial bleeds26.8%40.5%47.7%annual risk of acute myocardial infarction0.86%0.9%0.8%for 6 months then equal to aspirin . for 6 months then equal to aspirin . for the aspirin arm of the model , the relative risk of stroke was taken from a meta - analysis of multiple trials of stroke prevention in af . all other event probabilities were taken from active a , the results of which have been described elsewhere . while many trials have assessed the effectiveness of aspirin in patients with af , only the active trials have explicitly investigated the effectiveness of aspirin in patients who could not tolerate warfarin therapy . the apixaban arm of the model took clinical event probabilities from the averroes trial which investigated patients unsuitable for warfarin therapy . baseline stroke risk was assigned based on chads2 scores and bleeding risk based on hasbled scores . hasbled score was estimated from the weighted clinical risk factors described in the asap study . in the base case analysis , it was assumed that patients were 70 years old , with a chads2 score of 3 ( annual stroke risk 8.6% ) and a hasbled score of 3 ( annual haemorrhage risk 3.74% ) , which reflects the typical patient in the watchman asap study . to account for increasing risk with age , rates of embolic events increased 1.4 times per decade and rates of ich increased 1.97 times per decade , based on rates reported in the literature . patients who experienced an ischaemic event had a 2.6 times increase in the probability of experiencing a second ischaemic event . stroke disability outcomes were not captured in the asap study . therefore , modified rankin scale ( mrs ) disability data for laac patients were taken from the protect af trial of the watchman device . analysis of protect af showed 71% of strokes resulted in mrs scores of 02 , 5% resulted in mrs score of 3 , 5% resulted in mrs scores of 45 , and 19% resulted in mrs score of 6 ( death ) . these data were used to assign patients to disability states following a stroke , which impacted both qol and costs for disability - related care . quality of life was captured in the model as utility values , which reflect decrements to life quality based on health states . as is conventional , utilities used within the model were rated on a scale of 01 , with 0 representing death and 1 a state of perfect health . the model incorporated qol adjustments for each disability state , as derived from the literature . a utility value for  well with laac of 1.0 was developed using sf-12 data collected during the watchman asap study . the study found that laac patients experienced qol improvements across 11 of 12 domains , with only general health remaining the same following implantation . a utility value for  well on apixaban of 0.994 was taken from published cost - effectiveness analyses of apixaban . utility values reported in the literature for patients with af have ranged from 0.774 to 1 . in this analysis , well utility values were used as multipliers against a baseline utility of 0.82 for well patients with af at age 70 years . this value was taken from the literature , as it captured the decremented qol due to age and burden of af . utility was reduced by 22% per decade to account for general age - related decline based on data from euroqol . disutilities , one - time deductions to qol to account for an acute event , were applied for the laac procedure and all acute events . quality - adjusted life years were calculated by multiplying the length of time in a given state by the utility for that state . the analysis considered direct medical costs as well as costs associated with long - term disability care in a facility . data on costs were collected from multiple sources including the german diagnosis related group ( g - drg ) system for 2014 , german pharmaceutical price lists and published literature on stroke and disability costs in germany ( table  2 ) . table  2cost inputseventcostg - drgsourcelaac device and procedure9136f95aminor ischaemic stroke8249b39cmajor ischaemic stroke31 829b39a , b42aminor haemorrhagic stroke4357b70d , b70emajor haemorrhagic stroke16 802b70a , b70b , b44csystemic embolism2226b69dtia3999b69a , b69b , b69c , b69dmajor gastrointestinal bleeding2096g69a , g67b , g67c , g73zmajor extra cranial bleeding outside of the gastrointestinal1301d62zmyocardial infarction5331f60a , f60b , f41a , f41bquarterly cost of functional independence post - stroke875naquarterly cost of moderate disability post - stroke2745naquarterly cost of severe disability post - stroke4285naquarterly cost of aspirin11naestimatequarterly cost of apixaban292na the laac procedure received a unique g - drg in 2012 which was the basis for its cost . additional costs related to procedural adverse events including pericardial effusion , femoral pseudoaneurysm , and bleeding complications were factored into the total costs of the procedure . uncertainty of model parameters was assessed using one - way and probabilistic sensitivity analyses ( psa ) . for treatment - specific inputs , all event rates , costs , and health utilities the one - way sensitivity analysis explored the impact on model outcomes from a variation in input parameters of 20% unless otherwise noted , which includes available 95% confidence intervals . adherence is an important consideration when comparing a device - based therapy to a lifelong pharmacologic therapy . the impact of different rates of non - clinical discontinuation for aspirin and apixaban were explored in sensitivity analyses with the lower bound for discontinuation set to zero for complete adherence . the one - way sensitivity analysis also quantified the impact of changing patient characteristics , including baseline stroke and bleeding risks and utility score . model parameters were fitted to a distribution with the mean equivalent to the base case and an interval of 20% around the mean . exceptions were the same as those noted above with the additional exception of procedure and pharmaceutical costs , whose upper bounds were set equal to the base case , with the assumption that costs were likely to decrease over time . all cost parameters were assumed to follow a normal distribution , event probabilities and health utilities were fitted to a beta distribution , and relative risks assumed a log normal distribution . the dirichlet distribution was selected for mutually exclusive events such as the severity of stroke . the psa was based on a monte carlo approach with 5000 iterations of the model over a 10-year time frame . as germany does not use a cost per qaly threshold in its decision - making process , the threshold was set in accordance with nice guidelines at  30 000/qaly . left atrial appendage closure yielded more qalys than aspirin ( 1.45 vs. 1.44 ) and apixaban ( 2.65 vs. 2.64 ) at 2 and 4 years , respectively . it was cost saving compared with aspirin at 7 years and apixaban at 8 years ( figure  2 ) . at 5 years , laac was cost effective compared with aspirin with an icer of  16 971 . left atrial appendage closure was cost effective compared with apixaban , with an icer of  9040 by year 7 . left atrial appendage closure was both cost saving and more effective ( i.e. dominant ) than aspirin and apixaban at 8 years . by 10 years , laac was 25% less expensive than aspirin and 15% less expensive than apixaban while providing 0.6 additional qalys relative to aspirin and 0.2 relative to apixaban ( table  3 ) . table  3costs , life years , qalys , and icers at 10 years for three risk profiles.scenario ( annual stroke risk / annual bleeding risk)total costsincremental costs ( vs. aspirin)life years  qalysincremental qalys ( vs. aspirin)icer ( vs. aspirin)icer ( vs. apixaban)base case ( 8.6%/3.7% )  laac15 837cost saving7.574.820.61dominantdominant  apixaban18 869cost saving7.394.590.38dominant  aspirin21 0777.004.21dominatedlow risk ( 2.2%/1.9% )  laac12 52958767.805.030.1346 56251 771  apixaban10 38237297.784.990.0944 012  aspirin66537.684.90high risk ( 10.9%/12.5% )  laac19 236cost saving7.294.530.75dominantdominant  apixaban25 596cost saving7.004.160.38dominant  aspirin29 0216.613.78dominated 
 figure  2cumulative costs in the base case analysis over 20 years . cost curves depict sharp growth in costs for aspirin and apixaban in first 10 years of therapy . costs , life years , qalys , and icers at 10 years for three risk profiles . cost curves depict sharp growth in costs for aspirin and apixaban in first 10 years of therapy . the cost effectiveness of laac relative to comparators was generally robust to changes in the input variables . relative to aspirin , the one - way sensitivity analyses showed that the model was most sensitive to variations in baseline risk of stroke , cost of laac , laac implantation success , baseline annual bleeding risk , rate of discontinuation of aspirin , and cost of severe disability ( figure  3 ) . relative to apixaban , the model remained most sensitive to these inputs along with cost of apixaban . left atrial appendage closure was cost saving in all cases except for variations in the baseline risk of stroke . the icer was <  30 000 per qaly for all patients with baseline chads2 scores > 1 , but exceeded this threshold for those with a score of 1 or lower , a population for which laac is typically not employed . figure  3one - way sensitivity analysis of incremental costs per qaly for laac vs. aspirin over 10 years . one - way sensitivity analysis shows the deviation from the base case outcomes that result from varying individual inputs to the model . one - way sensitivity analysis of incremental costs per qaly for laac vs. aspirin over 10 years . one - way sensitivity analysis shows the deviation from the base case outcomes that result from varying individual inputs to the model . the psa simulations yielded incremental costs for laac vs. aspirin within a 95% confidence interval that ranged from a cost savings of  1630 to  9148 ( figure  4 ) . left atrial appendage closure resulted in increased life years and qalys and was cost saving compared with aspirin and apixaban in 99 and 94% of simulations , respectively . figure  4cost - effectiveness plane of laac vs. aspirin at 10 years . left atrial appendage closure is most likely to be more effective and less expensive than aspirin over 10 years . cost - effectiveness plane of laac vs. aspirin at 10 years . left atrial appendage closure is most likely to be more effective and less expensive than aspirin over 10 years . the cost effectiveness of laac relative to comparators was generally robust to changes in the input variables . relative to aspirin , the one - way sensitivity analyses showed that the model was most sensitive to variations in baseline risk of stroke , cost of laac , laac implantation success , baseline annual bleeding risk , rate of discontinuation of aspirin , and cost of severe disability ( figure  3 ) . relative to apixaban , the model remained most sensitive to these inputs along with cost of apixaban . left atrial appendage closure was cost saving in all cases except for variations in the baseline risk of stroke . the icer was <  30 000 per qaly for all patients with baseline chads2 scores > 1 , but exceeded this threshold for those with a score of 1 or lower , a population for which laac is typically not employed . figure  3one - way sensitivity analysis of incremental costs per qaly for laac vs. aspirin over 10 years . one - way sensitivity analysis shows the deviation from the base case outcomes that result from varying individual inputs to the model . one - way sensitivity analysis of incremental costs per qaly for laac vs. aspirin over 10 years . one - way sensitivity analysis shows the deviation from the base case outcomes that result from varying individual inputs to the model . the psa simulations yielded incremental costs for laac vs. aspirin within a 95% confidence interval that ranged from a cost savings of  1630 to  9148 ( figure  4 ) . left atrial appendage closure resulted in increased life years and qalys and was cost saving compared with aspirin and apixaban in 99 and 94% of simulations , respectively . figure  4cost - effectiveness plane of laac vs. aspirin at 10 years . left atrial appendage closure is most likely to be more effective and less expensive than aspirin over 10 years . cost - effectiveness plane of laac vs. aspirin at 10 years . left atrial appendage closure is most likely to be more effective and less expensive than aspirin over 10 years . this analysis demonstrates that laac with the watchman device is a cost - effective strategy for managing non - valvular af patients who can not tolerate warfarin therapy . in the base case analysis , the icer compared with aspirin was  16 971 at 5 years , well below the commonly cited  30 000 threshold . further , laac was dominant over both aspirin and apixaban at 8 years , indicating that it is not only cost effective , but indeed cost saving and more effective than alternatives . using the willingness - to - pay threshold of  30 000 per qaly , there was a > 99% probability that laac is cost effective in patients with contraindications to warfarin at 10 years . for lack of other viable treatment strategies , aspirin had long been the default standard of care for stroke prevention in warfarin - contraindicated patients . recently , new pharmaceutical strategies have emerged , and in particular , apixaban has demonstrated similar bleeding risk and improvement in stroke prevention relative to aspirin . however , the issue of therapy discontinuation is an important one and merits further consideration . adherence to a pharmaceutical regimen has long been a challenge for many clinicians managing patients with af . helgason et al . found that over 6 years , 132 of 229 patients ( 58% ) initially prescribed warfarin therapy following a stroke had stopped taking their medication . and , even apixaban has been plagued with similar patient compliance issues . in the averroes study , 17.9% of patients in the apixaban group discontinued therapy per year for either clinical or non - clinical reasons . on the other hand , by its very nature , non - adherence is not possible with laac ; that is , once implanted , there is no of course , in the asap study , watchman implantation was followed by 6 months of dual anti - platelet therapy with aspirin and clopidogrel , and lifelong aspirin thereafter . so , it does remain possible that watchman patients may not remain fully adherent to their prescribed aspirin regimen . however , there is no indication that there is a significant risk to discontinuation of dual anti - platelet therapy likely because patients know that clopidogrel treatment is only required for a finite time duration . furthermore , even the 6-month course of dual anti - platelet therapy is likely to become truncated ; indeed , the current practice at many centres in europe is to treat with dual anti - platelet therapy for only 23 months after watchman implantation . the cost of laac is understandably higher in the year of the procedure  related to the cost of the procedure itself and the possibility of procedure - related complications . however , since these are one - time costs , laac is associated with only minimal cost accrual thereafter . this is in distinct contrast to treatment with any of the noacs that are effective at reducing the risk of stroke , but come with a substantial and continuing annual cost . the stroke disability outcomes as assessed during protect af and leveraged here are favourable for laac : the majority of strokes ( 71% ) after watchman implantation are non - disabling and thus result in functional independence . accordingly , future trials on stroke prevention strategies should provide more transparent data on disability outcomes following a stroke . this analysis utilized the chads2 score as the basis for assigning risk of stroke to be consistent with the asap , active , and averroes studies . since these studies were undertaken , the european society of cardiology guidelines for the management of af have been revised to recommend use of the cha2ds2vasc score . the base case results in this analysis correspond to a cha2ds2vasc score of 56 . as with chads2 results , the cost effectiveness of laac relative to aspirin increases with higher cha2ds2vasc score and decreases with lower cha2ds2vasc scores . to the best of our knowledge , only one other analysis has been published on the cost effectiveness of stroke prevention in af patients with contraindications to warfarin . assessed the cost effectiveness of apixaban compared with aspirin and found that apixaban was inferior to aspirin over a trial - length horizon but dominant over a 10-year time horizon . our analysis similarly found the icers for both laac and apixaban to improve over time . there are limitations fundamental to any modelling analysis , in that it is a simplification of reality and can not represent all clinical permutations . our model allowed for only one clinical event per 3-month cycle , leveraged data from multiple clinical studies with different time horizons , and extrapolates out to 20 years . model results are based on data from randomized controlled studies and may not be representative of real - world clinical practice . additionally , the model reflects the german healthcare system and costs , and the icers may not be easily generalizable to other healthcare systems . patients with contraindications to warfarin have been difficult to study resulting in few data sources on long - term outcomes . the watchman asap data used in this analysis covered 14.4 months of follow - up , and the study was not powered to assess the long - term risk of haemorrhage or myocardial infarction . our analysis has used the only available study of aspirin in af patients who can not tolerate warfarin therapy . finally , as clinical probabilities for this analysis were taken from a study of the watchman device , results modelled here are specific to that device and can not be assumed to represent a class effect for laac . of course , this manuscript provides a methodology that could be reasonably followed to examine the cost effectiveness of other laac devices in warfarin - contraindicated patients . there are limitations fundamental to any modelling analysis , in that it is a simplification of reality and can not represent all clinical permutations . our model allowed for only one clinical event per 3-month cycle , leveraged data from multiple clinical studies with different time horizons , and extrapolates out to 20 years . model results are based on data from randomized controlled studies and may not be representative of real - world clinical practice . additionally , the model reflects the german healthcare system and costs , and the icers may not be easily generalizable to other healthcare systems . patients with contraindications to warfarin have been difficult to study resulting in few data sources on long - term outcomes . the watchman asap data used in this analysis covered 14.4 months of follow - up , and the study was not powered to assess the long - term risk of haemorrhage or myocardial infarction . our analysis has used the only available study of aspirin in af patients who can not tolerate warfarin therapy . finally , as clinical probabilities for this analysis were taken from a study of the watchman device , results modelled here are specific to that device and can not be assumed to represent a class effect for laac . of course , this manuscript provides a methodology that could be reasonably followed to examine the cost effectiveness of other laac devices in warfarin - contraindicated patients . left atrial appendage closure has the potential to dramatically change the management of patients with af at risk for both stroke and bleeding . the recent european society of cardiology and the american heart association / american stroke association guidelines suggest that laac be considered for these high - risk patients . clinical results indicate that laac with the watchman device is a safe and effective treatment strategy . and this work was supported by boston scientific ( marlborough , ma , usa ) , which manufacturers the watchman device discussed in this manuscript . funding to pay the open access publication charges for this article was provided by boston scientific , inc .
aimsatrial fibrillation ( af ) patients with contraindications to oral anticoagulation have had few options for stroke prevention . recently , 
 a novel oral anticoagulant , apixaban , and percutaneous left atrial appendage closure ( laac ) have emerged as safe and effective therapies for stroke risk reduction in these patients . 
 this analysis assessed the cost effectiveness of laac with the watchman device relative to apixaban and aspirin therapy in patients with non - valvular af and contraindications to warfarin therapy.methods and resultsa cost - effectiveness model was constructed using data from three studies on stroke prevention in patients with contraindications : the asap study evaluating the watchman device , the active a trial of aspirin and clopidogrel , and the averroes trial evaluating apixaban . 
 the cost - effectiveness analysis was conducted from a german healthcare payer perspective over a 20-year time horizon 
 . left atrial appendage closure yielded more quality - adjusted life years ( qalys ) than aspirin and apixaban by 2 and 4 years , respectively . at 5 years , laac was cost effective compared with aspirin with an incremental cost - effectiveness ratio ( icer ) of  16 971 . left atrial appendage closure was cost effective compared with apixaban at 7 years with an icer of  9040 . left atrial appendage closure was cost saving and more effective than aspirin and apixaban at 8 years and remained so throughout the 20-year time horizon.conclusionsthis analysis demonstrates that laac with the watchman device is a cost - effective and cost - saving solution for stroke risk reduction in patients with non - valvular af who are at risk for stroke but have contraindications to warfarin .