Reasons for Warfarin Discontinuation in ORBIT-AF
Reasons for Warfarin Discontinuation in ORBIT-AF
Over 1 year of follow-up, approximately 1 (10.1%) in 10 patients discontinued warfarin therapy. This discontinuation rate was significantly higher (17.1%) among patients who started warfarin therapy in the prior year. We also observed differential persistence by AF diagnosis type, which varies with age. Compared with new-onset patients, lower discontinuation rates were documented for patients with paroxysmal, persistent, or permanent AF, who are more likely to be older compared with newly diagnosed patients. The majority of warfarin discontinuations were classified as patient related (88.9%), compared with only 22.9% that were classified as event related. Finally, the most commonly documented reasons for warfarin discontinuation were physician preference, patient refusal/preference, or a bleeding event.
Our overall rate of discontinuation, although still substantial, was lower than in prior studies, where reported discontinuation rates have ranged from 20% to more than 50%. An analysis of the MarketScan database reported a discontinuation rate of 51.7% over 30 months of follow-up. However, this analysis was conducted using administrative claims and during a period where discount pharmacy programs were introduced; so the rate of discontinuation may be artificially inflated because of patients switching to low-cost generics. Another study of approximately 41,000 AF patients in the General Practice Research Database of Great Britain reported a 1-year discontinuation rate of 30%. However, this study included a small proportion of patients with CHADS2 > 2 and did not include data on patients who were managed in anticoagulation clinics, factors we found to be strongly associated with warfarin persistence. A recent study of warfarin-treated AF patients in Ontario reported a discontinuation rate of 31.8%, with the highest discontinuation rates reported for those enrolled in earlier study years. The higher rates of persistence observed in ORBIT-AF may reflect contemporary trends toward better utilization of resources for therapeutic monitoring. Furthermore, patients who are willing to participate in a clinical registry may represent a subpopulation more likely to persist on recommended therapies than the overall AF population.
Another possibility for the lower observed rates of warfarin discontinuation in ORBIT-AF is the high proportion of study participants who recently began taking warfarin. Prior studies have noted important differences in warfarin persistence among new users compared with prevalent users. The ATRIA study reported a 1-year warfarin discontinuation rate of 26.3% among 4,188 newly treated patients. Furthermore, patients who persisted on warfarin therapy during the first year were more likely to remain on therapy thereafter. Another analysis of recently hospitalized AF patients reported greater likelihood of discontinuation among new starts compared with those who were taking warfarin prior to hospitalization. These results are consistent with our findings, with a substantially higher rate of 1-year discontinuation among new starts (17.1%) compared to the overall study population (10.1%). Prevalent warfarin users likely represent a subset of patients who are able to adhere to therapy and in whom warfarin is well tolerated, as evidenced by the lower rates of both discontinuation and bleeding events compared with newly diagnosed patients previously reported. Correspondingly, we found that newly treated patients were more likely to report discontinuation due to a bleeding event or inability to adhere than prevalent warfarin users. Additionally, median time in therapeutic range was higher for those who persisted on warfarin therapy than for those who discontinued. The lower median time in therapeutic range among those who discontinued may reflect suboptimal OAC adherence during the first year of therapy, consistent with the 6.0% of new start patients with "inability to adhere/monitor" listed as the reason for warfarin discontinuation, compared with 2.5% of prevalent warfarin users.
In the present study, younger patients and those with lower stroke risk were more likely to discontinue than older and higher-risk patients. These results are consistent with those of the ATRIA study, which found that patients with CHADS2 of 0 or 1 were more than twice as likely to discontinue warfarin as those with CHADS2 of 4 to 6. Patients with higher stroke risk may perceive a more favorable risk-benefit ratio of anticoagulation than those in the lower risk categories, which may promote more optimal monitoring and adherence. Notably, physician preference and patient preference were more commonly listed as discontinuation reasons among patients with CHADS2 < 2 compared with CHADS2 > 2, which may reflect a perceived lack of benefit associated with warfarin therapy. Younger age has been reported as a risk factor for warfarin discontinuation in a number of prior studies. Existing evidence suggests that older patients are less likely to be initiated on warfarin than younger patients, even after accounting for eligibility. Thus, older warfarin-treated patients may represent a preselected population perceived to be more likely to persist on therapy and to have a lower risk of complications.
In addition to overall discontinuation, we assessed factors associated with 2 discontinuation subtypes based on reported reasons for stopping warfarin: event-related and patient-related discontinuation. Only hematocrit was modestly associated with event-related discontinuation in baseline characteristics models. This result may reflect heterogeneity in the reasons we identified as "event related" or in the baseline characteristics of patients who discontinue for these reasons. As expected, we observed strong associations between cardiovascular-related, bleeding-related, and non–cardiovascular-/non–bleeding-related hospitalizations and both patient- and event-related discontinuation when including clinical events in secondary regression models.
Although hospitalization events were strongly associated with increased odds of discontinuation, recent evidence suggests that the estimated risk-benefit ratio of adverse warfarin-related events to reduced stroke risk may be overestimated in clinical practice. In a Swedish cohort of 182,000 AF patients, anticoagulation was associated with a net clinical benefit for all cross-classifications of CHADS2 and HAS-BLED bleeding risk score; only a very small minority (0.4%) was identified in which net clinical benefit was outweighed by bleeding risk. Despite this evidence, provider concerns about anticoagulant safety persist and may substantially affect OAC treatment decisions. Hylek and colleagues reported that physician safety concerns were cited as the reason for 81% of observed warfarin discontinuations among newly treated patients. Data from a recent series of interviews of cardiologists and internal medicine physicians reported that a major treatment barrier was clinician reluctance due to safety concerns. These results are consistent with those from the present study, where the most commonly reported reason for warfarin discontinuation was physician preference. Because reasons for discontinuation were not mutually exclusive, it is possible that physician preference included discontinuations that were also due to bleeding risk. However, bleeding risk was only identified as a reason for discontinuation in 9.8% of patients, suggesting that physician preference may encompass additional factors beyond concerns about bleeding.
Discussion
Over 1 year of follow-up, approximately 1 (10.1%) in 10 patients discontinued warfarin therapy. This discontinuation rate was significantly higher (17.1%) among patients who started warfarin therapy in the prior year. We also observed differential persistence by AF diagnosis type, which varies with age. Compared with new-onset patients, lower discontinuation rates were documented for patients with paroxysmal, persistent, or permanent AF, who are more likely to be older compared with newly diagnosed patients. The majority of warfarin discontinuations were classified as patient related (88.9%), compared with only 22.9% that were classified as event related. Finally, the most commonly documented reasons for warfarin discontinuation were physician preference, patient refusal/preference, or a bleeding event.
Our overall rate of discontinuation, although still substantial, was lower than in prior studies, where reported discontinuation rates have ranged from 20% to more than 50%. An analysis of the MarketScan database reported a discontinuation rate of 51.7% over 30 months of follow-up. However, this analysis was conducted using administrative claims and during a period where discount pharmacy programs were introduced; so the rate of discontinuation may be artificially inflated because of patients switching to low-cost generics. Another study of approximately 41,000 AF patients in the General Practice Research Database of Great Britain reported a 1-year discontinuation rate of 30%. However, this study included a small proportion of patients with CHADS2 > 2 and did not include data on patients who were managed in anticoagulation clinics, factors we found to be strongly associated with warfarin persistence. A recent study of warfarin-treated AF patients in Ontario reported a discontinuation rate of 31.8%, with the highest discontinuation rates reported for those enrolled in earlier study years. The higher rates of persistence observed in ORBIT-AF may reflect contemporary trends toward better utilization of resources for therapeutic monitoring. Furthermore, patients who are willing to participate in a clinical registry may represent a subpopulation more likely to persist on recommended therapies than the overall AF population.
Another possibility for the lower observed rates of warfarin discontinuation in ORBIT-AF is the high proportion of study participants who recently began taking warfarin. Prior studies have noted important differences in warfarin persistence among new users compared with prevalent users. The ATRIA study reported a 1-year warfarin discontinuation rate of 26.3% among 4,188 newly treated patients. Furthermore, patients who persisted on warfarin therapy during the first year were more likely to remain on therapy thereafter. Another analysis of recently hospitalized AF patients reported greater likelihood of discontinuation among new starts compared with those who were taking warfarin prior to hospitalization. These results are consistent with our findings, with a substantially higher rate of 1-year discontinuation among new starts (17.1%) compared to the overall study population (10.1%). Prevalent warfarin users likely represent a subset of patients who are able to adhere to therapy and in whom warfarin is well tolerated, as evidenced by the lower rates of both discontinuation and bleeding events compared with newly diagnosed patients previously reported. Correspondingly, we found that newly treated patients were more likely to report discontinuation due to a bleeding event or inability to adhere than prevalent warfarin users. Additionally, median time in therapeutic range was higher for those who persisted on warfarin therapy than for those who discontinued. The lower median time in therapeutic range among those who discontinued may reflect suboptimal OAC adherence during the first year of therapy, consistent with the 6.0% of new start patients with "inability to adhere/monitor" listed as the reason for warfarin discontinuation, compared with 2.5% of prevalent warfarin users.
In the present study, younger patients and those with lower stroke risk were more likely to discontinue than older and higher-risk patients. These results are consistent with those of the ATRIA study, which found that patients with CHADS2 of 0 or 1 were more than twice as likely to discontinue warfarin as those with CHADS2 of 4 to 6. Patients with higher stroke risk may perceive a more favorable risk-benefit ratio of anticoagulation than those in the lower risk categories, which may promote more optimal monitoring and adherence. Notably, physician preference and patient preference were more commonly listed as discontinuation reasons among patients with CHADS2 < 2 compared with CHADS2 > 2, which may reflect a perceived lack of benefit associated with warfarin therapy. Younger age has been reported as a risk factor for warfarin discontinuation in a number of prior studies. Existing evidence suggests that older patients are less likely to be initiated on warfarin than younger patients, even after accounting for eligibility. Thus, older warfarin-treated patients may represent a preselected population perceived to be more likely to persist on therapy and to have a lower risk of complications.
In addition to overall discontinuation, we assessed factors associated with 2 discontinuation subtypes based on reported reasons for stopping warfarin: event-related and patient-related discontinuation. Only hematocrit was modestly associated with event-related discontinuation in baseline characteristics models. This result may reflect heterogeneity in the reasons we identified as "event related" or in the baseline characteristics of patients who discontinue for these reasons. As expected, we observed strong associations between cardiovascular-related, bleeding-related, and non–cardiovascular-/non–bleeding-related hospitalizations and both patient- and event-related discontinuation when including clinical events in secondary regression models.
Although hospitalization events were strongly associated with increased odds of discontinuation, recent evidence suggests that the estimated risk-benefit ratio of adverse warfarin-related events to reduced stroke risk may be overestimated in clinical practice. In a Swedish cohort of 182,000 AF patients, anticoagulation was associated with a net clinical benefit for all cross-classifications of CHADS2 and HAS-BLED bleeding risk score; only a very small minority (0.4%) was identified in which net clinical benefit was outweighed by bleeding risk. Despite this evidence, provider concerns about anticoagulant safety persist and may substantially affect OAC treatment decisions. Hylek and colleagues reported that physician safety concerns were cited as the reason for 81% of observed warfarin discontinuations among newly treated patients. Data from a recent series of interviews of cardiologists and internal medicine physicians reported that a major treatment barrier was clinician reluctance due to safety concerns. These results are consistent with those from the present study, where the most commonly reported reason for warfarin discontinuation was physician preference. Because reasons for discontinuation were not mutually exclusive, it is possible that physician preference included discontinuations that were also due to bleeding risk. However, bleeding risk was only identified as a reason for discontinuation in 9.8% of patients, suggesting that physician preference may encompass additional factors beyond concerns about bleeding.
Source...