Maintaining appropriate patients with atrial fibrillation on warfarin therapy is vitally important because clinical outcomes are strongly dependent upon remaining on anticoagulation[11
]. Conversely, there may be individuals at low stroke risk or with elevated risk from warfarin in whom discontinuation of therapy is appropriate. In our ATRIA cohort, more than one in four patients with atrial fibrillation newly started on warfarin discontinued therapy within the first year of treatment. Although there was a high rate of discontinuation in the first year, people who remained on therapy at the end of the first year were then less likely to discontinue warfarin in subsequent years. In addition, sizable fractions of people who discontinued warfarin eventually restarted therapy, leading to a relatively stable prevalence of warfarin use in the overall cohort over time.
It is challenging to determine what proportion of warfarin persistence vs. discontinuation was clinically appropriate. Patients with low stroke risk may not derive much benefit from warfarin. We found that people with the lowest predicted stroke risk were more likely to discontinue warfarin than those with additional stroke risk factors and higher CHADS2
scores, an observation noted in some prior studies of warfarin use[7
]. These results may reflect a rational assessment of the net benefit of anticoagulation by prescribing clinicians and their patients.
There may also be clinically appropriate reasons to discontinue therapy. Our study found that individuals with lower proportions of time spent in the therapeutic INR range were more likely to discontinue warfarin. We were unable to determine the precise reasons for poorer INR control. Poor INR control may have been a marker for non-adherence to warfarin leading to subsequent discontinuation, or poor control may have led to concerns about the safety of continuing warfarin[13
As expected, discontinuation of warfarin was high after hospitalizations for a hemorrhagic event, but because the overall rate of hemorrhage hospitalizations in the cohort was low, such events could only account for a small fraction of discontinuations. It is possible that more minor, outpatient hemorrhagic events resulted in additional patients discontinuing therapy. The youngest patients were the most likely to discontinue warfarin therapy, a finding that has been observed in other analyses of warfarin adherence [12
]. Patients age 85 years and older were not more likely to discontinue warfarin than those aged 65-84 years old, despite the higher risk of hemorrhage among older adults[16
Although warfarin discontinuation rates have varied across randomized clinical trial settings[17
], it was notably high in the older patients enrolled in the recent Birmingham Atrial Fibrillation Treatment of the Aged Trial (BAFTA). After a mean follow-up period of 2.7 years, 33% of elderly patients discontinued warfarin compared to a 24% discontinuation rate on aspirin[20
]. Of note, a large number of potential subjects in the BAFTA trial were excluded because their physicians thought warfarin would be beneficial, which may have selected for less suitable warfarin candidates. The BAFTA study also did not provide discontinuation rates stratified by age group, being study of older patients. Observational studies have found that warfarin discontinuation is frequently due to concerns about bleeding complications or safe anticoagulation management, as well as issues of patient adherence and preference[12
]. One study of 651 patients prescribed oral anticoagulants after ischemic stroke observed a 22% discontinuation rate after 1 year. Bleeding was the reason cited for 36.4% of those stopping anticoagulants, and “patient request” or “hassle to visit anticoagulation clinic” were the reasons cited in another 31.5% of patients[22
]. Another study found that among 153 patients aged ≥ 80 years, 26% discontinued warfarin within 1 year (excluding patients who died or who were in sinus rhythm), and the primary reason for discontinuation was due to concerns about the safety of anticoagulation[21
]. There was a high bleeding complication rate observed in this study which may have been related to a large proportion of patients who were recruited during an acute hospitalization. In addition, there was a 40% rate of concomitant warfarin and aspirin use, which may have led to increased bleeding complications. Although our study found low rates of hospitalizations for hemorrhage, it is possible that minor hemorrhages, such as epistaxis or superficial bruising that did not lead to hospitalization, could have contributed to warfarin discontinuation. A more in-depth investigation of the impact of minor bleeding while on anticoagulants would give a richer perspective to the reasons that people discontinue warfarin.
Our results highlight the dynamic nature of adherence to anticoagulant therapy. Even after discontinuing warfarin for at least 180 days, a substantial proportion of people restarted warfarin at some point over subsequent years. The balance of discontinuations and resumption of therapy resulted in a fairly stable prevalence of warfarin use after the first 2 years of warfarin anticoagulation. Nonetheless, the large fraction of patients who discontinue warfarin permanently has important implications for quality improvement programs. Programs that are primarily directed towards more widespread adoption of warfarin therapy in patients with atrial fibrillation must work to improve not only the initiation of therapy, but the persistence
of therapy in appropriate patients[23
]. The observation that patients with lower stroke risk and worse INR control were more likely to come off therapy, while patients with additional risk factors for stroke were more likely to remain on warfarin, suggests that clinicians have significant influence on whether patients continue to take warfarin or not. Quality measurements that rely on cross-sectional assessments of the proportion of patients taking warfarin will not be able to capture the dynamic process of warfarin initiation and discontinuation in individual patients.
There are several limitations to our study. The primary limitation is that we were unable to directly determine the specific reason for discontinuation. Some studies have found that concerns about safety and adherence are strongly associated with avoidance or discontinuation of warfarin[13
]. Although it is likely that such concerns influenced warfarin discontinuation in our study, we lacked direct assessments of individual decision-making. Our study was also unable to capture outpatient hemorrhagic events that did not lead to hospitalization, but may have led to concerns about the safety of continuing on warfarin. Our measure of warfarin use and discontinuation may be subject to some errors in timing because we relied on an algorithm based on the number of pills prescribed to determine the length of warfarin therapy along with interim INR testing. In addition, our assessments of clinical factors associated with stroke risk were obtained using computerized clinical databases, which may introduce some level of misclassification. Our analysis was not able to capture comprehensive aspirin use, since it was available without a prescription. Since our study period largely preceded the publication of the results of the Atrial Fibrillation Follow-up Investigation of Rhythm Management trial in 2002[24
], it is possible that some physicians discontinued warfarin in patients with long periods of sinus rhythm; our study was not able to determine which patients had only a single episode of atrial fibrillation followed by prolonged sinus rhythm[25
Warfarin largely reverses the risk of stroke attributable to atrial fibrillation. Multiple guidelines recommend warfarin therapy in patients with atrial fibrillation with additional stroke risk factors, a clinical profile describing the majority of patients with atrial fibrillation[28
]. In this large, community-based cohort of patients newly starting warfarin for atrial fibrillation, more than one-fourth discontinued therapy within the first year. Although hemorrhage events leading to hospitalization greatly increased the risk of warfarin discontinuation, the rate of such hemorrhages was too low to account for more than a small fraction of all discontinuations. It is probable that difficult warfarin control and concern about bleeding risk led patients and/or clinicians to stop warfarin. Quality indicators that rely simply on rates of warfarin use for atrial fibrillation will be unlikely to capture appropriate vs. inappropriate discontinuation of anticoagulation. Stroke prevention programs should consider the net benefit of warfarin for individual patients with atrial fibrillation, weighing the risks and benefits, and be attentive towards maintaining anticoagulation in appropriate patients.
What is Known
- Warfarin is widely recommended for the prevention of atrial fibrillation-related stroke
- Cross-sectional studies show that many patients with atrial fibrillation are not on warfarin, but few describe which patients stop taking warfarin
What this Article Adds
- More than one in four patients newly starting warfarin in this large, community-based cohort discontinued therapy within 1 year
- Patients with fewer stroke risk factors and poorer warfarin control were more likely to discontinue therapy, suggesting that a portion of those who discontinue warfarin might be doing so because of limited benefits or excess risks
- Stroke-prevention efforts should address the appropriate persistence of warfarin therapy in patients with atrial fibrillation