Our findings demonstrate that nonadherence to warfarin occurs to a substantial degree in patients despite being closely monitored and counseled in specialized anticoagulation clinics. Participants appeared 6 times more likely to miss pills than to take extra pills, which would put them at greater risk of underanticoagulation and thromboembolism. In addition, adherence was found to decrease with time after initiation of warfarin use but rebound between 6 and 12 months. Adherence as measured by MEMS caps identified more nonadherence than either clinician assessment or patient self-reports and was associated with anticoagulation control, independent of these other methods of assessing adherence.
Few other studies have reported on adherence to anticoagulant therapy. A study using pill counts reported approximately 90% adherence with warfarin.7
Our study found a lower rate of adherence using MEMS caps, as would be expected given the known overestimation of adherence resulting from pill counts.8,9
Two small, short-term studies have made use of MEMS caps to characterize adherence to an anticoagulation regimen. One single-center study of phenprocoumon found better adherence than in our study (7.2% incorrect cap openings).8
However, the small size (n
30) of this cohort, who were selected from among 6,500 treated at the clinic, and the short follow-up period (≤3 months) make comparisons with our multicenter, longer-term study difficult. Another study found 80% correct bottle openings among warfarin patients, similar to our findings.9
Unlike our study, this prior study included only patients selected for a randomized trial, was small (n
40), and had a median duration of follow-up of only 83 days (vs. our median duration of 126 days). None of these prior studies described how adherence changed over time.
The reasons for the change in adherence over time are unclear but did not appear to be because of a dropout effect. Perhaps patients were more diligent when initiating therapy; later began to miss more pills; and then, as a result of loss of anticoagulation and perhaps increased clinician instructions, again became more adherent. These findings suggest that patients may benefit from interventions to improve adherence, particularly in the several months after they initiate warfarin, but certainly throughout their course of therapy because adherence is still poor even in later months. Also, although clinicians may focus on adherence barriers at the beginning of treatment, barriers may crop up during treatment. Therefore, clinicians must recognize that adherence needs to be readdressed throughout follow-up, even in patients who may be adherent early in their therapy.
Although clinicians were statistically better than chance at correctly labeling a participant as adherent or not compared to the MEMS cap, their estimate was often different from that assessed by MEMS caps. Although MEMS caps are not the perfect measure of adherence, studies of other medications have suggested that clinicians do tend to overestimate adherence.10–12
This finding highlights the need for clinicians to encourage appropriate pill-taking behavior, even if the patient appears to be doing so. Whereas clinicians were less likely to incorrectly label a patient adherent when they had information on pill counts, they still concluded that more than 75% of nonadherent participants were adherent. This underscores the inaccuracy of pill counts.13–15
Our data also suggest that self-report, at least as typically reported in clinical practice, may underestimate nonadherence in warfarin users. This finding is consistent with previous studies that have shown that patient self-reports can be inaccurate measures.13–15
In terms of the limitations of our study, analyses of participant adherence relied on the use of electronic pill caps, which may not reflect actual pill taking. Many participants did not use the MEMS caps directly on a pill bottle, although their MEMS-cap adherence was similar to those who did use the cap on their pill bottles. In addition, we could not determine whether patients prescribed different doses on different days actually took the correct dose, which would likely have underestimated nonadherence. In addition, participants knew they were being monitored, which may have improved their adherence. In general, however, electronic pill caps are considered the most accurate method of assessing pill-taking behavior.5,16
Furthermore, even accounting for clinician assessment and patient reports of adherence, MEMS-cap-measured adherence was still associated with anticoagulation control.
Our findings also may not be fully generalizable to warfarin users outside of the anticoagulation clinic population.17,18
Nonetheless, anticoagulation clinics are becoming the standard-of-care for patients on warfarin,18,19
and the inclusion of anticoagulation clinics minimizes confounding by variability in practice patterns. Moreover, our clinic sites provided geographic and socioeconomic diversity, thus enhancing generalizability.
Clinicians were not blinded to the INR, which might have influenced their assessment of adherence. Whether this led to an advantage in estimating adherence (i.e., if the INR was low in the setting of poor adherence) or a disadvantage (assuming good adherence because the INR was in range, which can occur if warfarin dose has been titrated to a patient’s consistent level of nonadherence), our findings underscore the difficulty of judging patient adherence even with monitoring of INR.
In conclusion, patients at specialized anticoagulation clinics incorrectly take their warfarin medication on approximately 20% of days of intended therapy, a clinically meaningful level of nonadherence.6
Adherence also declines significantly in the first several months of therapy. Finally, clinicians’ subjective impressions of patient adherence – even when based on the patient’s INR levels or pill counts – and patients’ self-reports do not correlate well with electronically measured adherence. To reduce rates of nonadherence, clinicians treating patients with warfarin should continue to emphasize strict adherence, even among patients whom they believe are adherent and throughout the course of therapy.