It is no secret that warfarin, an oral vitamin K antagonist (VKA), is a narrow-therapeutic index anticoagulant with several caveats, including a need for close monitoring and dose assessment and patient adherence with the medication and monitoring. This fact helped allow the pharmacy profession to segue into serving in a clinical capacity as a component of a multidisciplinary healthcare team. Due to the recent FDA approval of anticoagulants that do not require frequent monitoring and dose assessment, it is understandable that clinicians would begin further research whether or not the current maximum recommended warfarin dose assessment interval could safely extend beyond 4 weeks.1
Based on a 1998 British guideline and retrospective analysis published in 2000 that reported patients with a very stable prothrombin time (PT) could safely wait 12 to 14 weeks, respectively, between PT testing, Schulman et al. conducted a randomized, blinded, single center, noninferiority trial that investigated whether assessment of warfarin dosing every 12 weeks was as effective as every 4 weeks.2-4 The study enrolled 250 patients receiving long-term warfarin, whose dose was unchanged for at least 6 months. Patients were randomized to receive dosing assessment every 12 weeks (n=124) or every 4 weeks (n=126) for 12 months. For blinding purposes, patients in the 12-week group were tested every 4 weeks and a sham international normalized ratio (INR) within the target range was reported for two of the three 4-week periods. If the sham INR was found to be extreme (INR < 1.5 or ≥ 4.5), the true results were reported to the physician. Though two-thirds of the INRs reported in the 12-week group were sham values, these patients did receive supportive contact with clinic staff at each 4-week interval.
The results of the investigator’s intention to treat analysis showed that the percentage of time in the therapeutic range in the 12-week group was noninferior to the 4-week group (71.6% ± 20.0% vs. 74.1% ± 18.8%, respectively; noninferiority P=0.020). In addition, fewer patients in the 12-week group than in the 4-week group had any dose changes (37.1% vs. 55.6%, respectively; P=0.004). This result should be expected since patients in the 12-week group were only eligible for dose adjustments one-third of the time than patients in the 4-week week group. Other secondary outcomes, including number of extreme INRs, major bleeding events, thromboembolism, and death did not differ between groups. The authors concluded that assessment of warfarin dosing every 12 weeks seems to be safe and noninferior to assessment every 4 weeks.
However, this study is not without limitations. The study was not a true evaluation of a 12-week INR monitoring and dose assessment interval for various reasons. Patients were contacted via telephone every 4 weeks regardless, that could have resulted in better patient adherence in the 12-week group compared to if they only had supportive contact every 12 weeks. Extreme INR values were reported in the 12-week group to allow for appropriate intervention to ultimately avoid adverse events, such as bleeding and thrombotic events. This potentially led to lower adverse consequences in this study, which in the real world such extreme INR values would have been unnoticed with 12-week follow-up. The study ...