The hazards of interrupting anticoagulation therapy in atrial fibrillation.

Atrial fibrillation (AF) is the most commonly encountered clinical arrhythmia and is associated with a substantial burden of morbidity (mainly thrombo-embolism) and mortality. Vitamin K antagonists such as warfarin are highly effective for the prevention of stroke and systemic embolism in patients with AF, but their use is hampered by multiple food and drug interactions, the need for routine coagulation monitoring, and a high risk of bleeding complications. Hence warfarin not only is underutilized, but among those who are prescribed warfarin the treatment is frequently interrupted or permanently discontinued. No large studies have explored the possible impact of stopping warfarin on the short-term risk of subsequent major adverse cardiovascular outcomes, such as stroke and death, in patients with AF. Raunsø and co-workers have now reported the results of a Danish nationwide retrospective cohort study in which they explored outcomes after warfarin interruption in patients with AF. Patients with a first hospitalization for AF in the period 1 January 1997 to 31 December 2008 were identified using the Danish National Patient Registry, and warfarin interruption was determined by cross-linkage with prescription claims from the Danish Registry of Medicinal Product Statistics. The primary outcome of the study was hospitalization for thrombo-embolism (ischaemic stroke, transient ischaemic attack, or unspecified stroke), pulmonary embolism or systemic arterial embolism, or allcause death. Among 149 151 patients with a first hospitalization for AF during the 12 year study period, 48 989 filled a prescription for warfarin a median of 6 days after being discharged from hospital. Remarkably, 35 396 patients or 72% of the entire cohort had at least one warfarin treatment interruption during a mean of 3.5 years of followup. The median age for patients receiving warfarin was 71 years, the median CHADS2 score was 1.41, and the overall incidence rate of thrombo-embolism or death was 6.9 per 100 patient years. One-half of these events occurred during treatment interruption, and the incidence rate of thrombo-embolism or death during the first 90 days after stopping warfarin was 31.6 per 100 patient years. The strengths of the report by Raunsø et al. are the inclusion of an unselected ‘real-life’ AF population, the long follow-up duration, and the use of a robust primary outcome measure, hospitalization for thrombo-embolism and all-cause death. The study also has several limitations, including lack of information on bleeding, uncertainty about the accuracy of warfarin dosing estimations (which may have led to error in estimating the timing of warfarin interruption), and inability to distinguish temporary from permanent interruption. The most important limitation would appear to be lack of information concerning the reason for warfarin interruption, which complicates interpretation of the association between treatment interruption and outcome. Potential explanations for the findings of an association between treatment interruption and risk of thrombo-embolism or death are illustrated in Figure 1. One possible explanation is that the event that prompted the treatment interruption (e.g. bleeding, trauma, or surgery) might also have been the cause of thrombo-embolism or death (‘confounding’). Without detailed information on the reason for interruption, the potential for confounding cannot be excluded. A second possible explanation is that the events that occurred during interruption of warfarin simply reflect loss of protection against thrombo-embolism in patients with persistent risk factors (‘indirectly causal’). However, this explanation cannot account for the very high rate of thrombo-embolism or death observed during the first 90 days because patients who underwent warfarin interruption had a mean CHADS2 score of 1.34 which, if untreated, is associated with an annual risk of stroke of ,5%. A third possible explanation is that warfarin interruption is associated with rebound hypercoagulability that increases the risk of thrombo-embolism (‘directly causal’). Warfarin prevents thrombosis by inhibiting synthesis of vitamin K-dependent coagulation proteins, thereby preventing thrombin generation. Withdrawal of