The results of this large population-based study indicate that warfarin is associated with a net clinical benefit in preventing ischemic strokes in patients with AF, while overall, no net clinical benefit is observed with aspirin. Furthermore, this study presents for the first time, the net clinical benefit of warfarin classified according to different levels of anticoagulation. Our results confirm that the net clinical benefit of warfarin is limited to patients within therapeutic range, and thus emphasize the need to adequately maintain patients within that range. While our results confirm previous findings [8
] that high risk patients, such as those with a history of ischemic stroke and high CHADS2
scores are those most likely to benefit from this therapy, they also justify physician concerns that warfarin may not be indicated for patients with a history of bleeds. Similar patterns were observed with aspirin in subgroup analyses, although the net clinical benefits were more modest than those observed with warfarin. Finally, our results indicate that the net clinical benefit of warfarin becomes apparent only after 3
months of continuous use, highlighting the importance of improving treatment persistence in patients using this therapy.
To our knowledge, this is one of the largest population-based studies to have evaluated the net clinical benefit of warfarin and aspirin in patients with AF. We observed that only 50% of the cohort was ever exposed to warfarin during follow-up, demonstrating underutilization which is consistent with other studies [4
]. We also found that patients with a history of stroke and those without a history of bleeds were the ones most likely to benefit from warfarin therapy, thus identifying populations for whom this therapy may or may not be appropriate. Finally, the net clinical benefit of warfarin was maintained with longer periods of continuous use. This novel finding emphasizes the need to improve treatment persistence, as 26% to 30% of patients with AF discontinue warfarin within the first year of treatment [24
As observed by others [9
], we did not find any net clinical benefit with aspirin overall. However, we did observe a net clinical benefit in patients with low CHADS2
scores (0 and 1), populations for whom aspirin is typically indicated. These net clinical benefits were however, lower than those observed with warfarin. Finally, while aspirin had a net clinical benefit in patients with a history of stroke, no benefit was observed in those with no history of bleeds. Overall, our aspirin results need to be interpreted with caution. Unlike warfarin, aspirin is available over-the-counter, possibly leading to exposure misclassifications. While chronic aspirin users typically receive prescriptions for this drug, which is dispensed almost free of charge in in the UK population, it is possible that some patients were misclassified as unexposed, leading to an underestimation of an already weak treatment effect.
This population-based study has a number of strengths and some potential limitations. This was a large population-based cohort of patients with AF, followed for up to 16
years, enabling the identification of a large number of cases. In addition, because medical and drug information in the GPRD is prospectively collected, the possibility of recall bias was eliminated. However, drug information in the GPRD represents prescriptions written by general practitioners. As such, it is unknown whether prescriptions were actually filled at the pharmacy and whether patients fully adhered with the treatment regimen. Such non-differential misclassification of exposure would have biased the results towards the null. Another limitation is that stroke events may be underreported in the GPRD, which would lead to an underestimation of the treatment effects. Furthermore, ischemic strokes were defined on the basis of a specific diagnostic code for this event or a diagnostic code of ‘stroke’ with no mention of the subtype. Since stroke subtypes are not always specified in the GPRD files, it is possible that some hemorrhagic strokes were misclassified as being ischemic. However, this potential bias is likely to have been minimal as the vast majority of strokes are ischemic (>80%), and our overall rate was very similar to the one reported in the previous study (2.0% per year versus 2.1% per year, respectively) [8
]. Finally, as with any observational study, confounding by indication is a concern, whereby the risk profile of patients prescribed warfarin or aspirin is likely to be different from the one of those not prescribed any antithrombotic therapy. Although we adjusted for a number of potential confounding factors including BMI, excessive alcohol use, and smoking which are often absent in administrative databases, residual confounding may still be present.
We assessed the net clinical benefit of warfarin and aspirin on the basis of comparing their benefits in ischemic stroke prevention to their risks in increasing the incidence of ICH. However, it would have been of interest to compare other potential benefits (such as prevention of MI in warfarin users [26
]) to other risks associated with these therapies, such as major bleeding events (other than ICH). Unfortunately, the GPRD does not collect detailed information to objectively classify the severity of bleeding events (such as those events requiring hospitalization, and those associated with decreases in hemoglobin, or those requiring red blood cell transfusions). Additional studies are needed to consider the net clinical benefit of warfarin and aspirin in the context of a broader range of outcomes.
In summary, our study provides the net clinical benefit of warfarin and aspirin in patients with AF in the natural setting of clinical practice. Our results indicate that patients taking warfarin outside of the recommended therapeutic range are unlikely to benefit from this therapy, while aspirin confers a weak net clinical benefit in selected populations. Finally, our findings emphasize the need to identify high risk populations that would benefit the most from warfarin therapy, and ensure that such patients are maintained within therapeutic range, while identifying strategies to improve treatment persistence.