IS AGE A RISK FACTOR FOR WARFARIN‐RELATED MAJOR BLEEDS IN ELDERLY PATIENTS WITH ATRIAL FIBRILLATION?

To the Editor: Age is an independent risk factor of major bleeding during warfarin therapy. One recent meta-analysis pooling six trials with a total of 1,939 participants estimated that warfarin used to treat nonvalvular atrial fibrillation in older people was associated with major bleeding at the rate of 1.8 per 100 patient-years in patients younger than 75, but the rate of major bleeding increased to 3.2 per 100 patient-years in patients aged 75 and older. As people age, they tend to have more coexisting diseases. Some coexisting diseases, such as hypertension, were also associated with bleeding during warfarin therapy. In addition, two scoring systems used age as prediction risk of warfarin-related bleeding. According to these two scoring systems a person aged 65 and older with or without other risk prediction factors has a medium risk of bleeding. Based on these findings, at least age can be used as a marker for risk factor of warfarin-related bleeding, although an observational study reported by Drs. Adelhafiz and Wheeldon in this journal has challenged this. They found comparable rates of major bleeding between older people younger than 75 and aged 75 and older. Similar findings were also reported in two other studies cited by Drs. Adelhafiz and Wheeldon and one additional study found by my literature search. The question is why age was not a risk factor for bleeding during warfarin therapy in these studies. After reviewing the four studies that failed to show age as a risk factor for warfarin-related bleeding, it is likely that one major possibility was that the small sample size in the four negative studies provided less power to detect major bleeding. The first negative study cited by Drs. Adelhafiz and Wheeldon had 328 participants, of whom 204 were aged 60 to 69 as control group and 124 were aged 75 and older as the elderly group. The second study cited by Drs. Adelbafiz and Wheeldon had a large sample size, but 139 of 461 patients were aged 75 and older with atrial fibrillation, and 139 were younger than 70 with atrial fibrillation. Even with such a low percentage rate of atrial fibrillation, bleeding and major bleeding tended to be higher in the older group and did not reach statistical significance (P 5.07 and .19, respectively), which means that this study might not be a true negative. The study reported by Drs. Adelbafiz and Wheeldon included only 402 elderly patients almost equally divided into younger and older groups. One additional negative study that I found was the Second Copenhagen Atrial Fibrillation, Aspirin, and Anticoagulation Study, in which the total number of participants in the warfarin and warfarin-plus-aspirin groups was 167 and 171, respectively. The second potential reason for negative studies of warfarin-related major bleeding was that patients might have better monitoring, because three of four negative studies were conducted at an anticoagulant clinic. Finally, it is unclear whether there were few risk factors of warfarin-related bleeding in negative studies. Taken together, based on small sample size and special research setting (anticoagulant clinic), from four negative results, we should not discard age as a risk factor for warfarin-related major bleeding in older people with atrial fibrillation. Higher risk of warfarin-related major bleeding as people aged could still be true based on previous systemic review and meta-analysis. While waiting for more negative studies with large sample sizes and in a general population we should inform patients about warfarin-related major bleeding and promote an informed and individualized decision.