The evidence for current clinical practice in long term anticoagulation for patients with non-rheumatic atrial fibrillation is not strong. Our search strategy identified five randomised control trials that had compared long term anticoagulation with antiplatelet treatment. The primary annual event rate in the trials varied from 1.7% to 10.6%, reflecting marked clinical heterogeneity in risk among patients included in the different trials. Although the trials were set up to examine the effects of treatment in non-rheumatic atrial fibrillation, most included a proportion of patients with histories of myocardial infarction, transient ischaemic attack or stroke, and heart failure. Such patients would be expected to contribute to the heterogeneity in the effects observed because of their higher risk of cardiovascular disease. Although cardiovascular risk varied markedly between the trials, there was no clear relation between cardiovascular risk and the proportion of higher risk patients included.
Methodological explanations for trial heterogeneity may be more important than previous clinical histories. The randomised control trials were small in number, two were stopped prematurely, and only one showed a difference in effect (favouring anticoagulation). This trial was methodologically weaker in design than the others and may introduce bias in evaluation of treatment effects. Exclusion of methodologically weaker studies from a meta-analysis is a recognised aspect of sensitivity analyses that aim to determine how much the pooled effect is dependent on one or more trials with specific characteristics.
The trials showed variation in the degree of blinding of outcome assessment used. When non-fatal events are counted, failure to blind outcome assessors to treatment received might bias ascertainment of stroke events that may be difficult to diagnose. Even with fatal events knowledge of treatment allocation may bias attribution of causes of death, although this is less likely. Consequently, effects of treatment on mortality are probably more robust that those based on non-fatal or combined non-fatal and fatal outcomes.
Despite our findings indicating uncertain benefit from anticoagulation in terms of reduced risk from fatal and non-fatal cardiovascular disease in non-rheumatic atrial fibrillation, it is clear that these trials, individual and pooled, are underpowered. To detect a 25% superiority of anticoagulation over antiplatelet treatment with an event rate of 10%, a power of 80%, and a significance of 5%, trials would require 4920 patients for each treatment group. The trials together comprised only 3298 patients, which gives the pooled data only 60% power to detect a difference of this size.
Our search included trials not incorporated in previous reviews of long term anticoagulation compared with antiplatelet treatment. These reviews have consistently reported substantial benefits from long term anticoagulation, and this may be because of failure to include all the available randomised control trials,2,4,22
the use of composite fatal and non-fatal end points,23,24
and the use of fixed effects models despite significant heterogeneity.5,23,25
Furthermore, inclusion of the recently published PATAF trial reduces the effect of long term anticoagulation in comparison with antiplatelet treatment.19
The European atrial fibrillation trial compared warfarin and aspirin in high risk patients with non-rheumatic atrial fibrillation who had suffered a recent transient ischaemic attack or minor stroke.26
The investigators allocated patients eligible for anticoagulation to receive either warfarin, aspirin, or placebo and patients who were not eligible for anticoagulation to aspirin or placebo. The analysis was confined to pooling both aspirin groups. Consequently, these findings are difficult to interpret.
Although the pooled effects on mortality were not significant, the confidence intervals were wide. For vascular deaths, anticoagulation may be up to 37% better than aspirin or as much as 17% worse. For all the outcomes considered an effect of anticoagulation as large as that observed in placebo comparisons (for instance, a 68% reduction in risk) can be excluded by the pooled data of this direct comparison. Patients with non-rheumatic atrial fibrillation may not derive any greater benefit in terms of reduced death from cardiovascular disease with long term anticoagulation than with antiplatelet treatment. The findings conflict with the findings of randomised control trials that compared anticoagulation with placebo and antiplatelet with placebo in patients with non-rheumatic atrial fibrillation. However, our direct comparison of the two treatments is the appropriate way to estimate treatment effects and shows how indirect comparisons tend to overinflate effect sizes. Our analysis also emphasises the importance of examining sources of heterogeneity in meta-analysis and, in particular, trial quality.
Risk of bleeding is linked to the quality of anticoagulant control, and the recommended intensity of anticoagulation for non-rheumatic atrial fibrillation is an international normalised ratio of 2-3.21
Major bleeding was 45% more common in patients who received anticoagulation. Bleeding would probably be more common in routine clinical practice than in trials in which patient selection has occurred.
None of the trials considered differences in the costs of treatment. Outpatient clinics are currently experiencing a 6-24% cumulative increase in referrals for long term anticoagulation.27
This current demand has encouraged the uptake of alternative organisational options such as computer aided dosing,28
near patient testing,29
and nurse-led services.30
A previous study estimated that a policy of anticoagulation of all those eligible for treatment and use of aspirin for the remainder would be 15 times as expensive as a universal policy of giving aspirin to everyone with non-rheumatic atrial fibrillation.31
Given the uncertainty over the greater efficacy of anticoagulation, its undoubted hazards, and considerations of cost effectiveness we would strongly favour antiplatelet drugs in preference to long term anticoagulation. Thus, the need for the large scale expansion of outpatient anticoagulation services may be less clear.
Further large scale randomised control trials are needed to compare the costs, benefits, and risk of long term anticoagulation versus antiplatelet treatment in patients with non-rheumatic atrial fibrillation. The effects of different intensities of anticoagulation, with inclusion of detailed data on adequate therapeutic control, would need to be explored, as would the effects of treatment in different cardiovascular disease risk groups as the absolute benefits of anticoagulant treatment (if found) will have to be offset against risks of bleeding. In the meantime, the hospital physician and general practitioner will have to decide how to treat patients with non-rheumatic atrial fibrillation. Firstly, a diagnosis is needed to exclude thyrotoxicosis and other underlying causes. The patients in this systematic review included patients from both hospital clinics and general practice, predominately without evidence of underlying cardiovascular disease. For such patients who are already receiving anticoagulation and are happy and stable on this treatment, our results show that there is little to chose between the two treatment options, except cost. For new patients, some doctors may consider it unwise to risk the potential hazards of major bleeding, with the associated costs to the patient and the health service, and will chose an antiplatelet drug. Patient preferences also need to be taken into account as evidence shows that antiplatelet treatment is the favoured option in circumstances of uncertainty of benefit.32
We hope that healthcare providers will be prepared to randomise patients to new adequately powered trials to compare the costs, benefits, and adverse effects of anticoagulation with antiplatelet treatment.
What is already known on this topic
Compared with placebo or control long term anticoagulation in patients with non-rheumatic atrial fibrillation reduces the risk of non-fatal stroke, whereas antiplatelet treatment has less benefit
Indirect comparisons of the effects of the two treatment options may be biased by different selection criteria used in trials leading to differences in prognosis unrelated to treatment and may overestimate treatment effects found
What this study adds
In a direct comparison, the effects of long term anticoagulation compared with antiplatelet treatment for non-rheumatic atrial fibrillation are consistent both with major treatment benefits and with modest harm for fatal stroke and non-fatal stroke and vascular deaths
Major bleeding was more common in patients receiving anticoagulation, and the evidence to support long term anticoagulation is weak
Further large scale randomised control trials are needed to establish the value of long term anticoagulation in patients with non-rheumatic atrial fibrillation