Editor's Note: Based on Lamberts M, Olesen JB, Ruwald MH, et al. Bleeding after initiation of multiple antithrombotic drugs, including triple therapy, in atrial fibrillation patients following myocardial infarction and coronary intervention:  A nationwide cohort study. Circulation 2012; 126:1185-93.

Introduction

Atrial fibrillation (AF) is a known risk factor for stroke, the risk of which is reduced by treatment with anticoagulants such as warfarin. Patients who undergo percutaneous coronary intervention (PCI), or experience a myocardial infarction (MI), are often treated with dual antiplatelet therapy, such as aspirin and clopidogrel, to reduce the risk of death or recurrent infarction, or stent thrombosis. Patients with AF who subsequently undergo PCI or experience MI may therefore require treatment with all three drugs, so-called triple therapy (TT). Patients on TT have an increased risk for bleeding events, which has been associated with an increased risk of mortality.¹ The timing of bleeding events for patients on TT is not well characterized. The current study was undertaken to evaluate the time course of bleeding events on various antithrombotic regimens in patients with AF admitted to the hospital for MI or PCI.²

Methods

This study evaluated patients using the National Patient Registry in Denmark, which tracks each hospitalization in Denmark. Patients age ≥30 years with AF who were hospitalized for MI or PCI were identified. The Danish Registry of Medicinal Product Statistics was used to obtain prescription drug information for each patient. Patients were then characterized as one of the following based on medication regimen: single antiplatelet therapy (aspirin or clopidogrel), dual antiplatelet therapy (aspirin and clopidogrel), single vitamin K antagonist (VKA) therapy (warfarin or phenprocoumon), VKA plus single antiplatelet therapy, or TT. For each patient, the HAS-BLED and CHADS2 risk scores were calculated. The primary outcome of the study was nonfatal or fatal bleeding. Nonfatal bleeding was defined by diagnosis at hospitalization, and fatal bleeding was determined from a cause of death registry. Secondary endpoints included cardiovascular death, death from stroke, nonfatal MI, and nonfatal stroke. Patients were followed for one year. Bleeding risk was assessed for each regimen at multiple time points.

Results

From 2001 to 2009, a total of 11,480 subjects met the study criteria. Sixty-one percent of the patients were male. The mean age was 75.6 years. There were 8,775 subjects (76.4%) enrolled due to MI, and 17% of those underwent PCI within one week. The remaining 2,705 patients (23.6%) had PCI. The mean HAS-BLED score was 2.1, and the mean CHADS2 score was 1.5. Over 9% of patients had a history of a bleeding episode prior to the study. The rate of TT was low: 13.3% at the time of discharge, 9.9% at day 90, 7.9% at day 180. Regimens including clopidogrel were more likely when PCI was performed.

Overall, 728 patients experienced a bleeding event (6.3%) over a mean follow-up of 288.1 days. There were 10 fatal bleeding events. The highest bleeding rate was for TT, at 14.3 per 100 person years. Compared to VKA plus single antiplatelet regimen, the hazard ratio was 1.41 (95% CI 1.10-1.81). There was a trend towards increased bleeding events with increased intensity of therapy. Compared to VKA plus single antiplatelet therapy, TT had no improvement in the secondary endpoints of cardiac death, MI, and ischemic stroke. However, there was a trend towards increased secondary events with decreasing intensity of antithrombotic therapy (20.1 per 100 person years on TT compared to 26.9 for VKA monotherapy and 26.3 for dual antiplatelet therapy).

In the first 30 days, the bleeding rate was 22.6 per 100 person years for patients on TT, compared to 20.3 for VKA plus single antiplatelet and 14.3 for dual antiplatelet therapy. The risk of bleeding on TT was higher in the first 30 days than in days 180-360 (Incidence Rate Ratio 2.35, 95% CI 1.37-4.03). Similar front-loading of events occurred with all of the regimens that included antiplatelet therapy, while for VKA monotherapy there was no significant increase in bleeding risk for the first 30 days compared to days 180-360. Nevertheless, the increased risk of bleeding events on TT relative to other regimens was apparent across all time periods.

Subgroup analysis, based on age greater or less than 75, or CHADS2 score ≥2, showed no significant interactions.

Conclusion

The authors conclude that the risk of bleeding in patients on TT is particularly high in the first 30 days after MI or PCI, and remains elevated when compared to less intense antithrombotic regimens. They suggest that TT has no safe therapeutic window, and should only be prescribed after a careful evaluation of bleeding risk.

Perspective

In most instances when antithrombotic agents are used, the physician is weighing the risk of increased bleeding events against the benefit of reduced ischemic events. Nowhere is this balance more precarious than in the use of combined warfarin, aspirin, and clopidogrel, so-called triple therapy (TT). Patients on TT are known to have an elevated risk of bleeding compared to other antithrombotic regimens, and even nonfatal bleeding episodes are associated with an increased mortality.¹ Yet TT is recommended for patients with AF who experience an MI or undergo PCI.³

The current study found that the risk of bleeding is highest for patients on TT. This is not surprising, as it was already shown in an analysis from this same registry. The current study adds to the literature by showing that the highest risk of bleeding on TT is in the first 30 days, and is substantially reduced after 90 days. Yet the risk of bleeding remains higher in those patients on TT compared to other regimens. Without randomization, it is difficult to determine whether this is because the risk is truly highest in those first 30 days, or because clinicians ensured that the highest risk patients were only on short courses of TT. The fact that such a small percentage of the patients were on TT may also affect the generalizability of the data, as selection bias may surely have occurred in choosing the patients’ regimens. In a study where 37% of patients had AF and were treated with PCI, only 13% were on TT at discharge. Although it is not exactly clear how many of the PCI patients had stents implanted, less than two-thirds of the PCI patients were discharged on dual antiplatelet therapy. Whether this would be the case in the USA seems unlikely. Without more information on the mechanism of antithrombotic regimen selection, it is difficult to interpret the results.

The authors focus primarily on the risks of TT, and suggest that it not be used without careful evaluation. Yet they also find a reduction in ischemic events, specifically cardiovascular death, MI, and stroke, with increasing intensity regimens. Compared to both VKA monotherapy and dual antiplatelet therapy, TT had an additional 7.2 bleeding events per 100 person years of follow-up. But TT had 6.8 fewer ischemic events than VKA monotherapy and 6.2 fewer events than dual antiplatelet therapy. Using net adverse clinical events, as is often done in studies of various anticoagulant regimens, there may be no significant net harm from TT. One interesting finding was the relative increase in bleeding events for TT compared to VKA plus single antiplatelet regimens with no improvement in ischemic events.

Whether TT is the best therapy for patients with AF who experience an MI or undergo PCI will not be clearly known until there are large randomized trials. The current recommendations arise from randomized data that suggest that in certain situations either warfarin therapy or dual antiplatelet therapy is necessary. The ACTIVE-W trial proved that oral anticoagulation is superior to a combination of aspirin and clopidogrel in the prevention of stroke.4 Multiple studies have shown that dual antiplatelet therapy reduces stent thrombosis compared to warfarin.^5,6 Less is known in the setting of MI without PCI.

Just as this study suggests, the feasibility of VKA plus antiplatelet monotherapy instead of TT should be evaluated. The WOEST Trial, recently presented at the European Society of Cardiology 2012 meeting, evaluated 573 patients on oral anticoagulation undergoing PCI and suggested that warfarin plus clopidogrel may be superior to TT, both for bleeding events and ischemic events.⁷ This small trial has not yet been published, and may require a larger trial before the guidelines change. The ISAR-TRIPLE study is underway, and will test a shorter duration of antiplatelet therapy in 600 patients with AF receiving a drug-eluting stent.⁸ Of course, dual antiplatelet therapy is only required for 30 days in patients receiving a bare metal stent. The timing and need for dual antiplatelet therapy in patients with AF on VKA who experience an MI but do not undergo PCI will also require future research.

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References

1. Hansen ML, Sorensen R, Clausen MT, et al. Risk of bleeding with single, dual, or triple therapy with warfarin, aspirin, and clopidogrel in patients with atrial fibrillation. Arch Intern Med 2010; 170:1433-41.
2. Lamberts M, Olesen JB, Ruwald MH, et al. Bleeding after initiation of multiple antithrombotic drugs, including triple therapy, in atrial fibrillation patients following myocardial infarction and coronary intervention:  A nationwide cohort study. Circulation 2012; 126:1185-93.
3. Faxon DP, Eikelboom JW, Berger PB, et al. Antithrombotic therapy in patients with atrial fibrillation undergoing coronary stenting: a North American perspective: executive summary. Circ Cardiovasc Interv 2011; 4:522–34.
4. Connolly S, Pogue J, Hart R, et al. Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W): a randomised controlled trial. Lancet 2006; 367:1903-12.
5. Leon MB, Baim DS, Popma JJ, et al. A clinical trial comparing three antithrombotic-drug regimens after coronary-artery stenting. N Eng J Med 1998; 339:1665-71.
6. Bertrand ME, Legrand V, Boland J, et al. Randomized multicenter comparison of conventional anticoagulation versus antiplatelet therapy in unplanned and elective coronary stenting: The Full Anticoagulation Versus Aspirin and Ticlopidine (FANTASTIC) study. Circulation 1998; 98:1597-1603.
7. Hughes S. WOEST: Drop aspirin in stent patients on oral anticoagulants. TheHeart.org. August 28, 2012. http://www.theheart.org/article/1439915.do. Last accessed January 31, 2013.
8. Triple Therapy in Patients on Oral Anticoagulation After Drug Eluting Stent Implantation (ISAR-TRIPLE). ClinicalTrials.gov. http://www.clinicaltrials.gov/ct2/show/NCT00776633. Last Accessed January 31, 2013.

Keywords: Anticoagulants, Aspirin, Atrial Fibrillation, Denmark, Myocardial Infarction, Percutaneous Coronary Intervention, Phenprocoumon, Stroke, Thrombosis, Warfarin

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