By Yen Tibayan, MD and Joaquin E. Cigarroa, MD

News from the Interventional Council | Interventional cardiologists frequently encounter the dilemma of balancing thrombosis prevention and the risk of bleeding in a patient with atrial fibrillation (AF) requiring percutaneous coronary intervention (PCI). Incorporating novel oral anticoagulants (NOAC) further complicates this issue.

Traditionally, oral anticoagulation with warfarin has been the standard prophylaxis used to minimize thromboembolism secondary to AF; this has proven superior to dual antiplatelet therapy (DAPT) with aspirin and clopidogrel in preventing strokes in patients with moderate or high thrombotic risk (relative risk = 1.44; p = 0.0003).¹ Conversely, DAPT with aspirin and a P2Y12 receptor inhibitor is used to minimize stent thrombosis after PCI with stent placement. For drug-eluting stents (DES), DAPT is prescribed for up to 1 year. Accordingly, in the not-uncommon scenario of patients with AF and concomitant coronary artery disease (CAD) requiring PCI, a triple antithrombotic regimen (TAT) including warfarin, aspirin, and clopidogrel has been utilized to minimize cerebrovascular and coronary events. This regimen, however, carries the unfortunate cost of increased bleeding.²

How Can We Solve This Dilemma?
Several strategies to decrease bleeding risk in this population have been proposed:

• Utilization of risk scores (i.e. CHADS2, CHA2DS2-VASc, HAS-BLED) to assess risk versus benefit of oral anticoagulant therapy
• Prioritizing the use of bare-metal stents over DES in patients requiring oral anticoagulant therapy, because it exposes patients to less duration of heightened bleeding risk
• Using newer-generation DES over first-generation stents because it may require less than 1 year of DAPT
• Administration of proton pump inhibitors in select cohorts to decrease gastrointestinal bleeding

The strategy of using only one antiplatelet agent after PCI has also been investigated. In the WOEST study, 573 patients requiring oral anticoagulant therapy were randomized to the dual combination of warfarin and clopidogrel or to TAT with warfarin, clopidogrel, and aspirin.³ Warfarin and clopidogrel was associated with less bleeding than TAT (19.4% vs 44.4% at 1 year; HR = 0.36; p < 0.001), but the study was underpowered to draw conclusions regarding coronary risk—including stent thrombosis.

Novel oral anticoagulants (NOACs), such as the direct thrombin inhibitor dabigatran and the factor Xa inhibitors rivaroxaban and apixaban, have emerged as promising alternatives to warfarin for stroke prophylaxis in nonvalvular AF. Each compares favorably to warfarin in ease of use with a rapid onset, wide therapeutic window, and little interaction with food intake or other medications.

In the RE-LY trial, dabigatran demonstrated a lower rate of cerebrovascular accident (CVA) and systemic embolization compared with warfarin, with an overall major bleeding risk comparable to warfarin but an increased risk of gastrointestinal bleeding.⁴ In the ROCKET-AF trial, rivaroxaban was non-inferior to warfarin in the prevention of CVA and systemic embolization, with a comparable major bleeding risk.⁵ In the ARISTOTLE trial, apixaban was associated with less stroke and systemic embolization and less bleeding than warfarin.⁶

Given their increasing use, interventional cardiologists have to decide how to incorporate NOACs into the treatment of patients with AF and concomitant CAD requiring PCI. As of now, data regarding the efficacy and safety of combined NOAC and antiplatelet therapy in AF and PCI are limited to post-hoc analyses⁷ and prospective trials comparing NOACs with placebo in patients with recent acute coronary syndrome (ACS) on standard antiplatelet therapy.

In the RE-DEEM study, for instance, dabigatran added to DAPT in patients with ACS resulted in increased major bleeding (7.8% vs 2.2%; HR = 42.7; 95% CI 1.85-9.81).⁸ Similarly, in the ATLAS ACS-TIMI 46 study, the addition of rivaroxaban 20 mg daily to DAPT increased major bleeding (17.8% vs 3.8%; HR = 5.12; 95% CI 3.22-8.14).⁹

In both trials, lower NOAC dosages were associated with less bleeding, but these dosages are not approved for thromboembolic prophylaxis in AF. In the APPRAISE 2 trial, the addition of twice-daily apixaban 5 mg to standard antiplatelet therapy in patients with ACS was also associated with more major bleeding events (3.2% vs 1.2%; HR = 2.59; 95% CI 1.50-4.46; p = 0.001), including an increased rate of intracranial and fatal bleeding.¹⁰

Thus, when NOACs are used with standard DAPT in ACS, bleeding events are consistently increased, which raises concern about the safety of NOACs in AF patients undergoing PCI. While there is no clear signal of excess cardiovascular risk with this approach to date, further investigation into optimal dosing of NOAC and concomitant use of single versus dual antiplatelet therapy is certainly warranted. The results from two such ongoing randomized clinical trials—PIONEER AF-PCI examining rivaroxaban with single or dual antiplatelet therapy and RE-DUAL PCI studying dabigatran with single antiplatelet therapy—are eagerly anticipated.

For now, patients who have a low risk of thromboembolism should be treated with dual antiplatelet therapy alone. Others should be offered antithrombotic therapy coupled with DAPT to minimize both the risk of stroke and stent thrombosis—with the knowledge that the greatest experience exists for warfarin, low-dose aspirin, and clopidogrel.

For patients who have a high risk of bleeding, it is not unreasonable to use warfarin coupled with clopidogrel alone, and, given the lack of data regarding NOACs coupled with aspirin and either ticagrelor or prasugrel, this approach should be avoided. Ongoing clinical trials will determine if there is a better approach utilizing NOACs with either single or dual antiplatelet therapy.

References

1. Connolly S, Pogue J, Hart R, et al. Lancet. 2006;367:1903-12.
2. Hansen ML, Sørensen R, Clausen MT, et al. Arch Intern Med. 2010;170:1433-41.
3. Dewilde WJ, Oirbans T, Verheugt FW, et al. Lancet. 2013;381:1107-15.
4. Connolly SJ, Ezekowitz MD, Yusuf S, et al. N Engl J Med. 2009;361:1139-51.
5. Patel MR, Mahaffey KW, Garg J, et al. N Engl J Med. 2011;365:883-91.
6. Granger CB, Alexander JH, McMurray JJV, et al. N Engl J Med. 2011;365:981-92.
7. Dans AL, Connolly S, Brueckmann M. Concomitant use of antiplatelet therapy with dabigatran or warfarin in the randomized evaluation of long-term anticoagulation therapy (RE-LY) trial. Presented at the 2011 European Society of Cardiology Congress.
8. Oldgren J, Budaj A, Granger CB, et al. Eur Heart J. 2011;32:2781-9.
9. Mega JL, Braunwald E, Mohanavelu S, et al. Lancet. 2009;374:29-38.
10. Alexander JH, Lopes RD, James S, et al. N Engl J Med. 2011;365:699-70.

Yen Tibayan, MD, and Joaquin E. Cigarroa, MD, are from the Knight Cardiovascular Institute at Oregon Health & Science University in Portland, Oregon.

Keywords: CardioSource WorldNews Interventions

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