By Paul A. Gurbel, MD; Udaya S. Tantry, PhD; Aung Myat, BSc, MBBS, MRCP; Eli I. Lev, MD

Chronic oral anticoagulant therapy (OAC) is implemented to prevent fibrin-centric thromboembolic events (FCTE) in patients with atrial fibrillation (AF), mechanical heart valves, deep vein thrombosis, pulmonary embolism, and left ventricular thrombi.¹ The guidelines are clear: lifelong OAC should be administered to patients with AF who are at moderate-to-high risk of thromboembolism.²

Of note, OAC with warfarin was shown to be superior to dual antiplatelet therapy (DAPT) with aspirin and clopidogrel in the prevention of vascular events in patients with AF plus one or more risk factors for stroke.³ It has also been prospectively demonstrated that DAPT with aspirin and a thienopyridine is superior to aspirin and warfarin in the prevention of platelet-centric thrombotic events (PCTE), such as stent thrombosis.⁴ Therefore, administration of uninterrupted DAPT for 1-12 months, depending on the type of stent used, is recommended.^5,6

In everyday practice, however, things are not so cut and dry. Cardiologists regularly encounter patients requiring prophylaxis against both types of events.

It is estimated that ~5% of patients undergoing stenting also meet criteria for OAC.⁷ Several trials in the bare-metal stent era have shown that, in patients who have undergone stenting, DAPT was superior to warfarin and aspirin in reducing 30-day major adverse cardiac events after the procedure.⁴

Entering the Triple Antithrombotic Therapy Era?

Recently, it has been reported that, in patients who have undergone stenting and also require OAC, triple antithrombotic therapy (TAT) with warfarin, aspirin, and clopidogrel was associated with a lower rate of stent thrombosis (compared to patients treated with warfarin and aspirin alone).⁸ On the other hand, in patients with AF, TAT was associated with a 3.7-fold higher risk of bleeding compared with warfarin monotherapy.⁹ Thus, the management of patients undergoing stenting with an indication for TAT requires a fine balance between the prevention of FCTE, PCTE, and bleeding.

In the recent WOEST (What is the Optimal antiplatElet and anticoagulant therapy in patients with oral anticoagulation and coronary StenTing) trial, a study of 573 patients with AF undergoing PCI, there was a 64% relative reduction in rates of major and minor bleeding with warfarin plus clopidogrel therapy, compared to TAT, at 1 year. In addition, there was no significant difference in the occurrence of the secondary ischemic endpoints of death, MI, stroke, target vessel revascularization, and stent thrombosis. These findings suggest that patients on long-term OAC undergoing stenting may be treated more safely and effectively with concomitant clopidogrel without aspirin.¹⁰

Major bleeding has been significantly associated with increased mortality. In addition, even minor bleeding has been associated with worse clinical outcomes (such as MI, stent thrombosis, and death). Blood transfusions also have been independently associated with increased mortality and morbidity.^11,12

Some general measures may be adopted to mitigate bleeding risk. Alterations in procedural techniques during PCI and pharmacotherapy may significantly reduce bleeding rates and improve patient long-term outcomes. For example, radial access is associated with fewer major bleeding complications than femoral access, so this route may be preferable in patients on OAC.¹² Bare-metal stents should be considered in preference to drug-eluting stents (DES), unless the anatomical or clinical characteristics of the case dictate a strong benefit with DES.

How Do We Curb Bleeding and Thrombotic Risk?

Is there a role for monitoring the antithrombotic effects of OAC and DAPT? Currently, the INR has been widely used to guide warfarin therapy to reduce bleeding and thrombotic risk. However, there are limited data available regarding monitoring the effects of new OACs.

The role of platelet function testing in guiding antiplatelet therapy to reduce ischemic risk remains controversial largely because prospective randomized trials of platelet function testing have failed. These failures have been attributed to various factors, including:

• enrollment of low-risk patients resulting in a low event rate and underpowering;
• the suboptimal strategy of high-dose clopidogrel to overcome high platelet reactivity;
• incomplete protocol implementation; and
• non-uniform methodology to assess endpoint occurrence.

At the same time, there are limited data available regarding the relation of platelet function testing to bleeding in patients treated with DAPT. A therapeutic window for P2Y¹² receptor reactivity has been proposed in patients treated with DAPT but not validated prospectively.¹³

Currently, there are no large scale prospective data to demonstrate the efficacy and safety of personalized antiplatelet therapy in stented patients whether or not they are on OAC. Platelet function testing may play an important role in the group of patients who require OAC in order to avoid bleeding complications.

OAC Plus DAPT

More research is necessary to examine the relation of the pharmacodynamic effects of the new OAC medications (direct thrombin inhibitors and factor Xa inhibitors) combined with antiplatelet drugs to bleeding. Recently, a subanalysis of the Randomized Evaluation of Long-term Anticoagulation Therapy (RE-LY) trial, demonstrated that concomitant antiplatelet therapy appeared to increase the risk of major bleeding in both study groups, without affecting the advantages of dabigatran over warfarin.¹⁴ On the other hand, the combination of the newer antiplatelet P2Y¹² receptor blocker, prasugrel, with OAC was associated with an alarmingly high rate of bleeding, even in patients who had a high platelet reactivity while on clopidogrel and, should, therefore, be avoided at the present time.¹⁵

Despite the limited information on the efficacy and safety of TAT, the indication for and duration of TAT has been recently addressed in specific guidelines based on stent type, clinical setting (ACS versus elective), and hemorrhagic risk.⁷ The recent WOEST trial shed additional light as to the balance of bleeding and ischemic event reduction during combination antiplatelet and OAC therapy,¹⁰ and in the future, several other considerations for TAT will have to be explored, such as:

• Large-scale prospective studies to assess the utility of "guided triple therapy" based on platelet function testing and anticoagulation monitoring
• The therapeutic window concept suggested to maximize the efficacy and safety of DAPT in patients treated with TAT (where it may be even more clinically important)
• The need for a multidisciplinary approach, with initial assessment and risk stratification based on patient-related risk factors for thrombosis and bleeding, and objective measurements of platelet function and coagulation

Balancing the intensity of the two therapies may be facilitated by a laboratory method(s) that can simultaneously assess both coagulation and platelet reactivity in these bleeding- and thrombosis-prone patients.

---

References

1. Guyatt GH, Akl EA, Crowther M, et al. Chest. 2012;141:7S-47S.
2. Fuster V, Ryden LE, Cannom DS, et al. J Am Coll Cardiol. 2006;48:854-906.
3. Connolly SJ, Pogue J, Hart RG, et al. N Engl J Med. 2009;360:2066-78.
4. Rubboli A, Milandri M, Castelvetri C, Cosmi B. Cardiology. 2005;104:101-6.
5. Levine GN, Bates ER, Blankenship JC, et al. J Am Coll Cardiol. 2011;58:e44-122.
6. Wijns W, Kolh P, Danchin N, et al. Eur Heart J. 2010;31:2501-55.
7. Lip GY, Huber K, Andreotti F, et al. Eur Heart J. 2010;31:1311-8.
8. Karjalainen PP, et al. Eur Heart J. 2007;28:726-32.
9. Hansen ML, Sorenson R, Clausen MT, et al. Arch Intern Med. 2010;170:1433-41.
10. Dewilde WJ, Oirbans T, Verheugt FW, et al, Lancet. 2013;381:1107-15.
11. Rao SV, Eikelboom JA, Granger CB, et al. Eur Heart J. 2007;28:1193-204.
12. Vavalle JP, Rao SV. J Invasive Cardiol. 2009;21:21A-24A.
13. Gurbel PA, Becker RC, Mann KG, et al. J Am Coll Cardiol. 2007;50:1822-34.
14. Dans AL, Connolly SJ, Wallentin L, et al. Circulation. 2013;127:634-40.
15. Sarafoff N. J Am Coll Cardiol. 2013;61:2060-6.

Paul A. Gurbel, MD, is director, and Udaya S. Tantry, PhD, is laboratory director at the Sinai Center for Thrombosis Research in Baltimore. Aung Myat, BSc, MBBS, MRCP, is from King's College London British Heart Foundation Centre of Research Excellence at St Thomas' Hospital in London. Eli I. Lev is from the Cardiology Department at Rabin Medical Center in Petah-Tikava, Israel, and the Tel-Aviv University in Israel.

Keywords: Stroke, Platelet Aggregation Inhibitors, Drug-Eluting Stents, Pulmonary Embolism, Risk Factors, Ticlopidine, Pyridines, Piperazines, Blood Transfusion, Thromboembolism, beta-Alanine, Benzimidazoles, Venous Thrombosis, Factor Xa, Fibrin, Heart Valves

< Back to Listings