Effects Of New Oral Anticoagulant Agents In Patients With Acute Coronary Syndrome

Current studies provide evidence on the effects of new oral anticoagulants (NOACs) i.e. apixaban, rivaroxaban, and dabigatran, in patients placed on antiplatelet therapy after percutaneous coronary intervention (PCI) for acute coronary syndrome (ACS). We found that when these drugs were added to a single antiplatelet agent (i.e. P2Y12 inhibitor), there was neither an increase in major bleeding risk nor a reduction in major adverse cardiovascular events (MACE).

However, when these agents were used with dual antiplatelet therapy (DAPT) i.e. a combination of aspirin and P2Y12 inhibitor drug (clopidogrel, ticagrelor or prasugrel), there was twice a risk of major bleeding events and a modest reduction in MACE. Drug wise, rivaroxaban plus DAPT was the most effective combination for prevention of MACE, while dabigatran plus a single antiplatelet agent was the safest approach in terms of major bleeding events.

Why are these findings significant?

PCI with stent implantation is the standard of care for patients with ACS.  Despite this treatment, these patients remain at a higher risk of recurrent myocardial infarction and stent thrombosis due to elevated circulating levels of thrombin during first few months¹. DAPT is considered the cornerstone of the management to prevent these events; however, even with the optimal DAPT, approximately 10% patients continue to experience MACE¹.  This has generated a substantial interest among the scientific community to optimize antithrombotic therapy in addition to standard DAPT.

In previous studies, warfarin has shown to reduce ischemic events when used in combination with antiplatelet therapy². However, this reduction in ischemic endpoints was achieved at the expense of excessive bleeding events. Moreover, warfarin therapy has its own issues such as unpredictable pharmacodynamics, drugs and dietary interactions and narrow therapeutic window requiring constant laboratory monitoring; which make the use of this drug difficult.

The newer NOACs are free of such restrictions and have partially replaced warfarin in the modern clinic practice. These drugs have shown promising results for prevention of stroke in patients with non-valvular atrial fibrillation (NVAF) and treatment of thromboembolism in patients with deep venous thrombosis or pulmonary embolism or post orthopedic surgery with a relatively safer bleeding profile compared with warfarin. Nevertheless, little was known that whether their beneficial effects could be expanded to patients with recent ACS. This study attempted to answer these questions by stratifying the analysis according to the intensity of background antiplatelet therapy.

Addition of another antithrombotic agent on top of a standard antiplatelet agent entails a tradeoff between reduction in MACE and a higher bleeding risk. To encounter the higher risk of bleeding, recent studies have looked into a new therapeutic approach. A combination of warfarin with single clopidogrel had shown to be safer and equally effective strategy compared with triple therapy i.e. oral anticoagulation plus DAPT³. This approach was tested in two contemporary studies of NOACs involving reduced dose rivaroxaban and full dose dabigatran in patients who underwent PCI and had concomitant NVAF^4,5. The main concern with this approach is its predominant focus on safety (major bleeding) with a tendency to compromise the efficacy (prevention of MACE).

Our study showed that there were no significant clinical effects with the use of NOACs with single antiplatelet therapy and that the use of NOACs with DAPT increased major bleeding events with a marginal protection against MACE. These findings demonstrate that NOACs are unlikely to generate any meaningful favorable impact on ischemic outcomes in patients with ACS and can potentially promote excessive bleeding, especially when added to DAPT. Therefore until new evidence provides further insight into this matter, practitioners should avoid adding NOACs to single antiplatelet therapy or DAPT in ACS subjects unless the NOAC are clinically necessary for another indication such as coexisting NVAF or venous thromboembolism. In such scenario, the dosage and duration of the anti-thrombotic and antiplatelet therapy should be individually tailored to each patient based on the risk of thromboembolism, ischemia, and hemorrhage.

How was this study conducted?

This study was a meta-analysis of all the randomized controlled trials to date on the use of NOACs in ACS population. The study was conducted according to Cochrane Collaboration guidelines and was reported in accordance with Preferred Reporting Items for Systematic Review and Meta-Analyses report. A total of 31,574 patients were analyzed. The mean age of study participants was 64 years, 76% were males, 22% had a history of myocardial infarction and 32% had diabetes mellitus. For final interpretation of the results, we relied on generic invariance weighted random effects model to combine outcomes from each trial. The principal summary statistic was hazard ratio with 95 % confidence interval. Q-statistic was used to estimate heterogeneity and was quantified by I². There was significant heterogeneity in the studies.

These findings are described in the article entitled Meta-analysis of the safety and efficacy of the oral anticoagulant agents (apixaban, rivaroxaban and dabigatran) in patients with acute coronary syndrome, recently published in the American Journal of Cardiology. This work was conducted by Safi U. Khan, Adeel Arshad, Irbaz Bin Riaz, Swapna Talluri, Fahad Nasir and Edo Kaluski. Both the first and senior author belong to Guthrie Health System/Robert Packer Hospital, Sayre, PA.

References:

1. Libby P. Mechanisms of acute coronary syndromes. The New England journal of medicine. Aug 29 2013;369(9):883-884.
2. Hurlen M, Abdelnoor M, Smith P, Erikssen J, Arnesen H. Warfarin, aspirin, or both after myocardial infarction. The New England journal of medicine. Sep 26 2002;347(13):969-974.
3. Dewilde WJ, Oirbans T, Verheugt FW, et al. Use of clopidogrel with or without aspirin in patients taking oral anticoagulant therapy and undergoing percutaneous coronary intervention: an open-label, randomised, controlled trial. Lancet (London, England). Mar 30 2013;381(9872):1107-1115.
4. Cannon CP, Bhatt DL, Oldgren J, et al. Dual Antithrombotic Therapy with Dabigatran after PCI in Atrial Fibrillation. The New England journal of medicine. Aug 27 2017.
5. Gibson CM, Mehran R, Bode C, et al. Prevention of Bleeding in Patients with Atrial Fibrillation Undergoing PCI. The New England journal of medicine. Dec 22 2016;375(25):2423-2434.