Introduction

Atrial fibrillation (AF) is the most common cardiac arrhythmia encountered in everyday clinical practice. In 2010, it was estimated that AF affected 5.2 million Americans, and this number is projected to increase to 12.1 million by 2030.¹ With more than 80% of these patients having an indication for oral anticoagulation,² and approximately 35% of these patients having coronary artery disease,³ interventional cardiologists will increasingly encounter patients with ST-segment elevation myocardial infarction (STEMI) who are on oral anticoagulation. Currently, there is a wide variation in clinical practice in management of these patients due to paucity of literature and lack of consensus guidelines.⁴ With the increasing use of new oral anticoagulants (NOACs) – dabigatran, rivaroxaban, apixaban, edoxban – and advent of new antiplatelet agents – prasugrel and ticagrelor – the clinical decision-making in these patients regarding the choice of access site, peri-procedural antithrombotic and antiplatelet agents, and transition to long-term anticoagulation has become even more complex. This review article will address these issues, which arise in acute management of patients with STEMI who having been taking NOACs, and are undergoing primary percutaneous coronary intervention (PCI).

Arterial Access – Radial vs. Femoral

The optimal approach to arterial access in primary PCI in patients with acute coronary syndrome (ACS) remains controversial. In the RadIal Vs femorAL access for coronary intervention (RIVAL) study, both approaches were noted to be equally safe and effective.⁵ However, in a sub-group analysis of STEMI patients, radial approach was associated with a mortality benefit.⁵ Also, in the Minimizing Adverse Haemorrhagic Events by TRansradial Access Site and Systemic Implementation of angioX (MATRIX) trial, a recent multicenter randomized study of 8404 patients radial compared to femoral access in patients with ACS was shown to reduce the net adverse clinical events through a reduction in major bleeding and all-cause mortality.⁶

Patients on NOACs were not included in either of these trials. In the MATRIX trial, only 1.7% of the patients in each of the groups were on warfarin.⁶ However, in both these studies,^5,6 and in other trials,⁷ radial access has consistently been associated with reduced access site vascular complications compared to femoral access. Also, in studies on patients with uninterrupted warfarin therapy undergoing PCI, with mean international normalized ratio (INR) of 2.4, radial access was associated with reduced bleeding and vascular complications.⁸ Extrapolating these data to patients who are on NOACs, the authors of this Expert Analysis article strongly recommend radial over femoral approach whenever feasible.

Peri-procedural Anticoagulation

The most effective peri-procedural anticoagulation regimen to prevent ischemic complications without increasing the bleeding risk in patients with ACS remains to be defined. When patients on NOACs present with STEMI, the situation is even more complex due to the following concerns:

1. Should additional peri-procedural anticoagulation be used?
   In patients on warfarin with INR in the therapeutic range (2.0-3.0), PCI appears to be safe without the need for additional peri-procedural anticoagulation.⁹ It is unknown if this applies to NOACs. In a small randomized study involving 50 patients on dual antiplatelet therapy (DAPT) undergoing elective PCI, use of peri-procedural dabigatran did not provide sufficient anticoagulation during PCI.¹⁰ In contrast, in a similar small study, peri-procedural rivaroxaban given two to four hours prior to elective PCI appeared to provide adequate anticoagulation without increased risk of bleeding.¹¹ Until there are larger studies proving the safety and efficacy of performing PCI on NOACs without additional anticoagulation, it is recommended to give additional heparin or bivalirudin (and avoid glycoprotein [GP] IIb/IIIa inhibitors) regardless of the last NOAC dose, especially in patients presenting with STEMI where the thrombogenic state is exaggerated compared to patients undergoing elective PCI.¹²
2. How to monitor adequate anticoagulation?
   There is no rapid and reliable laboratory assay to monitor the degree of anticoagulation in patients on NOACs. Activated clotting time (ACT) is routinely used to guide heparin administration during PCI, as the dose of heparin has a linear relationship with ACT level.¹³ In contrast, other anticoagulant agents such as bivalirudin increase the ACT level, but do not have a linear correlation with ACT.¹⁴ Similarly, though ACT is prolonged by NOACs, it cannot be used to gauge the anticoagulant activity.¹² NOACs have a very small dose-dependent, or rather flat dose effect on ACT,^15,16 making it unreliable to use in an acute setting. Other coagulation assays are more time consuming and cannot be used practically in the setting of STEMI. Hence, rather than depending on laboratory assays, in patients taking NOACs, the timing of the last dose taken is of paramount importance.¹² All currently available NOACs reach a peak plasma level within one to four hours after ingestion, and reach the trough level between 12-24 hours.¹² Hence, in patients presenting with STEMI who have taken a NOAC within four hours of presentation, the risk of bleeding when giving additional anticoagulants or antiplatelet agents is at least theoretically higher than those who have taken the last dose of NOAC >12 hours before STEMI presentation. If using heparin as the additional peri-procedural anticoagulant, the routine target ACT level (250-300s) can be used for heparin titration, even in patients who are taking NOACs.¹²
3. Which additional anticoagulant agent should be used – heparin vs. bivalirudin?
   The two most commonly used anticoagulation drugs for primary PCI are bivalirudin (direct thrombin inhibitor) and heparin (indirect thrombin inhibitor), with or without GP IIb/IIIa inhibitors. In the most recent randomized trial involving 7,213 patients with ACS, there was no significant difference in major cardiovascular or net adverse clinical events between these two drugs.¹⁷ However, in this trial, and in other multicenter trials, bivalirudin was consistently noted to have reduced risk of major bleeding complications, including non-access site bleeding complications compared to heparin alone or with a combination of heparin and GP IIb/IIIa inhibitors.^17-19 Patients on NOACs were excluded from all these trials. Hence, it is unknown which of these drugs is a better choice in these patients. Given the consistently low rates of bleeding with bivalirudin compared to heparin, it may be prudent to use bivalirudin in patients who have taken the last dose of NOAC within four hours, and in elderly patients with impaired kidney function who are at increased risk of bleeding complications.

Acute and Long-term Antiplatelet Agents

Acute setting

Patients taking NOACs presenting with STEMI should receive a loading dose of aspirin (325 mg) and a P2Y₁₂ inhibitor.¹² In the randomized trials establishing the efficacy of ticagrelor or prasugrel over clopidogrel, patients on NOACs were not included.^20,21 The rate of major bleeding was significantly higher with ticagrelor and prasugrel compared to clopidogrel.^20,21 Though the current practice is highly variable in terms of the initial P2Y₁₂ inhibitor used, in patients taking NOACs, a loading dose of clopidogrel (600 mg) is preferable compared to the newer antiplatelet agents given the lower risk of bleeding associated with clopidogrel.

Long-term antiplatelet and anticoagulation regimen

Patients on triple therapy (DAPT plus oral anticoagulant, warfarin, or NOAC) are at increased risk of bleeding.^22,23 The best regimen and duration of therapy to prevent ischemic complications without increasing the risk of bleeding in patients with AF undergoing PCI is unknown. In the recent What is the Optimal antiplatElet & Anticoagulant Therapy in Patients With Oral Anticoagulation and Coronary StenTing (WOEST) randomized trial among patients requiring chronic anticoagulation therapy, the use of clopidogrel and warfarin without aspirin was associated with significant reduction in bleeding without an increase in the rate of thrombotic events.²⁴ It is unknown if these results could be extrapolated to the NOACs. There are no trials to date among patients requiring oral anticoagulation, comparing single antiplatelet agent (SAPT)/DAPT plus NOAC to SAPT/DAPT plus warfarin in post-ACS patients. Ongoing trials are evaluating various combinations of NOACs and antiplatelet agents in patients with AF undergoing PCI (A Study Exploring Two Strategies of Rivaroxaban (JNJ39039039; BAY-59-7939) and One of Oral Vitamin K Antagonist in Patients With Atrial Fibrillation Who Undergo Percutaneous Coronary Intervention (PIONEER AF PCI) and Evaluation of Dual Therapy With Dabigatran vs. Triple Therapy With Warfarin in Patients With AF That Undergo a PCI With Stenting (RE-DUAL PCI) study). However, until more data are available, the authors of this Expert Analysis article advocate use of triple therapy with warfarin (INR 2.0-2.5) rather than NOACs for the shortest duration possible, depending on the type of stent and individual bleeding risk. Use of bare metal stents or newer generation drug-eluting stents is preferred so as to minimize the duration of triple therapy. However, the latest updated European Heart Rhythm Association (EHRA) guidelines on use of NOACs recommend restarting the same NOAC in combination with SAPT or DAPT after discontinuation of parenteral anticoagulation in patients with ACS, based on expert opinion rather than currently available evidence.¹² It is recommended to reduce the doses of NOACs when combining with DAPT (dabigatran 110 mg twice-daily, apixaban 2.5 mg twice-daily, and rivaroxaban 15 mg once-daily or edoxaban 30 mg once-daily).¹²

In summary, patients with STEMI undergoing primary PCI on NOACs pose a challenging clinical situation to interventional cardiologists. The current literature is limited to guide in the management of these patients in terms of choosing the appropriate antiplatelet and anticoagulation regimens to balance the risk of ischemic events and bleeding. Until further data are available, the authors of this Expert Analysis article recommend use of radial access, loading dose of aspirin and clopidogrel, and additional peri-procedural anticoagulation with heparin or bivalirudin in the acute setting for these patients. Post-ACS, for patients at high risk of embolic events, triple therapy (DAPT plus warfarin or reduced-dose of NOAC) is recommended for as short a duration as possible.

References

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Keywords: Acute Coronary Syndrome, Adenosine, Aged, Anticoagulants, Antithrombins, Aspirin, Atrial Fibrillation, Benzimidazoles, Coronary Artery Disease, Drug-Eluting Stents, Expert Testimony, Heparin, Hirudins, International Normalized Ratio, Metals, Morpholines, Myocardial Infarction, Peptide Fragments, Percutaneous Coronary Intervention, Pharmaceutical Preparations, Piperazines, Platelet Aggregation Inhibitors, Platelet Membrane Glycoprotein IIb, Pyrazoles, Pyridines, Pyridones, Randomized Controlled Trials as Topic, Thiazoles, Thiophenes, Ticlopidine, Vitamin K, Warfarin, beta-Alanine

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