Cesar Jara, MD, FSCAI and Jayant Bagai, MD, FSCAI

Up to 10 percent of patients undergoing percutaneous coronary intervention (PCI) with stenting have an indication for oral anticoagulation (OAC), usually for atrial fibrillation (AF), venous thromboembolism (VTE), and mechanical valves. The combination of post-PCI dual antiplatelet therapy (DAPT) and OAC, so-called triple therapy (TT), is associated with a significant increase in the risk of bleeding. TT doubles the risk of serious bleeding and transfusions post-PCI, which, in turn, are associated with increased mortality.^{1, 2} Shorter duration TT regimens and dual therapy (DT), which include a single antiplatelet agent + OAC, have been investigated. Completed randomized controlled trials (RCTs) such as WOEST, ISAR-TRIPLE, PIONEER-AF, RE-DUAL PCI, and AUGUSTUS have shed important light on the efficacy and safety of this approach, and other trials such as ENTRUST are ongoing.^{1, 3–7} In this Tip of the Month, we provide a concise and practical approach for the management of patients with nonvalvular AF who need antiplatelet therapy post-PCI, based on published evidence and guidelines.^{8, 9}

A. Pre-PCI Considerations

1. Assess the need for PCI. Does the patient really need a stent? The 2017 appropriateness use criteria (AUC) for PCI can help to guide decision-making.
2. Assess the risk of stroke. Long-term OAC is recommended for CHA₂DS₂-VASc > 2 in men and > 3 in women.¹⁰
3. Assess the risk of bleeding. A HAS-BLED score of >3 is associated with a high bleeding risk but is not a reason to withhold anticoagulation. Instead, modification of risk factors and more cautious monitoring is recommended in such patients.

B. Considerations During PCI

1. Use radial access preferentially over femoral access for PCI in patients who require post-PCI anticoagulation.
2. Note that studies have shown the safety of four weeks of DAPT in patients at a high risk of bleeding after implantation of newer generation drug-eluting stents (DES), with superior efficacy compared to bare-metal stents (BMS).^{11, 12} Therefore, the use of BMS to lower DAPT duration can no longer be justified.
3. Ensure adequate clopidogrel and aspirin loading pre-PCI in all patients. Continuation of aspirin until hospital discharge is reasonable and should be considered even in patients in whom DT is planned on discharge.

C. Considerations After PCI

1. DT vs. TT
   1. The decision between DT and TT depends on the balance between ischemic risk (acute coronary syndrome (ACS), complex PCI, stent length > 60 mm, prior stent thrombosis (ST) or high DAPT score and bleeding risk. A summary, based on the 2017 European Society of Cardiology (ESC) guidelines and expert opinion from North America, is presented in Table 1.
   2. WOEST was the first trial to show that omission of aspirin from TT resulted in a highly significant 25 percent absolute risk reduction (number need to treat or NNT =4) without an increase in ischemic events (death, myocardial infarction [MI], stroke, revascularization, or ST). Limitations of this study included an open-label design and lack of power to assess for the difference in ST. In ISAR-TRIPLE, six weeks compared with six months TT was not associated with an increase in ischemic events but lowered the incidence of BARC 2-5 bleeding between six weeks and six months. In both these trials, the rate of ACS and complex PCI was low.^{1, 3}
   3. In the AUGUSTUS trial, TT was associated with a significant increase in the risk of bleeding at six months (HR 1.89, number need to harm or NNH=14) compared to DT. Omission of aspirin lowered bleeding by 47 percent.⁶
2. Antiplatelet agent considerations
   1. Most patients enrolled in recent studies were taking clopidogrel. Ticagrelor was used as part of DT in 12 percent of patients in RE-DUAL PCI. However, prasugrel and ticagrelor should not be used as a component of TT, as they significantly increase the risk of bleeding (Class III-harm, per 2017 ESC guidelines).
   2. Aspirin dose should typically not exceed 81 mg.
   3. Consider discontinuation of the antiplatelet agent from DT after one year in patients with low ischemic risk and after six months in patients with a high bleeding risk.
3. Anticoagulant considerations
   1. A summary of recent RCTs comparing DT and TT, including regimens comparing direct oral anticoagulants (DOAC) and warfarin, is presented in Table 2.
   2. Both the ESC guidelines and North American expert consensus document recommend using a DOAC instead of warfarin if there is no contraindication. It is reasonable to continue warfarin if the patient was tolerating it or if creatinine clearance is < 30 ml/min. The international normalized ratio (INR) target should be between 2-2.5.
   3. There is no role of withholding OAC in patients with AF post-PCI and treating them with just DAPT.¹³
   4. DOACs are not approved for “valvular AF,” which is defined as AF in the presence of a mechanical heart valve or moderate-to-severe mitral stenosis.
4. Tips to lower bleeding
   1. The following can lower bleeding: the routine use of proton pump inhibitors for gastric protection, avoidance of supra-therapeutic INR, blood pressure control, adjustment of DOAC dose based on creatinine clearance, patient education on signs and symptoms of bleeding, avoiding nonsteroidal anti-inflammatory drugs (NSAIDs) and alcohol, and closer monitoring of patients on TT and those with a HAS-BLED score >3.

Conclusion

For most patients with nonvalvular AF requiring OAC who undergo PCI, DT with an OAC and a P2Y12 inhibitor should be prescribed on hospital discharge. Aspirin should be given in the peri-PCI period and for up to one week post-PCI. In considering the choice of warfarin versus a DOAC for OAC, the recently reported AUGUSTUS trial demonstrated the superiority of apixaban over warfarin in combination with a P2Y12 inhibitor (almost always clopidogrel) to lower the risk of bleeding. The combination of apixaban and clopidogrel may provide the best balance between bleeding, stroke prevention, and ischemic outcomes. In selected patients with a high ischemic risk and low bleeding risk, TT with DAPT + OAC for one month, followed by DT, may be considered. After six to 12 months (depending on the balance between bleeding and ischemic risk), patients on DT should be switched to treatment with a single agent, namely an OAC. Given the large number of combinations of drugs, doses, and durations of therapy possible, the emphasis on individualized risk assessment, clinical judgment, and shared decision-making with the patient cannot be overstated.

References

1. Dewilde WJ, Oirbans T, Verheugt FW, et al. WOEST study investigators. 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. 2013 Mar 30;381(9872):1107-15.
2. Doyle BJ, Rihal CS, Gastineau DA, Holmes DR Jr. Bleeding, blood transfusion, and increased mortality after percutaneous coronary intervention: implications for contemporary practice. J Am Coll Cardiol. 2009 Jun 2;53(22):2019-27.
3. Fiedler KA, Maeng M, et al. Duration of Triple Therapy in Patients Requiring Oral Anticoagulation After Drug-Eluting Stent Implantation: The ISAR-TRIPLE Trial. J Am Coll Cardiol. 2015 Apr 28;65(16):1619-1629.
4. Gibson CM, Mehran R, Bode C, et al. Prevention of Bleeding in Patients with Atrial Fibrillation Undergoing PCI. N Engl J Med. 2016 Dec 22;375(25):2423-2434.
5. Cannon CP, Bhatt DL, Oldgren J, et al. RE-DUAL PCI Steering Committee and Investigators. Dual Antithrombotic Therapy with Dabigatran after PCI in Atrial Fibrillation. N Engl J Med. 2017 Oct 19;377(16):1513-1524.
6. Lopes RD, Heizer G, Aronson R, et al. Antithrombotic Therapy after Acute Coronary Syndrome or PCI in Atrial Fibrillation. N Engl J Med. 2019 Apr 18;380(16):1509-24.
7. Vranckx P, Lewalter T, Valgimigli M, et al. Evaluation of the safety and efficacy of an edoxaban-based antithrombotic regimen in patients with atrial fibrillation following successful percutaneous coronary intervention (PCI) with stent placement: Rationale and design of the ENTRUST-AF PCI trial. Am Heart J. 2018 Feb;196:105-112.
8. Valgimigli M, Bueno H, Byrne RA, et al. 2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS: The Task Force for dual antiplatelet therapy in coronary artery disease of the European Society of Cardiology (ESC) and of the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J. 2018 Jan 14;39(3):213-260.
9. Angiolillo DJ, Goodman SG, et al. Antithrombotic Therapy in Patients With Atrial Fibrillation Treated With Oral Anticoagulation Undergoing Percutaneous Coronary Intervention. Circulation. 2018 Jul 31;138(5):527-536.
10. January CT, Wann LS, et al. 2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation. Heart Rhythm. 2019 Jan 28;pii: S1547-5271(19)30037-2.
11. Morice MC, Talwar S, Gaemperli O, et al. Drug-coated versus bare-metal stents for elderly patients: A predefined sub-study of the LEADERS FREE trial. Int J Cardiol. 2017 Sep 15;243:110-      115.
12. Varenne O, Cook S, Sideris G, et al., on behalf of the SENIOR Investigators. Drug-eluting stents in elderly patients with coronary artery disease (SENIOR): a randomised single-blind trial. Lancet 2018 Jan 6;391:41-50. 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 Jun 10;367(9526):1903-12.

Table 1

Summary of treatment recommendations following PCI with DES in patients who need anticoagulation for other indication. These recommendations do not apply to BMS or patients with ACS who are managed medically. Peri-PCI aspirin and clopidogrel loading and continuation are recommended in all patients. DOACs should not be used for patients with mechanical valves. If DOACs are used for DT or TT, the doses studied in clinical trials may be considered, though dabigatran 110 mg BID is not approved for stroke prevention in the U.S.

A: aspirin; ACS: acute coronary syndrome; BMS: bare-metal stents; C: clopidogrel; DES: drug-eluting stents; DT: dual therapy; ESC: European Society of Cardiology; LOE: level of evidence; O: oral anticoagulant (direct oral anticoagulant: DOAC or vitamin K antagonist warfarin); PCI: percutaneous coronary intervention; TT: triple therapy

Table 2

Summary of recent major trials comparing DT and TT

ACS: acute coronary syndrome; AF: atrial fibrillation; DAPT: dual antiplatelet therapy; DT: dual therapy; MI: myocardial infarction; ST: stent thrombosis; TT: triple therapy