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Clinical Review  |   May 2020
Antithrombotic Therapy for Patients With Atrial Fibrillation and Acute Coronary Syndrome or Percutaneous Coronary Intervention
Author Notes
  • From the Department of Internal Medicine (Drs Tseng and Agrwal); the Division of Cardiovascular Diseases (Dr Shamoun); and Mayo Clinic Library Services (Ms Marks) at the Mayo Clinic in Phoenix, Arizona. 
  • Financial Disclosures: None reported. 
  • Support: None reported. 
  •  *Address correspondence to Neera Agrwal, MD, PhD, 13737 N 92nd St, Scottsdale, AZ 85260-7434. Email: agrwal.neera@mayo.edu
     
Article Information
Cardiovascular Disorders
Clinical Review   |   May 2020
Antithrombotic Therapy for Patients With Atrial Fibrillation and Acute Coronary Syndrome or Percutaneous Coronary Intervention
The Journal of the American Osteopathic Association, May 2020, Vol. 120, 345-349. doi:https://doi.org/10.7556/jaoa.2020.053
The Journal of the American Osteopathic Association, May 2020, Vol. 120, 345-349. doi:https://doi.org/10.7556/jaoa.2020.053
Abstract

1. What is the clinical question? What combination antithrombotic therapy is recommended for patients with atrial fibrillation with acute coronary syndrome or patients undergoing percutaneous coronary intervention?

2. What does the evidence say? Double therapy (DT) with clopidogrel and direct oral anticoagulants (specifically, dabigatran, rivaroxaban, and apixaban) is noninferior to warfarin-based therapies for most patients. Double therapy is noninferior to triple therapy (TT) and has less bleeding complications.

3. What is the take-home message for physicians? According to the latest guidelines by the ACC, AHA, ESC, and HRS, in patients with AF undergoing PCI, DT with DOACs (specifically dabigatran, rivaroxaban and apixaban) plus clopidogrel is acceptable. Patients undergoing PCI or with high ischemic risk may still benefit from TT for at least 1 month and up to 6 months before switching to DT. Currently, there is no specific guidance on long-term antiplatelet therapy in these patients. Duration of antiplatelet therapy, whether with DT or TT, should be based on current DAPT guidelines (depending on indication and type of intervention) and discussions with each patient's cardiologist.

Patients are increasingly receiving complex antithrombotic therapy regimens that include both oral anticoagulant and antiplatelet agents for a variety of indications. This includes patients with atrial fibrillation (AF) who require anticoagulation and in patients with coronary artery disease who require antiplatelet therapy (eg, after acute coronary syndrome [ACS] or percutaneous coronary intervention [PCI]). 
Anticoagulation in AF, according to the 2019 AF guidelines of the American College of Cardiology (ACC), American Heart Associaion (AHA), and the Heart Rhythm Society (HRS), is indicated when the CHADS2 VASc score (a clinical risk calculator used to determine stroke risk in patients with AF) is 2 or greater in men and 3 or greater in women.1 For nonvalvular AF, first-line oral anticoagulation therapy has traditionally consisted of warfarin but now includes direct oral anticoagulants (DOACs; dabigatran, rivaroxaban, apixaban, and edoxaban).1 Antiplatelet therapy is indicated in patients with ACS with or without PCI or stable ischemic heart disease undergoing PCI, and it typically consists of dual antiplatelet therapy (DAPT; aspirin with a P2Y12 inhibitor, especially ticagrelor or clopidogrel) for 1 to 12 months depending on the clinical situation and bleeding risk, according to the 2016 ACC/AHA and 2018 European Society of Cardiology (ESC) DAPT guideline updates.2,3 The combination of aspirin with a P2Y12 inhibitor allows for dual methods of platelet aggregation inhibition, since aspirin inhibits cyclooxygenase function in platelets while P2Y12 inhibitors inhibit adenosine diphosphate binding in platelets. 
Patients who take both anticoagulants and antiplatelet agents have a 5-fold increase in the risk of bleeding requiring transfusions and a 40% increase in the risk of hospitalization compared with patients who do not take antithrombotic therapy.4 Before DOACs, patients with AF were often given triple therapy (TT) with warfarin and DAPT after ACS or PCI. Triple therapy (oral anticoagulant, P2Y12 inhibitor, and low-dose aspirin) significantly increases the risk of major bleeding compared with double therapy (DT; oral anticoagulant and P2Y12 inhibitor).5-7 
Direct oral anticoagulants are now increasingly used for AF because of efficacy, safety, and ease of use. Previously, without clear clinical evidence or formal guidelines, combination antithrombotic therapy comprising DOACs and antiplatelet medications was uncertain. Furthermore, TT with these agents was also uncertain. As such, the 2019 ACC/AHA/HRS AF guidelines also provide guidance on the use of DOACs in combination antithrombotic therapy, as well as updated guidance on DT vs TT in certain common clinical scenarios.1 
In the present review, we examine the recent clinical trial results and the latest guidelines to help primary care physicians stay up to date. There are 2 general issues to be addressed in the care of these patients: (1) the efficacy and safety of DT vs TT, and (2) DOAC vs warfarin as the oral anticoagulant of choice. 
Summary of the Evidence
Results from 3 pivotal randomized controlled trials were included in the 2019 ACC/AHA/HRS AF guidelines: REDUAL-PCI (dabigatran vs warfarin), PIONEER AF-PCI (rivaroxaban vs warfarin), and WOEST (DT vs TT with warfarin as the anticoagulant).8-10 In early 2019, the AUGUSTUS trial (apixaban vs warfarin and DT vs TT) findings were published.11 
Concerning DT vs TT, the randomized controlled trials that evaluated their safety and efficacy demonstrated that DT was superior to TT in terms of improved bleeding outcomes. The WOEST trial compared DT vs TT with warfarin as the anticoagulant in patients with AF requiring PCI. They found that DT with warfarin had improved safety and efficacy compared with TT at the end of 1 year.9 Similarly, the AUGUSTUS trial showed that DT with apixaban had a lower risk of bleeding and was noninferior in efficacy (eg, in general, composite outcome of mortality and ischemic events) compared with TT with apixaban.11 Regarding DOAC therapy, in aggregate, the studies assessing the safety and efficacy of DOAC therapy (eg, REDUAL-PCI, PIONEER AF-PCI and AUGUSTUS, ENTRUST-AF PCI) demonstrated that DOAC therapy was noninferior to warfarin and, at times, superior to warfarin therapy in these patients in terms of safety.8,10,11 The results of the major randomized controlled trials are summarized in Table 1. 
Table 1.
Summary of Primary and Secondary Outcomes of Major RCTs in Patients With AF With ACS or PCI
Trial WOEST9 PIONEER AF-PCI8 RE-DUAL PCI10 AUGUSTUS11 ENTRUST-AF PCI12
Year 2013 2016 2017 2019 2019
N 563 2124 2725 4614 1506
Study design Multicenter, open-label RCT Multicenter, open-label RCT Multicenter, open-label RCT Multicenter, open-label RCT Multicenter, open-label RCT
Study population PCI PCI PCI ACS with or without PCI or SIHD with PCI PCI
Study groups Warfarin + P2Y12i vs warfarin + DAPT Rivaroxaban + P2Y12i vs warfarin + DAPT Dabigatran + P2Y12i vs warfarin + DAPT Apixaban + P2Y12i vs warfarin + P2Y12i Edoxaban + P2Y12i vs warfarin + DAPT
Study duration 12 months 12 months 14 months 6 months 12 months
Primary safety outcome Any bleeding by year 1 TIMI major/or minor bleeding or bleeding requiring medical attention Major or clinical relevant nonmajor bleeding Major or clinical relevant nonmajor bleeding Major or clinically relevant nonmajor bleeding
Result 19.4% vs 44.4%, HR, 0.36; 95% CI, 0.26-0.50; P<.0001 16.8% vs 26.7%, HR, 0.59; 95% CI, 0.47-0.76; P<.001 20.2% vs 25.7%; HR, 0.72; 95% CI, 0.58-0.88; P=.002 10.5% vs 14.7% HR, 0.69; 95% CI, 0.58-0.81; P<.001 17% vs 20%; HR, 0.83; 95%CI, 0.65-1.05; P=.001
Secondary efficacy outcome Death, MI revascularization, stroke, or stent thrombosis CV mortality, MI, stroke, or stent thrombosis Thromboembolic events, death, or unplanned revascularization Death or ischemic event CV mortality, stroke, systemic embolic event, MI, definite stent thrombosis
Result 11.1% vs 17.6%; HR, 0.60; 95% CI, 0.38-0.94; P=.025 6.5% vs 6.0%; HR, 1.08; 95% CI, 0.69-1.68; P=.75 11.8% vs 12.8%; HR, 0.89; 95% CI, 0.67-1.19; P=.44 6.5% vs 7.3%; HR, 0.89; 95% CI, 0.71-1.11; P=NS 7% vs 6%; HR, 1.06; 95%CI: 0.71-1.69; P=NS
Study limitations ▪ Open label
▪ Not powered to assess efficacy outcomes
▪ Difference in any bleeding driven by minor bleeding with unclear clinical significance
▪ Open label
▪ Not powered to assess efficacy outcomes
▪ Open label
▪ Not powered to assess efficacy outcomes
▪ Open label
▪ Not powered to assess efficacy outcomes
▪ Low percentage time in therapeutic range for warfarin
▪ Open label
▪ Not powered to assess efficacy outcomes
Clinical bottom line Warfarin DT had improved safety and efficacy compared with TT Rivaroxaban DT had improved safety and noninferior efficacy compared with warfarin TT Dabigatran DT had improved safety and noninferior efficacy compared with warfarin TT Apixaban DT had improved safety and noninferior efficacy compared with warfarin DT Edoxaban DT had noninferior safety and noninferior efficacy compared with warfarin DT

Abbreviations: ACC, American College of Cardiology; ACS, acute coronary syndrome; AF, atrial fibrillation; AHA, American Heart Association; DAPT, dual antiplatelet therapy; DT, double therapy; DOAC, direct oral anticoagulant; ESC, European Society of Cardiology; HRS, Heart Rhythm Society; NS, not significant; PCI, percutaneous coronary intervention; RCT, randomized controlled trial; SIHD, stable ischemic heart disease; TT, triple therapy.

Table 1.
Summary of Primary and Secondary Outcomes of Major RCTs in Patients With AF With ACS or PCI
Trial WOEST9 PIONEER AF-PCI8 RE-DUAL PCI10 AUGUSTUS11 ENTRUST-AF PCI12
Year 2013 2016 2017 2019 2019
N 563 2124 2725 4614 1506
Study design Multicenter, open-label RCT Multicenter, open-label RCT Multicenter, open-label RCT Multicenter, open-label RCT Multicenter, open-label RCT
Study population PCI PCI PCI ACS with or without PCI or SIHD with PCI PCI
Study groups Warfarin + P2Y12i vs warfarin + DAPT Rivaroxaban + P2Y12i vs warfarin + DAPT Dabigatran + P2Y12i vs warfarin + DAPT Apixaban + P2Y12i vs warfarin + P2Y12i Edoxaban + P2Y12i vs warfarin + DAPT
Study duration 12 months 12 months 14 months 6 months 12 months
Primary safety outcome Any bleeding by year 1 TIMI major/or minor bleeding or bleeding requiring medical attention Major or clinical relevant nonmajor bleeding Major or clinical relevant nonmajor bleeding Major or clinically relevant nonmajor bleeding
Result 19.4% vs 44.4%, HR, 0.36; 95% CI, 0.26-0.50; P<.0001 16.8% vs 26.7%, HR, 0.59; 95% CI, 0.47-0.76; P<.001 20.2% vs 25.7%; HR, 0.72; 95% CI, 0.58-0.88; P=.002 10.5% vs 14.7% HR, 0.69; 95% CI, 0.58-0.81; P<.001 17% vs 20%; HR, 0.83; 95%CI, 0.65-1.05; P=.001
Secondary efficacy outcome Death, MI revascularization, stroke, or stent thrombosis CV mortality, MI, stroke, or stent thrombosis Thromboembolic events, death, or unplanned revascularization Death or ischemic event CV mortality, stroke, systemic embolic event, MI, definite stent thrombosis
Result 11.1% vs 17.6%; HR, 0.60; 95% CI, 0.38-0.94; P=.025 6.5% vs 6.0%; HR, 1.08; 95% CI, 0.69-1.68; P=.75 11.8% vs 12.8%; HR, 0.89; 95% CI, 0.67-1.19; P=.44 6.5% vs 7.3%; HR, 0.89; 95% CI, 0.71-1.11; P=NS 7% vs 6%; HR, 1.06; 95%CI: 0.71-1.69; P=NS
Study limitations ▪ Open label
▪ Not powered to assess efficacy outcomes
▪ Difference in any bleeding driven by minor bleeding with unclear clinical significance
▪ Open label
▪ Not powered to assess efficacy outcomes
▪ Open label
▪ Not powered to assess efficacy outcomes
▪ Open label
▪ Not powered to assess efficacy outcomes
▪ Low percentage time in therapeutic range for warfarin
▪ Open label
▪ Not powered to assess efficacy outcomes
Clinical bottom line Warfarin DT had improved safety and efficacy compared with TT Rivaroxaban DT had improved safety and noninferior efficacy compared with warfarin TT Dabigatran DT had improved safety and noninferior efficacy compared with warfarin TT Apixaban DT had improved safety and noninferior efficacy compared with warfarin DT Edoxaban DT had noninferior safety and noninferior efficacy compared with warfarin DT

Abbreviations: ACC, American College of Cardiology; ACS, acute coronary syndrome; AF, atrial fibrillation; AHA, American Heart Association; DAPT, dual antiplatelet therapy; DT, double therapy; DOAC, direct oral anticoagulant; ESC, European Society of Cardiology; HRS, Heart Rhythm Society; NS, not significant; PCI, percutaneous coronary intervention; RCT, randomized controlled trial; SIHD, stable ischemic heart disease; TT, triple therapy.

×
When interpreting these results, it is important to note the limitations of each study. All studies were open-label, which may have introduced the possibility of observation bias. Also, because the primary outcomes for these 4 studies were safety outcomes related to bleeding, these studies were not specifically powered to assess for thrombotic outcomes and generally reported efficacy outcomes as aggregate outcomes. This factor may limit the strength of the conclusions for noninferiority in efficacy. Furthermore, there were study-specific limitations. In the WOEST trial, the statistical difference in bleeding outcomes was driven primarily by minor bleeding, which is of unclear clinical significance. In the AUGUSTUS trial, patients taking warfarin had comparatively lower time in the therapeutic range (59%) when compared with other major trials. Reduced time in the therapeutic range for patients in the warfarin treatment arm may have affected trial outcomes (eg, possibly more bleeding or more ischemic events than if international normalized ratio was better controlled). These limitations are summarized in Table 1. 
European guidelines specifically recommend against DOACs with prasugrel or ticagrelor in DT or TT given the lack of evidence and potential for increased bleeding based on registry data.3 American guidelines allow ticagrelor as an alternative to clopidogrel in DT with warfarin only. 
Regarding DT vs TT, the American and European guidelines differ slightly. According to the 2019 ACC/AHA/HRS AF guidelines, TT should be limited to 4 to 6 weeks and switched to DT. Otherwise, DT alone is also acceptable.1 The 2017 ESC DAPT guidelines, however, emphasize their recommendation of at least 1 month of TT after PCI.3 They also recommend at least 1 month and up to 6 months of TT if patients are considered to be of higher ischemic risk. These risk factors include (1) prior stent thrombosis while taking antiplatelet therapy, (2) stenting of last remaining patent coronary artery, (3) diffuse multivessel disease, especially in diabetic patients, (4) chronic kidney disease, and (5) at least 3 stents implanted, at least 3 lesions treated, bifurcation with 2 stents implanted, total stent length greater than 60 mm, or management of a chronic total occlusion.3 In general, both major guidelines recommend DT for most patients with average ischemic risk or higher bleeding risk. Otherwise, the guidelines—particularly the European guidelines—recommend TT for patients who undergo PCI with increased ischemic risk with average or lower bleeding risk. 
Duration of antiplatelet therapy is based on indication (eg, stable ischemic heart disease with PCI vs ACS, as well as type of stent used). In stable ischemic heart disease with PCI, bare metal stents require at least 1 month of antiplatelet therapy. Drug-eluting stents require at least 3 months of antiplatelet therapy; if there is a high risk of bleeding, 6 months is preferred. In ACS with or without PCI, antiplatelet therapy is recommended for at least 6 months if there is a high risk of bleeding; otherwise, 12 months is preferred. If TT with warfarin is used for more than 1 month, it is reasonable to switch to DT with warfarin after 4 to 6 weeks.2 European guidelines recommend at least 1 month of TT after PCI, particularly for patients with high-risk PCI.3 These considerations are summarized in Table 2. 
Table 2.
Summary of Antithrombotic Considerations in Patients With AF With ACS or PCI in North American and European Guidelines
Risk Anticoagulant DT vs TT Duration of Antiplatelet Therapy
Average ischemic risk Warfarin or DOAC1,3 ▪ North America: DT
▪ Europe: DT (consider TT for 4-6 wk if PCI)1,3
▪ SIHD-BMS: 1 mo
▪ SIHD-DES: 6 mo (3 mo reasonable)
High ischemic risk Warfarin or DOAC1,3 ▪ North America: TT for 1 month followed by DT for duration of treatment
▪ Europe: TT for 4-6 wk, and consider up to 6 mo followed by DT if extended therapy beyond 6 mo1,3
▪ ACS: 12 mo (6 mo reasonable)2,3
High bleeding risk Warfarin or DOACa Both North America and Europe: DT1,3

a Although warfarin can be used, based on the available randomized controlled trial evidence, direct oral anticoagulants (DOACs) cause less bleeding compared with warfarin. This consideration is not formally recommended in current guidelines.

Abbreviations: ACS, acute coronary syndrome; DT, double therapy; PCI, percutaneous coronary intervention; SIHD-BMS, stable ischemic heart disease bare-metal stent; SIHD-DES, SIHD drug-eluting stent; TT, triple therapy.

Table 2.
Summary of Antithrombotic Considerations in Patients With AF With ACS or PCI in North American and European Guidelines
Risk Anticoagulant DT vs TT Duration of Antiplatelet Therapy
Average ischemic risk Warfarin or DOAC1,3 ▪ North America: DT
▪ Europe: DT (consider TT for 4-6 wk if PCI)1,3
▪ SIHD-BMS: 1 mo
▪ SIHD-DES: 6 mo (3 mo reasonable)
High ischemic risk Warfarin or DOAC1,3 ▪ North America: TT for 1 month followed by DT for duration of treatment
▪ Europe: TT for 4-6 wk, and consider up to 6 mo followed by DT if extended therapy beyond 6 mo1,3
▪ ACS: 12 mo (6 mo reasonable)2,3
High bleeding risk Warfarin or DOACa Both North America and Europe: DT1,3

a Although warfarin can be used, based on the available randomized controlled trial evidence, direct oral anticoagulants (DOACs) cause less bleeding compared with warfarin. This consideration is not formally recommended in current guidelines.

Abbreviations: ACS, acute coronary syndrome; DT, double therapy; PCI, percutaneous coronary intervention; SIHD-BMS, stable ischemic heart disease bare-metal stent; SIHD-DES, SIHD drug-eluting stent; TT, triple therapy.

×
It should be noted that the current 2019 ACC/AHA/HRS AF guidelines for DT and TT with DOACs does not include ticagrelor, apixaban, or edoxaban. Based on the results of the AUGUSTUS trial and the ENTRUST-AF PCI trial, apixaban and edoxaban in DT may soon be formally recommended.11 A meta-analysis of the 4 pivotal DOAC trials showed that DT with DOACs had reduced risk of bleeding compared with TT plus warfarin, but because these studies were not powered to detect a difference in efficacy outcomes, the impact on death and ischemic end points is unclear.13 Furthermore, while the ACC DAPT score exists to determine the risks and benefits of prolonged DAPT, no such score exists for patients taking concomitant anticoagulation. The minimum duration of antiplatelet therapy in these patients is extrapolated from the existing DAPT guidelines, all of which may continue to change based on improved PCI technology and medical therapy. 
Conclusion
Based on the studies reviewed, current guidelines from the ACC, AHA, ESC, and HRS recommend DT or TT with any oral anticoagulant and clopidogrel. The 2019 US guidelines typically favor shorter duration of TT (4-6 weeks, then DT) than the 2017 European guidelines (TT ≥1 month, ≤6 months, then DT). Careful consideration of bleeding risk and ischemic risk should be individualized in these patients when deciding on DT or TT. The European guidelines provide guidance on risk factors associated with higher ischemic risk that may warrant TT for a longer duration. Despite these technical differences, there is growing evidence for the benefit of DT alone for these patients, with TT being restricted for short periods for a selected minority of patients. This is a changing field, and with further advancements in stent technology, further research will likely help elucidate the optimal antithrombotic regimen in these patients. 
References
Members Writing Group, 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: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. . Heart Rhythm. 2019;16(8):e66-e93. doi: 10.1016/j.hrthm.2019.01.024 [CrossRef] [PubMed]
Levine GN, Bates ER, Bittl JA, et al. 2016 ACC/AHA guideline focused update on duration of dual antiplatelet therapy in patients with coronary artery disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. . J Thorac Cardiovasc Surg. 2016;152(5):1243-1275. doi: 10.1016/j.jtcvs.2016.07.044 [CrossRef] [PubMed]
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;39(3):213-260. doi: 10.1093/eurheartj/ehx419 [CrossRef]
Abraham NS, Hartman C, Richardson P, Castillo D, Street RLJr, Naik AD. Risk of lower and upper gastrointestinal bleeding, transfusions, and hospitalizations with complex antithrombotic therapy in elderly patients. Circulation. 2013;128(17):1869-1877. doi: 10.1161/CIRCULATIONAHA.113.004747 [CrossRef] [PubMed]
Menozzi M, Rubboli A, Manari A, De Palma R, Grilli R. Triple antithrombotic therapy in patients with atrial fibrillation undergoing coronary artery stenting: hovering among bleeding risk, thromboembolic events, and stent thrombosis. Thromb J. 2012;10(1):22. doi: 10.1186/1477-9560-10-22 [CrossRef] [PubMed]
Enomoto Y, Iijima R, Tokue M, et al. Bleeding risk with triple antithrombotic therapy in patients with atrial fibrillation and drug-eluting stents. Cardiovasc Interv Ther. 2014;29(3):193-199. doi: 10.1007/s12928-013-0234-4 [CrossRef] [PubMed]
Faza NN, Mentias A, Parashar A, et al. Bleeding complications of triple antithrombotic therapy after percutaneous coronary interventions. Catheter Cardiovasc Interv. 2017;89(2):e64-e74. doi: 10.1002/ccd.26574 [CrossRef] [PubMed]
Gibson CM, Mehran R, Bode C, et al. Prevention of bleeding in patients with atrial fibrillation undergoing PCI. N Engl J Med. 2016;375(25):2423-2434. doi: 10.1056/NEJMoa1611594 [CrossRef] [PubMed]
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. 2013;381(9872):1107-1115. doi: 10.1016/S0140-6736(12)62177-1 [CrossRef] [PubMed]
Cannon CP, Bhatt DL, Oldgren J, et al. Dual antithrombotic therapy with dabigatran after PCI in atrial fibrillation. N Engl J Med. 2017;377(16):1513-1524. doi: 10.1056/NEJMoa1708454 [CrossRef] [PubMed]
Lopes RD, Heizer G, Aronson R, et al. Antithrombotic therapy after acute coronary syndrome or PCI in atrial fibrillation. N Engl J Med. 2019;380(16):1509-1524. doi: 10.1056/NEJMoa1817083 [CrossRef] [PubMed]
Table 1.
Summary of Primary and Secondary Outcomes of Major RCTs in Patients With AF With ACS or PCI
Trial WOEST9 PIONEER AF-PCI8 RE-DUAL PCI10 AUGUSTUS11 ENTRUST-AF PCI12
Year 2013 2016 2017 2019 2019
N 563 2124 2725 4614 1506
Study design Multicenter, open-label RCT Multicenter, open-label RCT Multicenter, open-label RCT Multicenter, open-label RCT Multicenter, open-label RCT
Study population PCI PCI PCI ACS with or without PCI or SIHD with PCI PCI
Study groups Warfarin + P2Y12i vs warfarin + DAPT Rivaroxaban + P2Y12i vs warfarin + DAPT Dabigatran + P2Y12i vs warfarin + DAPT Apixaban + P2Y12i vs warfarin + P2Y12i Edoxaban + P2Y12i vs warfarin + DAPT
Study duration 12 months 12 months 14 months 6 months 12 months
Primary safety outcome Any bleeding by year 1 TIMI major/or minor bleeding or bleeding requiring medical attention Major or clinical relevant nonmajor bleeding Major or clinical relevant nonmajor bleeding Major or clinically relevant nonmajor bleeding
Result 19.4% vs 44.4%, HR, 0.36; 95% CI, 0.26-0.50; P<.0001 16.8% vs 26.7%, HR, 0.59; 95% CI, 0.47-0.76; P<.001 20.2% vs 25.7%; HR, 0.72; 95% CI, 0.58-0.88; P=.002 10.5% vs 14.7% HR, 0.69; 95% CI, 0.58-0.81; P<.001 17% vs 20%; HR, 0.83; 95%CI, 0.65-1.05; P=.001
Secondary efficacy outcome Death, MI revascularization, stroke, or stent thrombosis CV mortality, MI, stroke, or stent thrombosis Thromboembolic events, death, or unplanned revascularization Death or ischemic event CV mortality, stroke, systemic embolic event, MI, definite stent thrombosis
Result 11.1% vs 17.6%; HR, 0.60; 95% CI, 0.38-0.94; P=.025 6.5% vs 6.0%; HR, 1.08; 95% CI, 0.69-1.68; P=.75 11.8% vs 12.8%; HR, 0.89; 95% CI, 0.67-1.19; P=.44 6.5% vs 7.3%; HR, 0.89; 95% CI, 0.71-1.11; P=NS 7% vs 6%; HR, 1.06; 95%CI: 0.71-1.69; P=NS
Study limitations ▪ Open label
▪ Not powered to assess efficacy outcomes
▪ Difference in any bleeding driven by minor bleeding with unclear clinical significance
▪ Open label
▪ Not powered to assess efficacy outcomes
▪ Open label
▪ Not powered to assess efficacy outcomes
▪ Open label
▪ Not powered to assess efficacy outcomes
▪ Low percentage time in therapeutic range for warfarin
▪ Open label
▪ Not powered to assess efficacy outcomes
Clinical bottom line Warfarin DT had improved safety and efficacy compared with TT Rivaroxaban DT had improved safety and noninferior efficacy compared with warfarin TT Dabigatran DT had improved safety and noninferior efficacy compared with warfarin TT Apixaban DT had improved safety and noninferior efficacy compared with warfarin DT Edoxaban DT had noninferior safety and noninferior efficacy compared with warfarin DT

Abbreviations: ACC, American College of Cardiology; ACS, acute coronary syndrome; AF, atrial fibrillation; AHA, American Heart Association; DAPT, dual antiplatelet therapy; DT, double therapy; DOAC, direct oral anticoagulant; ESC, European Society of Cardiology; HRS, Heart Rhythm Society; NS, not significant; PCI, percutaneous coronary intervention; RCT, randomized controlled trial; SIHD, stable ischemic heart disease; TT, triple therapy.

Table 1.
Summary of Primary and Secondary Outcomes of Major RCTs in Patients With AF With ACS or PCI
Trial WOEST9 PIONEER AF-PCI8 RE-DUAL PCI10 AUGUSTUS11 ENTRUST-AF PCI12
Year 2013 2016 2017 2019 2019
N 563 2124 2725 4614 1506
Study design Multicenter, open-label RCT Multicenter, open-label RCT Multicenter, open-label RCT Multicenter, open-label RCT Multicenter, open-label RCT
Study population PCI PCI PCI ACS with or without PCI or SIHD with PCI PCI
Study groups Warfarin + P2Y12i vs warfarin + DAPT Rivaroxaban + P2Y12i vs warfarin + DAPT Dabigatran + P2Y12i vs warfarin + DAPT Apixaban + P2Y12i vs warfarin + P2Y12i Edoxaban + P2Y12i vs warfarin + DAPT
Study duration 12 months 12 months 14 months 6 months 12 months
Primary safety outcome Any bleeding by year 1 TIMI major/or minor bleeding or bleeding requiring medical attention Major or clinical relevant nonmajor bleeding Major or clinical relevant nonmajor bleeding Major or clinically relevant nonmajor bleeding
Result 19.4% vs 44.4%, HR, 0.36; 95% CI, 0.26-0.50; P<.0001 16.8% vs 26.7%, HR, 0.59; 95% CI, 0.47-0.76; P<.001 20.2% vs 25.7%; HR, 0.72; 95% CI, 0.58-0.88; P=.002 10.5% vs 14.7% HR, 0.69; 95% CI, 0.58-0.81; P<.001 17% vs 20%; HR, 0.83; 95%CI, 0.65-1.05; P=.001
Secondary efficacy outcome Death, MI revascularization, stroke, or stent thrombosis CV mortality, MI, stroke, or stent thrombosis Thromboembolic events, death, or unplanned revascularization Death or ischemic event CV mortality, stroke, systemic embolic event, MI, definite stent thrombosis
Result 11.1% vs 17.6%; HR, 0.60; 95% CI, 0.38-0.94; P=.025 6.5% vs 6.0%; HR, 1.08; 95% CI, 0.69-1.68; P=.75 11.8% vs 12.8%; HR, 0.89; 95% CI, 0.67-1.19; P=.44 6.5% vs 7.3%; HR, 0.89; 95% CI, 0.71-1.11; P=NS 7% vs 6%; HR, 1.06; 95%CI: 0.71-1.69; P=NS
Study limitations ▪ Open label
▪ Not powered to assess efficacy outcomes
▪ Difference in any bleeding driven by minor bleeding with unclear clinical significance
▪ Open label
▪ Not powered to assess efficacy outcomes
▪ Open label
▪ Not powered to assess efficacy outcomes
▪ Open label
▪ Not powered to assess efficacy outcomes
▪ Low percentage time in therapeutic range for warfarin
▪ Open label
▪ Not powered to assess efficacy outcomes
Clinical bottom line Warfarin DT had improved safety and efficacy compared with TT Rivaroxaban DT had improved safety and noninferior efficacy compared with warfarin TT Dabigatran DT had improved safety and noninferior efficacy compared with warfarin TT Apixaban DT had improved safety and noninferior efficacy compared with warfarin DT Edoxaban DT had noninferior safety and noninferior efficacy compared with warfarin DT

Abbreviations: ACC, American College of Cardiology; ACS, acute coronary syndrome; AF, atrial fibrillation; AHA, American Heart Association; DAPT, dual antiplatelet therapy; DT, double therapy; DOAC, direct oral anticoagulant; ESC, European Society of Cardiology; HRS, Heart Rhythm Society; NS, not significant; PCI, percutaneous coronary intervention; RCT, randomized controlled trial; SIHD, stable ischemic heart disease; TT, triple therapy.

×
Table 2.
Summary of Antithrombotic Considerations in Patients With AF With ACS or PCI in North American and European Guidelines
Risk Anticoagulant DT vs TT Duration of Antiplatelet Therapy
Average ischemic risk Warfarin or DOAC1,3 ▪ North America: DT
▪ Europe: DT (consider TT for 4-6 wk if PCI)1,3
▪ SIHD-BMS: 1 mo
▪ SIHD-DES: 6 mo (3 mo reasonable)
High ischemic risk Warfarin or DOAC1,3 ▪ North America: TT for 1 month followed by DT for duration of treatment
▪ Europe: TT for 4-6 wk, and consider up to 6 mo followed by DT if extended therapy beyond 6 mo1,3
▪ ACS: 12 mo (6 mo reasonable)2,3
High bleeding risk Warfarin or DOACa Both North America and Europe: DT1,3

a Although warfarin can be used, based on the available randomized controlled trial evidence, direct oral anticoagulants (DOACs) cause less bleeding compared with warfarin. This consideration is not formally recommended in current guidelines.

Abbreviations: ACS, acute coronary syndrome; DT, double therapy; PCI, percutaneous coronary intervention; SIHD-BMS, stable ischemic heart disease bare-metal stent; SIHD-DES, SIHD drug-eluting stent; TT, triple therapy.

Table 2.
Summary of Antithrombotic Considerations in Patients With AF With ACS or PCI in North American and European Guidelines
Risk Anticoagulant DT vs TT Duration of Antiplatelet Therapy
Average ischemic risk Warfarin or DOAC1,3 ▪ North America: DT
▪ Europe: DT (consider TT for 4-6 wk if PCI)1,3
▪ SIHD-BMS: 1 mo
▪ SIHD-DES: 6 mo (3 mo reasonable)
High ischemic risk Warfarin or DOAC1,3 ▪ North America: TT for 1 month followed by DT for duration of treatment
▪ Europe: TT for 4-6 wk, and consider up to 6 mo followed by DT if extended therapy beyond 6 mo1,3
▪ ACS: 12 mo (6 mo reasonable)2,3
High bleeding risk Warfarin or DOACa Both North America and Europe: DT1,3

a Although warfarin can be used, based on the available randomized controlled trial evidence, direct oral anticoagulants (DOACs) cause less bleeding compared with warfarin. This consideration is not formally recommended in current guidelines.

Abbreviations: ACS, acute coronary syndrome; DT, double therapy; PCI, percutaneous coronary intervention; SIHD-BMS, stable ischemic heart disease bare-metal stent; SIHD-DES, SIHD drug-eluting stent; TT, triple therapy.

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