Role and Timing of Aspirin Therapy Following PCI in Patients With Atrial Fibrillation
2021; Elsevier BV; Volume: 144; Linguagem: Inglês
10.1016/j.amjcard.2020.12.017
ISSN1879-1913
Autores Tópico(s)Cardiac Arrhythmias and Treatments
ResumoIn patients with atrial fibrillation who undergo percutaneous coronary intervention (PCI), both anticoagulation and dual antiplatelet therapy (aspirin plus a P2Y12 inhibitor) are indicated. However, this "triple" antithrombotic therapy is associated with high rates of bleeding. Finding the right balance of reducing ischemic risk and protecting coronary stents from restenosis while not increasing bleeding risk is difficult. In the past 5 years, 6 randomized clinical trials have shown the benefit of dropping aspirin from the triple therapy regimen to create "dual" therapy (oral anticoagulants and P2Y12 inhibitors alone) with reductions in bleeding without a significant increase in ischemic events. Because of small trends toward higher risk of stent thrombosis, especially in higher risk patients with acute coronary syndromes, current recommendations call for dual therapy as the "default" regimen, but that risk stratification be used to help inform the decision on potentially using a brief period of triple therapy in selected high ischemic risk patients. For long-term therapy (after one year post-PCI), recent studies have found oral anticoagulation alone without any antiplatelet therapy has a favorable benefit risk ratio. Thus, while dropping aspirin at varying times post-PCI has become an attractive strategy in many patient groups, careful patient selection and individualized assessment of the risk:benefit balance is warranted. In patients with atrial fibrillation who undergo percutaneous coronary intervention (PCI), both anticoagulation and dual antiplatelet therapy (aspirin plus a P2Y12 inhibitor) are indicated. However, this "triple" antithrombotic therapy is associated with high rates of bleeding. Finding the right balance of reducing ischemic risk and protecting coronary stents from restenosis while not increasing bleeding risk is difficult. In the past 5 years, 6 randomized clinical trials have shown the benefit of dropping aspirin from the triple therapy regimen to create "dual" therapy (oral anticoagulants and P2Y12 inhibitors alone) with reductions in bleeding without a significant increase in ischemic events. Because of small trends toward higher risk of stent thrombosis, especially in higher risk patients with acute coronary syndromes, current recommendations call for dual therapy as the "default" regimen, but that risk stratification be used to help inform the decision on potentially using a brief period of triple therapy in selected high ischemic risk patients. For long-term therapy (after one year post-PCI), recent studies have found oral anticoagulation alone without any antiplatelet therapy has a favorable benefit risk ratio. Thus, while dropping aspirin at varying times post-PCI has become an attractive strategy in many patient groups, careful patient selection and individualized assessment of the risk:benefit balance is warranted. Long-term treatment with oral anticoagulants is indicated in patients with atrial fibrillation (AF) for the prevention of stroke and systemic embolism. Vitamin K antagonists (VKAs) such as warfarin have been the mainstay of therapy for such patients on the basis of evidence from placebo-controlled trials where an approximately 65% reduction in the risk of stroke has been seen.1Petersen P Boysen G Godtfredsen J Andersen ED Andersen B. Placebo-controlled, randomised trial of warfarin and aspirin for prevention of thromboembolic complications in chronic atrial fibrillation. The Copenhagen AFASAK study.Lancet Lond Engl. 1989; 1: 175-179https://doi.org/10.1016/s0140-6736(89)91200-2Abstract PubMed Scopus (0) Google Scholar,2Ezekowitz MD Bridgers SL James KE Carliner NH Colling CL Gornick CC Krause-Steinrauf H Kurtzke JF Nazarian SM Radford MJ et al.Warfarin in the prevention of stroke associated with nonrheumatic atrial fibrillation. Veterans affairs stroke prevention in nonrheumatic atrial fibrillation investigators.N Engl J Med. 1992; 327: 1406-1412https://doi.org/10.1056/NEJM199211123272002Crossref PubMed Scopus (1224) Google Scholar Furthermore, VKAs were superior to aspirin (ASA) and to dual antiplatelet therapy (DAPT, P2Y12 inhibitor and ASA) in prevention of stroke.3Mant J Hobbs FDR Fletcher K Roalfe A Fitzmaurice D Lip GYH Murray E BAFTA investigators; Midland Research Practices NetworkWarfarin versus aspirin for stroke prevention in an elderly community population with atrial fibrillation (the Birmingham Atrial Fibrillation Treatment of the Aged Study, BAFTA): a randomised controlled trial.Lancet. 2007; 370: 493-503https://doi.org/10.1016/S0140-6736(07)61233-1Abstract Full Text Full Text PDF PubMed Scopus (1367) Google Scholar,4Connolly S Pogue J Hart R Pfeffer M Hohnloser S Chrolavicius S Pfeffer M Hohnloser S Yusuf S ACTIVE Writing Group of the ACTIVE InvestigatorsClopidogrel 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 Lond Engl. 2006; 367: 1903-1912https://doi.org/10.1016/S0140-6736(06)68845-4Abstract Full Text Full Text PDF PubMed Scopus (1677) Google Scholar In contrast, for patients undergoing percutaneous coronary intervention (PCI) with stent implantation, treatment with dual antiplatelet therapy (with a P2Y12 inhibitor plus ASA) was superior to oral anticoagulation.5Stroke Prevention in Atrial Fibrillation StudyFinal results.Circulation. 1991; 84: 527-539https://doi.org/10.1161/01.cir.84.2.527Crossref PubMed Google Scholar, 6Warfarin versus aspirin for prevention of thromboembolism in atrial fibrillation: stroke prevention in atrial fibrillation II study.Lancet Lond Engl. 1994; 343: 687-691Google Scholar, 7Leon MB Baim DS Popma JJ Gordon PC Cutlip DE Ho KK Giambartolomei A Diver DJ Lasorda DM Williams DO Pocock SJ Kuntz RE A Clinical trial comparing three antithrombotic-drug regimens after coronary-artery stenting.N Engl J Med. 1998; 339: 1665-1671https://doi.org/10.1056/NEJM199812033392303Crossref PubMed Scopus (1629) Google Scholar, 8Schömig A Neumann FJ Kastrati A Schühlen H Blasini R Hadamitzky M Walter H Zitzmann-Roth EM Richardt G Alt E Schmitt C Ulm K A randomized comparison of antiplatelet and anticoagulant therapy after the placement of coronary-artery stents.N Engl J Med. 1996; 334: 1084-1089https://doi.org/10.1056/NEJM199604253341702Crossref PubMed Scopus (1873) Google Scholar Among patients with AF, the prevalence of coronary artery disease (CAD) is estimated to range from 17% to 47%, with approximately 5% to10% having undergone prior treatment with PCI.9Andrade JG Deyell MW Khoo C Lee M Humphries K Cairns JA. Risk of bleeding on triple antithrombotic therapy after percutaneous coronary intervention/stenting: a systematic review and meta-analysis.Can J Cardiol. 2013; 29: 204-212https://doi.org/10.1016/j.cjca.2012.06.012Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar For these patients with AF undergoing PCI, triple therapy had become the default antithrombotic strategy. However, several large registries reported that the risk of major bleeding with triple antithrombotic therapy is up to 3-fold higher than with oral anticoagulation alone or antiplatelet therapy.9Andrade JG Deyell MW Khoo C Lee M Humphries K Cairns JA. Risk of bleeding on triple antithrombotic therapy after percutaneous coronary intervention/stenting: a systematic review and meta-analysis.Can J Cardiol. 2013; 29: 204-212https://doi.org/10.1016/j.cjca.2012.06.012Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar, 10Nikolsky E Mehran R Dangas GD Yu J Parise H Xu K Pocock SJ Stone GW Outcomes of patients treated with triple antithrombotic therapy after primary percutaneous coronary intervention for ST-elevation myocardial infarction (from the Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction [HORIZONS-AMI] trial).Am J Cardiol. 2012; 109: 831-838https://doi.org/10.1016/j.amjcard.2011.10.046Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar, 11Verheugt FWA. Triple antithrombotic therapy after coronary stenting in the elderly with atrial fibrillation: necessary or too hazardous?.Am Heart J. 2012; 163: 531-534https://doi.org/10.1016/j.ahj.2012.01.018Crossref PubMed Scopus (3) Google Scholar, 12Lamberts M Olesen JB Ruwald MH Hansen CM Karasoy D Kristensen SL Køber L Torp-Pedersen C Gislason GH Hansen ML Bleeding after initiation of multiple antithrombotic drugs, including triple therapy, in atrial fibrillation patients following myocardial infarction and coronary intervention.Circulation. 2012; 126: 1185-1193https://doi.org/10.1161/CIRCULATIONAHA.112.114967Crossref PubMed Scopus (343) Google Scholar In addition, major bleeding is associated with an up to 5-fold increased risk of death following an acute coronary syndrome (ACS).13Steg PG Huber K Andreotti F Arnesen H Atar D Badimon L Bassand J-P De Caterina R Eikelboom JA Gulba D Hamon M Helft G Fox KAA Kristensen SD Rao SV Verheugt FWA Widimsky P Zeymer U Collet J-P Bleeding in acute coronary syndromes and percutaneous coronary interventions: position paper by the Working Group on Thrombosis of the European Society of Cardiology.Eur Heart J. 2011; 32: 1854-1864https://doi.org/10.1093/eurheartj/ehr204Crossref PubMed Scopus (288) Google Scholar,14Suh J-W Mehran R Claessen BE Xu K Baber U Dangas G Parise H Lansky AJ Witzenbichler B Grines CL Guagliumi G Kornowski R Wöhrle J Dudek D Weisz G Stone GW Impact of in-hospital major bleeding on late clinical outcomes after primary percutaneous coronary intervention in acute myocardial infarction the HORIZONS-AMI (Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction) trial.J Am Coll Cardiol. 2011; 58: 1750-1756https://doi.org/10.1016/j.jacc.2011.07.021Crossref PubMed Scopus (120) Google Scholar As such, investigators and clinicians are seeking better treatment strategies that improve safety while preserving efficacy. Early trials have evaluated ASA alone as antithrombotic therapy, but this has not been effective in reducing stroke, whereas warfarin is more effective.3Mant J Hobbs FDR Fletcher K Roalfe A Fitzmaurice D Lip GYH Murray E BAFTA investigators; Midland Research Practices NetworkWarfarin versus aspirin for stroke prevention in an elderly community population with atrial fibrillation (the Birmingham Atrial Fibrillation Treatment of the Aged Study, BAFTA): a randomised controlled trial.Lancet. 2007; 370: 493-503https://doi.org/10.1016/S0140-6736(07)61233-1Abstract Full Text Full Text PDF PubMed Scopus (1367) Google Scholar,15Själander S Själander A Svensson PJ Friberg L. Atrial fibrillation patients do not benefit from acetylsalicylic acid. Eur Eur Pacing Arrhythm Card Electrophysiol J Work Groups Card Pacing Arrhythm Card Cell Electrophysiol.Eur Soc Cardiol. 2014; 16: 631-638https://doi.org/10.1093/europace/eut333Crossref Scopus (56) Google Scholar,16Lip GYH. The role of aspirin for stroke prevention in atrial fibrillation.Nat Rev Cardiol. 2011; 8: 602-606https://doi.org/10.1038/nrcardio.2011.112Crossref PubMed Scopus (90) Google Scholar Aspirin monotherapy was no effective for stroke prevention compared with no antithrombotic treatment and was associated with a higher risk of ischemic stroke in elderly patients in one trial.15Själander S Själander A Svensson PJ Friberg L. Atrial fibrillation patients do not benefit from acetylsalicylic acid. Eur Eur Pacing Arrhythm Card Electrophysiol J Work Groups Card Pacing Arrhythm Card Cell Electrophysiol.Eur Soc Cardiol. 2014; 16: 631-638https://doi.org/10.1093/europace/eut333Crossref Scopus (56) Google Scholar Other trials also found that antiplatelet monotherapy is ineffective for stroke prevention and is potentially harmful, especially amongst elderly AF patients.3Mant J Hobbs FDR Fletcher K Roalfe A Fitzmaurice D Lip GYH Murray E BAFTA investigators; Midland Research Practices NetworkWarfarin versus aspirin for stroke prevention in an elderly community population with atrial fibrillation (the Birmingham Atrial Fibrillation Treatment of the Aged Study, BAFTA): a randomised controlled trial.Lancet. 2007; 370: 493-503https://doi.org/10.1016/S0140-6736(07)61233-1Abstract Full Text Full Text PDF PubMed Scopus (1367) Google Scholar,16Lip GYH. The role of aspirin for stroke prevention in atrial fibrillation.Nat Rev Cardiol. 2011; 8: 602-606https://doi.org/10.1038/nrcardio.2011.112Crossref PubMed Scopus (90) Google Scholar Two more recent trials have also found also that anticoagulation is superior to antiplatelet therapy. In the Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events (ACTIVE-W) trial, patients with AF were randomized to receive oral anticoagulation therapy (n=3371) or ASA (75 to100 mg) plus clopidogrel (n=3335). The study had to be stopped early because of superiority of oral anticoagulation therapy over antiplatelet therapy. The risk of stroke, systemic embolus, myocardial infarction (MI), or cardiovascular death (CVD) occurred at a 3.9% annual rate for those on anticoagulation versus 5.6% for ASA plus clopidogrel; the relative risk [RR] was1.44 (1.18 to 1.76; p = 0.0003). The difference on stroke was even greater, with annual rates of 1.4% versus 2.4% (RR 1.72, 95% CI 1.24 to 2.37; p = 0.001). As such, this trial established the inferiority of antiplatelet therapy, and the superiority of oral anticoagulation.4Connolly S Pogue J Hart R Pfeffer M Hohnloser S Chrolavicius S Pfeffer M Hohnloser S Yusuf S ACTIVE Writing Group of the ACTIVE InvestigatorsClopidogrel 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 Lond Engl. 2006; 367: 1903-1912https://doi.org/10.1016/S0140-6736(06)68845-4Abstract Full Text Full Text PDF PubMed Scopus (1677) Google Scholar The other trial, Apixaban Versus Acetylsalicylic Acid to Prevent Stroke in Atrial Fibrillation Patients Who Have Failed or Are Unsuitable for Vitamin K Antagonist Treatment (AVERROES) evaluated a non-vitamin K antagonist oral anticoagulant (NOAC) versus antiplatelet therapy. This trial randomized 5,599 patients with AF who were at increased risk for stroke and for whom VKA therapy was felt unsuitable or had been declined. They were randomized to receive apixaban or ASA (81 to 324 mg per day). The trial also had to be stopped by data and safety monitoring board due to overwhelming efficacy in the anticoagulation arm. The primary outcome, stroke or systemic embolism, occurred in 51 patients (1.6% per year) in the apixaban group versus 113 (3.7% per year) in the ASA group (HR with apixaban, 0.45; 95% confidence interval [CI],0.32 to 0.62; p <0.001). Bleeding was similar between full-dose apixaban and ASA (which was largely administered at the 81 mg daily dose), 1.4% per year with apixaban versus 1.2% per year with aspirin (HR with apixaban, 1.13; 95% p = 0.57); Thus, anticoagulation with apixaban reduced stroke by half without an increase in bleeding. As such, use of either ASA monotherapy or ASA plus clopidogrel is not recommended for stroke prevention in atrial fibrillation. For a patient with AF and at risk of stroke, anticoagulation is a necessary component of any antithrombotic regimen. Dual antiplatelet therapy was also felt to be necessary based on prior trials. Given the potency of P2Y12 inhibitors, however, investigators began to question whether ASA could be dropped to limit ongoing bleeding risk. The What is the Optimal antiplatelet and anticoagulant therapy in patients with oral anticoagulation and StenTing (WOEST) trial was the initial study evaluating triple versus double therapy.17Dewilde WJ Oirbans T Verheugt FWA Kelder JC De Smet BJGL Herrman J-P Adriaenssens T Vrolix M Heestermans AACM Vis MM Tijsen JGP van 't Hof AW ten Berg JM WOEST study investigatorsUse of clopidogrel with or without aspirin in patients taking oral anticoagulant therapy and undergoing percutaneous coronary intervention: an open-label, randomised, controlled trial.Lancet Lond Engl. 2013; 381: 1107-1115https://doi.org/10.1016/S0140-6736(12)62177-1Abstract Full Text Full Text PDF PubMed Scopus (1244) Google Scholar These investigators randomized patients who were taking oral anticoagulation with a VKA for any indication, including AFib in approximately 2/3 of patients, but also including mechanical heart valves or venous thromboembolism. Following PCI, all continued the oral anticoagulation and clopidogrel, and were randomized to continuing or dropping ASA, thus comparing triple versus double antithrombotic therapy. Patients randomized to double therapy had significantly lower rates of bleeding when compared with those randomized to triple therapy.17Dewilde WJ Oirbans T Verheugt FWA Kelder JC De Smet BJGL Herrman J-P Adriaenssens T Vrolix M Heestermans AACM Vis MM Tijsen JGP van 't Hof AW ten Berg JM WOEST study investigatorsUse of clopidogrel with or without aspirin in patients taking oral anticoagulant therapy and undergoing percutaneous coronary intervention: an open-label, randomised, controlled trial.Lancet Lond Engl. 2013; 381: 1107-1115https://doi.org/10.1016/S0140-6736(12)62177-1Abstract Full Text Full Text PDF PubMed Scopus (1244) Google Scholar Ischemic events were also lower in the double therapy arm, although the number of events was low, resulting in wide confidence intervals. Nevertheless, these data suggested that double therapy with an oral anticoagulant and P2Y12 inhibitor, without aspirin, was a very promising new strategy to reduce bleeding in patients with AFib undergoing PCI. The Open-Label, Randomized, Controlled, Multicenter Study Exploring 2 Treatment Strategies of Rivaroxaban and a Dose-Adjusted Oral Vitamin K Antagonist Treatment Strategy in Subjects with Atrial Fibrillation who Undergo Percutaneous Coronary Intervention (PIONEER18Gibson CM Mehran R Bode C Halperin J Verheugt FW Wildgoose P Birmingham M Ianus J Burton P van Eickels M Korjian S Daaboul Y et al.Prevention of bleeding in patients with atrial fibrillation undergoing PCI.N Engl J Med. 2016; 375: 2423-2434https://doi.org/10.1056/NEJMoa1611594Crossref PubMed Scopus (914) Google Scholar AF-PCI) trial was the first randomized trial to compare double vs triple therapy using a NOAC. Patients with AF who underwent PCI were randomized into 3 groups: a dual therapy group with rivaroxaban 15 mg plus P2Y12 inhibitor, rivaroxaban 2.5 mg 2 times per day plus P2Y12 inhibitor and ASA, or VKA plus a P2Y12 inhibitor and ASA. Of note, the dose in the dual therapy arm was 75% of the full anticoagulation dose, which has not been evaluated for reduction of stroke risk.18Gibson CM Mehran R Bode C Halperin J Verheugt FW Wildgoose P Birmingham M Ianus J Burton P van Eickels M Korjian S Daaboul Y et al.Prevention of bleeding in patients with atrial fibrillation undergoing PCI.N Engl J Med. 2016; 375: 2423-2434https://doi.org/10.1056/NEJMoa1611594Crossref PubMed Scopus (914) Google Scholar The primary end point was the rate of clinically significant bleeding, a composite of Thrombolysis in Myocardial Infarction (TIMI) major/minor bleeding or bleeding requiring medical attention. The risk of bleeding was lower in the dual therapy group as well as in the low-dose rivaroxaban triple therapy group compared with VKA triple therapy (16.8% vs 18.0% vs 26.7%, p<0.001). There were no significant differences in a composite end point of death, myocardial infarction (MI), or stroke between the rivaroxaban 15 mg plus P2Y12 inhibitor and the VKA plus DAPT cohort (HR 1.08; 95%CI 0.69 to 1.68), although the number of events was low and the study was not powered for ischemic outcomes.18Gibson CM Mehran R Bode C Halperin J Verheugt FW Wildgoose P Birmingham M Ianus J Burton P van Eickels M Korjian S Daaboul Y et al.Prevention of bleeding in patients with atrial fibrillation undergoing PCI.N Engl J Med. 2016; 375: 2423-2434https://doi.org/10.1056/NEJMoa1611594Crossref PubMed Scopus (914) Google Scholar The next trial comparing dual versus triple therapy was the Randomized Evaluation of Dual Antithrombotic Therapy with Dabigatran versus Triple Therapy with Warfarin in Patients with Nonvalvular Atrial Fibrillation Undergoing Percutaneous Coronary Intervention (RE-DUAL-PCI), which compared double therapy with 2 different doses of dabigatran (110 mg twice daily and 150 mg twice daily) as compared with triple therapy with VKA.19Cannon CP Bhatt DL Oldgren J Lip GYH Ellis SG Kimura T Maeng M Merkely B Zeymer U Gropper S Nordaby M Kleine E Harper R Manassie J Januzzi JL Ten Berg JM Steg PG Hohnloser SH RE-DUAL PCI Steering Committee and InvestigatorsDual antithrombotic therapy with dabigatran after PCI in atrial fibrillation.N Engl J Med. 2017; 377: 1513-1524https://doi.org/10.1056/NEJMoa1708454Crossref PubMed Scopus (755) Google Scholar Taking into account the results of WOEST and PIONEER AF-PCI, the "triple therapy" strategy tested in RE-DUAL PCI only lasted 3 months for patients who had a drug eluting stent, and 1 month for those with a bare metal stent, after which it was de-escalated to dual therapy. The primary end point of International Society on Thrombosis and Haemostasis (ISTH) major or clinically relevant non-major bleeding was significantly reduced in both dabigatran dual therapy groups: in the dabigatran 110 mg (HR 0.52; 95%CI 0.42 to 0.63) and 150 mg (HR 0.72; 95%CI 0.58 to 0.88) as compared with triple therapy with VKA.19Cannon CP Bhatt DL Oldgren J Lip GYH Ellis SG Kimura T Maeng M Merkely B Zeymer U Gropper S Nordaby M Kleine E Harper R Manassie J Januzzi JL Ten Berg JM Steg PG Hohnloser SH RE-DUAL PCI Steering Committee and InvestigatorsDual antithrombotic therapy with dabigatran after PCI in atrial fibrillation.N Engl J Med. 2017; 377: 1513-1524https://doi.org/10.1056/NEJMoa1708454Crossref PubMed Scopus (755) Google Scholar Notably, the rates of intracranial hemorrhage were lower in the dabigatran double therapy cohorts as compared with VKA triple therapy. A pre-specified non-inferiority analysis found no difference in rates of combined thrombotic events or death between the dual and triple therapy groups. The rate was 13.7% in the 2 dual-therapy groups combined versus 13.4% for VKA triple therapy (HR, 1.04; 95% CI, 0.84 to 1.29; p = 0.005 for noninferiority).19Cannon CP Bhatt DL Oldgren J Lip GYH Ellis SG Kimura T Maeng M Merkely B Zeymer U Gropper S Nordaby M Kleine E Harper R Manassie J Januzzi JL Ten Berg JM Steg PG Hohnloser SH RE-DUAL PCI Steering Committee and InvestigatorsDual antithrombotic therapy with dabigatran after PCI in atrial fibrillation.N Engl J Med. 2017; 377: 1513-1524https://doi.org/10.1056/NEJMoa1708454Crossref PubMed Scopus (755) Google Scholar Multiple subgroups of patients have been evaluated from the RE-DUAL PCI cohort and all have yielded the same pattern, with lower risk of bleeding with the dual therapy strategy vs. warfarin triple therapy. These include patients with ACS versus stable CAD, with and without diabetes, those receiving a drug eluting stent vs. bare metal stent, older and younger patients.20Oldgren J Steg PG Hohnloser SH Lip GYH Kimura T Nordaby M Brueckmann M Kleine E Ten Berg JM Bhatt DL Cannon CP Dabigatran dual therapy with ticagrelor or clopidogrel after percutaneous coronary intervention in atrial fibrillation patients with or without acute coronary syndrome: a subgroup analysis from the RE-DUAL PCI trial.Eur Heart J. 2019; 40: 1553-1562https://doi.org/10.1093/eurheartj/ehz059Crossref PubMed Scopus (46) Google Scholar, 21Maeng M Steg PGabriel Bhatt DL Hohnloser SH Nordaby M Miede C Kimura T Lip GYH Oldgren J Ten Berg JM Cannon CP RE-DUAL PCI Steering Committee and InvestigatorsDabigatran dual therapy versus warfarin triple therapy post-PCI in patients with atrial fibrillation and diabetes.JACC Cardiovasc Interv. 2019; 12: 2346-2355https://doi.org/10.1016/j.jcin.2019.07.059Crossref PubMed Scopus (8) Google Scholar, 22Ten Berg JM Steg PG Bhatt DL Hohnloser SH de Veer A Nordaby M Miede C Kimura T Lip GYH Oldgren J Cannon CP RE-DUAL PCI Steering Committee and InvestigatorsComparison of the effect of age (< 75 Versus ≥ 75) on the efficacy and safety of dual therapy (Dabigatran + Clopidogrel or Ticagrelor) versus triple therapy (Warfarin + Aspirin + Clopidogrel or Ticagrelor) in patients with atrial fibrillation after percutaneous coronary intervention (from the RE-DUAL PCI Trial).Am J Cardiol. 2020; 125: 735-743https://doi.org/10.1016/j.amjcard.2019.11.029Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar In addition, the complexity of the PCI and risk scores of both ischemic events and bleeding events have all been examined – with the same benefit of dual therapy seen over triple therapy.23Berry NC Mauri L Steg PG Bhatt DL Hohnloser SH Nordaby M Miede C Kimura T Lip GYH Oldgren J Ten Berg JM Cannon CP Effect of lesion complexity and clinical risk factors on the efficacy and safety of dabigatran dual therapy versus warfarin triple therapy in atrial fibrillation after percutaneous coronary intervention: a subgroup analysis from the REDUAL PCI trial.Circ Cardiovasc Interv. 2020; 13e008349https://doi.org/10.1161/CIRCINTERVENTIONS.119.008349Crossref PubMed Scopus (11) Google Scholar,24Lip GYH Mauri L Montalescot G Ozkor M Vardas P Steg PG Bhatt DL Hohnloser SH Miede C Nordaby M Brueckmann M Kreuzer J Kimura T Oldgren J Ten Berg JM Cannon CP Relationship of stroke and bleeding risk profiles to efficacy and safety of dabigatran dual therapy versus warfarin triple therapy in atrial fibrillation after percutaneous coronary intervention: an ancillary analysis from the RE-DUAL PCI trial.Am Heart J. 2019; 212: 13-22https://doi.org/10.1016/j.ahj.2019.02.006Crossref PubMed Scopus (8) Google Scholar The Antithrombotic Therapy after Acute Coronary Syndrome or PCI in Atrial Fibrillation (AUGUSTUS) trial compared regimens with both VKA and apixaban in a 2 × 2 factorial design to either apixaban or VKA, and then to either a P2Y12 inhibitor with ASA or placebo. This study randomized patients with AF who underwent PCI and or who presented with ACS. The primary end point of ISTH major bleeding and clinically relevant non-major bleeding was reduced with apixaban compared with VKA (HR, 0.69; 95%CI 0.58 to 0.81). The composite rate of bleeding was increased with ASA versus placebo (HR 1.89; 95%CI 1.59 to 2.24). Apixaban was associated with a reduction in the risk of death or hospitalization versus VKA (23.5% vs 27.4%; HR, 0.83; 95% CI, 0.74 to 0.93; p = 0.002); there was a similar incidence of ischemic events. The risk of these end points was similar comparing aspirin and placebo.25Lopes RD Heizer G Aronson R Vora AN Massaro T Mehran R Goodman SG Windecker S Darius H Li J Averkov O Bahit MC Berwanger O Budaj A Hijazi Z Parkhomenko A Sinnaeve P Storey RF Thiele H Vinereanu D Granger CB Alexander JH AUGUSTUS InvestigatorsAntithrombotic therapy after acute coronary syndrome or PCI in atrial fibrillation.N Engl J Med. 2019; 380: 1509-1524https://doi.org/10.1056/NEJMoa1817083Crossref PubMed Scopus (453) Google Scholar An analysis of stent thrombosis was also performed in AUGUSTUS.26Lopes RD Leonardi S Wojdyla DM Vora AN Thomas L Storey RF Vinereanu D Granger CB Goodman SG Aronson R Windecker S Thiele H Valgimigli M Mehran R Alexander JH Stent thrombosis in patients with atrial fibrillation undergoing coronary stenting in the AUGUSTUS Trial.Circulation. 2020; 141: 781-783https://doi.org/10.1161/CIRCULATIONAHA.119.044584Crossref PubMed Scopus (49) Google Scholar The number (proportion) of patients with definite or probable stent thrombosis at 6 months did not differ significantly but followed a pattern: it was lowest for apixaban plus ASA (5, 0.57%), followed by VKA plus ASA (6, 0.69%), then apixaban without ASA (8, 0.91%) and was highest for VKA without ASA (11, 1.26%). The rates tended to be lower with use of ASA. Although these differences were not significant, using point estimates alone, the number needed to treat to avoid 1 stent thrombosis was 222 for ASA versus placebo while the number needed to harm, to cause 1 major bleeding event, was 41.26Lopes RD Leonardi S Wojdyla DM Vora AN Thomas L Storey RF Vinereanu D Granger CB Goodman SG Aronson R Windecker S Thiele H Valgimigli M Mehran R Alexander JH Stent thrombosis in patients with atrial fibrillation undergoing coronary stenting in the AUGUSTUS Trial.Circulation. 2020; 141: 781-783https://doi.org/10.1161/CIRCULATIONAHA.119.044584Crossref PubMed Scopus (49) Google Scholar The final triple vs. double therapy trial was the Edoxaban Treatment versus Vitamin K Antagonists in Patients with Atrial Fibrillation Undergoing Percutaneous Coronary Intervention (ENTRUST-AF PCI) trial. This trial compared edoxaban and clopidogrel to VKA, clopidogrel, and ASA in patients with AF who underwent PCI.27Vranckx P Valgimigli M Eckardt L Tijssen J Lewalter T Gargiulo G Batushkin V Campo G Lysak Z Vakaliuk I Milewski K Laeis P Reimitz P-E Smolnik R Zierhut W Goette A Edoxaban-based versus vitamin K antagonist-based antithrombotic regimen after successful coronary stenting in patients with atrial fibrillation (ENTRUST-AF PCI): a randomised, open-label, phase 3b trial.The Lancet. 2019; 394: 1335-1343https://doi.org/10.1016/S0140-6736(19)31872-0Abstract Full Text Full Text PDF PubMed Scopus (258) Google Scholar The rate of major or clinically relevant bleeding was not significantly reduced in the edoxaban dual therapy group (17%) versus VKA triple therapy (20%, HR, 0.83 (95% CI 0.65 to 1.05; p = 0.0010 for noninferiority, p = 0.12 for superiority). The main efficacy outcome (composite of CVD, stroke, systemic embolic event, MI, or definite stent thrombosis) revealed annualized event rates of 7.3% for edoxaban double therapy versus 6.9% for VKA triple therapy (HR, 1.06 [0.71 to 1.69]). Thus, the findings were generally consist
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