TCTAP 2021 Virtual
Antithrombotics after TAVR: seeking an optimal strategy in an unsolved game
Duk-Woo Park, MD, PhD (Asan Medical Center, Korea), addressed issues related to optimal antithrombotic regimen in patients treated with transcatheter aortic valve replacement (TAVR) during a lecture presented at TCTAP 2021 Virtual that kicked off April 21. Park highlighted the most relevant recent trial results and underscored the benefits of oral anticoagulation (OAC) monotherapy and single antiplatelet therapy (SAPT) in patients with and without pre-TAVR indication for OAC, respectively. He pointed out that despite the data concerning the association between antithrombotic regimen and subclinical trans-catheter heart valve thrombosis, a clear link between this phenomenon and hard adverse clinical events has yet to be demonstrated. Thromboembolic and bleeding complications still remain common adverse events after TAVR. For a considerable time, the proposed recommendations concerning management of antithrombotic therapy in patients undergoing TAVR were based on expert opinion, with treatment strategies empirically on par with the ones adopted in percutaneous coronary intervention (PCI). In 2011, a research team led by Gian Ussia, MD (Ferrarotto Hospital, University of Catania, Italy)1did not find superiority of adding clopidogrel to aspirin for three months after TAVR in a small randomized sample size. In 2017, the ARTE randomized controlled trial (RCT) on 222 patients showed SAPT (versus dual antiplatelet therapy, DAPT) tended to reduce the occurrence of early major adverse events following TAVR2. Only in recent years have new RCTs reassessed the issue, shedding light on existing uncertainties. In fact, the GALILEO randomized controlled trial published in 2019 proved for the first time that - in patients without an established indication for OAC after TAVR - a treatment strategy including rivaroxaban (10mg daily) was associated with a higher risk of death or thromboembolic complications and a higher risk of bleeding than an antiplatelet-based strategy3. Based on the evidence, the 2020 ACC/AHA Guideline on the management of patients with valvular heart disease suggested SAPT and three- to six-month DAPT for TAVR recipients as “reasonable” strategies in the absence of other indications for OAC, albeit without a strong level of evidence(respectively, COR:2a/LOE B and COR:2b/LOE:B)4. Recently, important new findings have emerged from the POPular TAVI trial last March and October. The RCT was designed to assess outcomes in two different cohorts: cohort B and A. In cohort B, patients before TAVR were randomized 1:1 ratio to either not receive clopidogrel or to receive clopidogrel for three months in addition to OAC for appropriate indications. In cohort A, TAVR patients without an indication for long-term OAC were randomized in a 1:1 ratio to receive aspirin alone versus aspirin plus clopidogrel for three months. One-year primary outcomes were defined as all bleeding and non-procedure-related bleeding. The two one-year secondary outcomes were a composite of death from cardiovascular causes, non-procedure-related bleeding, stroke, or myocardial infarction (MI) and a composite of death from cardiovascular causes, ischemic stroke, or MI. In cohort B, OAC alone was associated with a lower incidence of serious bleeding events than dual antithrombotic therapy (DAT) (primary endpoints’ RR 0.63 and 0.64; 95% CI 0.43-0.90 and 0.44-0.92; P values 0.01 and 0.02, respectively); yet, OAC alone was respectively superior and non-inferior concerning the two assessed secondary endpoints5. In cohort A, the one-year incidence of bleeding (primary endpoints’ RR 0.57 and 0.61; 95% CI 0.42-0.77 and 0.44-0.83; P values 0.001 and 0.005, respectively) and the composite of bleeding or thromboembolic events (RR 0.74; 95% CI for superiority, 0.57-0.95; P=0.04) were significantly less frequent with SAPT than with DAPT administered for three months6. The recently published European Society of Cardiology (ESC) consensus document for TAVR patients not treated with PCI in the previous three months7 endorsed the evidence from these trials. The consensus document underscores that the choice of the optimal antithrombotic regimen is complex in TAVR patients undergoing recent PCI ( First Author/Trial Year Compared Strategies Populations Primary Endpoints Timeline Main Result Ussia et al1 2011 3-months DAPT vs. ASA 79 patients without underlying indication for OAC or recent stent implantation Composite of death, MI, major stroke, LTB, or urgent conversion to surgery 6 months Primary end point: No significant difference for SAPT vs DAPT (15% vs. 18% respectively; p=0.85) Rodés-Cabau et al/ARTE2 2017 3-months DAPT vs. ASA 222 patients without underlying indication for OAC or recent stent implantation Composite of death, MI, stroke or TIA, or LTMB 3 months Primary end point: 15.3% vs. 7.2% for DAPT and SAPT respectively (OR, 2.31; 95% CI, 0.95-5.62; P=0.065) Dangas et al/GALILEO3 2019 Rivaroxaban 10 mg + 3-months ASA vs. ASA+ 3-mo Clopidogrel 1644 patients without an established indication for OAC Death, any stroke, MI, symptomatic valve thrombosis, DVT/PE, non-central nervous system systemic embolism, life- threatening, disabling or major VARC-2 bleeding 17 months Primary end point: 9.8% vs. 7.2% for DAT vs. DAPT (OR, 1.35; 95% confidence CI, 1.01-1.81; P=0.04) Brouwer J et al/POPULAR TAVI - Cohort A6 2020 3-months DAPT vs ASA 665 patients without an established indication for OAC 1)All bleeding (including minor, major, and life-threatening or disabling bleeding) and 2)Non-procedure-related bleeding 12 months Primary end points: 1) 15.1% vs. 26.6% for SAPT and DAPT respectively (OR, 0.57; 95% CI, 0.42-0.77; P=0.001) and 2) 15.1% vs. 24.9% for SAPT and DAPT respectively (OR, 0.61; 95% CI, 0.44-0.83; P=0.005) Nijenhuis VJ et al/ POPULAR TAVI - Cohort B5 2020 OAC + 3-months clopidrogrel vs OAC alone 326 patients receiving OAC for appropriate indications 1)all bleeding (including minor, major, and life-threatening or disabling bleeding) and 2)non-procedure-related bleeding 12 months Primary end points: 1) 21.7% vs. 34.6% for OAC alone and DAT respectively (OR, 0.63; 95% CI, 0.43-0.90; P=0.01) and 2) 21.7% vs. 34% for OAC alone and DAT respectively (OR, 0.64; 95% CI, 0.44-0.92; P=0.02) Collet JP et al/ ATLANTIS8 Ongoing Apixaban vs. standard of care Estimated 1509 patients Efficacy: Death, MI, stroke, systemic emboli, bioprosthesis thrombus, DVT/PE; safety: life-threatening, disabling or major VARC-2 bleeding 12 months - Van Mieghem NM et al/ENVISAGE-TAVI AF9 Ongoing Edoxaban ± antiplatelet therapy vs VKA ± antiplatelet therapy Estimated 1400 patients with atrial fibrillation Efficacy: death, MI, stroke, systemic embolism, valve thrombosis, ISTH major VARC-2 bleeding; Safety: ISTH major bleeding 24 months - Park H et al/ ADAPT-TAVR10 Ongoing 6-months Edoxaban vs. 6-months ASA+clopidogrel Estimated 220 patients without indication for long-term OAC Leaflet thrombosis of 4 dimension-computed tomography scan 6 months - ASA: acetylsalicylic acid; CI: confidence interval; DAPT: dual antiplatelet therapy; DAT: dual antithrombotic therapy; DVT: deep vein thrombosis; ISTH: International Society of Thrombosis and Haemostasis; LTB: life-threatening bleeding; LTMB: life-threatening and major bleeding; MI: myocardial infarction; OAC: oral anticoagulation; OR: odds ratio; PE: pulmonary embolism; SAPT: single antiplatelet therapy; TIA: transient ischemic attack; VARC-2: Valve Academic Research criteria; VKA: vitamin K antagonist. 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