Antithrombotics after TAVR: seeking an optimal strategy in an unsolved game

April 24th Hot Topics Session of TCTAP 2021 Virtual

Duk-Woo Park, MD (Asan Medical Center, Seoul, South 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 (<3 months) and suggests considering a shorter DAPT (one- to three-months for chronic coronary syndromes and three- to six-months for acute coronary syndromes) for patients without OAC indications, or post-stenting DAT (avoiding the prolonged triple antithrombotic therapy) for patients needing OAC7.

A topic of interest in this field involves the subclinical leaflet thrombosis - a frequent phenomenon identifiable in up to a quarter of TAVR patients on antiplatelet therapy. However, radiological hypoattenuated leaflet thickening (HALT) and hypoattenuation affecting motion (HAM) can be reversed by OAC initiation or even regress spontaneously without changing antithrombotic therapy. Meanwhile, the clinical impact of subclinical thrombosis remains unknown.

Another undeciphered aspect concerns the type of OAC for this population: whether TAVR patients are best treated with VKA or NOAC is unknown. Ongoing RCTs (Table 1) are assessing the safety and efficacy of antithrombotic regimens including apixaban (ATLANTIS8) and edoxaban (ENVISAGE TAVI-AF9 and ADAPT-TAVR10). An overview of the available RCTs is presented in Table 1.

Finally, finding the optimal antithrombotic regimen after TAVR can have significant repercussions on the direct comparison of transcatheter and surgical aortic valve replacement, Park said, noting that a non-negligible number of events occurring in the TAVR subgroup could be related to improper antithrombotic therapy, reducing the overall benefit of the less invasive strategy. Park said, ¡°The optimum strategy is not simple to achieve, considering the TAVR procedure along with alternative access sites and valve-in-valve implantation are all under-represented in the currently published RCTs, and patients¡¯ characteristics, comorbidities, and/or co-medications can predispose them to bleeding and thrombosis complications. Despite available evidence suggesting minimalistic antithrombotic strategies after TAVR, the issue is still not fully addressed and the puzzle not yet completely solved.¡±

Reference

  1. Ussia GP, Scarabelli M, Mulè M, et al. Dual antiplatelet therapy versus aspirin alone in patients undergoing transcatheter aortic valve implantation. Am J Cardiol. 2011 Dec 15;108(12):1772-6.
  2. Rodés-Cabau J, Masson JB, Welsh RC, et al.
    Aspirin Versus Aspirin Plus Clopidogrel as Antithrombotic Treatment Following Transcatheter Aortic Valve Replacement With a Balloon-Expandable Valve: The ARTE (Aspirin Versus Aspirin + Clopidogrel Following Transcatheter Aortic Valve Implantation) Randomized Clinical Trial. JACC Cardiovasc Interv. 2017 Jul 10;10(13):1357-1365.
  3. Dangas GD, Tijssen JGP, Wöhrle J, et al.
    A Controlled Trial of Rivaroxaban after Transcatheter Aortic-Valve Replacement. N Engl J Med. 2020 Jan 9;382(2):120-129.
  4. Otto CM, Nishimura RA, Bonow RO, et al. 2020 ACC/AHA Guideline for the Management of Patients With Valvular Heart Disease: Executive Summary: A Report of the American College of Cardiology/American Heart Association Joint Committee onClinical Practice Guidelines. J Am Coll Cardiol. 2021 Feb 2;77(4):450-500.
  5. Nijenhuis VJ, Brouwer J, Delewi R, et al. Anticoagulation with or without Clopidogrel after Transcatheter Aortic-Valve Implantation. N Engl J Med. 2020 Apr 30;382(18):1696-1707. doi: 10.1056/NEJMoa1915152. Epub 2020 Mar 29.PMID: 32223116 Clinical Trial.
  6. Brouwer J, Nijenhuis VJ, Delewi R, et al. Aspirin with or without Clopidogrel after Transcatheter Aortic-Valve Implantation. N Engl J Med. 2020 Oct 8;383(15):1447-1457. doi: 10.1056/NEJMoa2017815. Epub 2020 Aug 30.
  7. Ten Berg J, Sibbing D, Rocca B, et al. Management of antithrombotic therapy in patients undergoing transcatheter aortic valve implantation: a consensus document of the ESC Working Group on Thrombosis and the European Association of Percutaneous Cardiovascular Interventions (EAPCI), in collaboration with the ESC Council on Valvular Heart Disease. Eur Heart J. 2021 Apr 5:ehab196.
  8. Collet JP, Berti S, Cequier A, et al. Oral anti-Xa anticoagulation after trans-aortic valve implantation for aortic stenosis: The randomized ATLANTIS trial. Am Heart J. 2018 Jun;200:44-50.
  9. Van Mieghem NM, Unverdorben M, Valgimigli M, et al. Edoxaban Versus standard of care and their effects on clinical outcomes in patients having undergone Transcatheter Aortic Valve Implantation in Atrial Fibrillation-Rationale and design of the ENVISAGE-TAVI AF trial. Am Heart J. 2018 Nov;205:63-69.
  10. Park H, Kang DY, Ahn JM, et al. Rationale and design of the ADAPT-TAVR trial: a randomised comparison of edoxaban and dual antiplatelet therapy for prevention of leaflet thrombosis and cerebral embolisation after transcatheter aortic valve replacement. BMJ Open. 2021 Jan 5;11(1):e042587.

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 ¡¾ antiplatelet therapy vs VKA ¡¾ 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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Editor: Alfonso Ielasi, MD (Interventional and Clinical Cardiology Unit, Istituto Clinico Sant¡¯ Ambrogio, Milan, Italy)

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