Optimising pharmacology after transcatheter aortic valve replacement: Lessons from the POPular TAVI trial

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(l-r) Harold Dauerman, Rony Lahoud and Newton Phuong

Writing for Cardiovascular News, Harold Dauerman, Rony Lahoud and Newton Phuong from the University of Vermont Larner College of Medicine, Burlington, USA reflect on the implications of the POPular TAVI trial and how it is shaping approaches to antiplatelet therapy after TAVI.

Patients undergoing transcatheter aortic valve implantation (TAVI) face dual risks: platelet dysfunction, thrombocytopenia and acquired von Willebrand’s disease are associated with enhanced bleeding complications1,2, yet platelet activation and thrombotic complications may also occur3.  During the first decade of TAVI, the default pharmacologic approach has been defined by the history of coronary intervention, foreign body mediated platelet activation and thrombosis concerns: thus, post TAVI patients are prescribed dual antiplatelet therapy for three‒six months (in situations that do not require oral anticoagulation)4,5.

This approach though may ignore two unique facts related to TAVI technology and patients: (1) Patients undergoing surgical bioprosthetic aortic valve replacement do not require dual antiplatelet therapy—why would a transfemoral bioprosthetic aortic valve require a different post procedure pharmacology than an open sternotomy bioprosthetic aortic valve? (2) Patients with severe aortic stenosis have a long, unique history of bleeding risk related to gastrointestinal dysplasia and acquired von Willebrand’s disease: this enhanced bleeding risk is not routinely encountered in patients with acute coronary syndromes and coronary stenting. We have previously shown that patients undergoing TAVI have a unique haemostatic defect demonstrated by less thrombin generation and a significant prolongation of clotting time consistent with a differential risk of bleeding compared to patients undergoing PCI for AMI6. Randomised clinical trials are just now beginning to clarify optimal pharmacology with respect to the unique population and risk set inherent in the severe AS population.

Recently, the POPular TAVI trial reported  important findings from the randomised cohort A7: 665 TAVI patients (with no indication for oral anticoagulation) were randomised to oral single versus dual antiplatelet therapy for three months. The results are consistent with the hypothesis that TAVI patients present a unique and heightened risk of bleeding: 15.1% of patients receiving aspirin alone and 26.6% of patients receiving aspirin plus clopidogrel had bleeding events within 12 months of the procedure (p=0.001). It should be noted that a dual antiplatelet regimen resulted in increased bleeding across multiple severity classifications: minor, as well as major, life-threatening or disabling bleeding. The dual antiplatelet regimen also increased non-procedural bleeding (15.1% vs. 24.9%; p=0.005), somewhat strangely defined as non-BARC 4 related severe bleeds even if they occurred at the access site. A composite secondary outcome of non-procedural bleeding and thromboembolic events (cardiovascular death, stroke, myocardial infarction) demonstrated superiority for aspirin vs. aspirin and clopidogrel (23% vs. 31%, p=0.04).  In addition to the somewhat unusual method of classifying procedural vs non-procedural bleeding, two caveats should be noted: (1) The trial was not adequately powered to compare thromboembolic complications alone. (2) The results can not comment on the influence of antiplatelet or anticoagulation therapy on potential valve failure due to leaflet thickening or thrombosis.

What if we used a shorter duration (ie, 30 days instead of three months) of dual antiplatelet regimen in an effort to mitigate thrombotic and bleeding risks simultaneously? POPular TAVI  would not support such an approach. Nearly all bleeding events occurred in the first 30 days, with a majority of events actually occurring in the first 48 hours (67.4% and 76% of all bleeding events on dual or single antiplatelet regimen respectively). Importantly, the risk of bleeding within 48 hours of the procedure was higher for patients on a dual vs. single therapy (18 % vs. 11.5%, p=0.02).

These findings are consistent with three other recent trials that suggest no benefit for more intense antiplatelet therapy or anticoagulation as a routine strategy after TAVI: ARTE8, POPular TAVI cohort B9  and GALILEO trials10. The ARTE trial included 222 TAVI patients randomised to single vs. double antiplatelet therapy. Patients on aspirin and clopidogrel had a higher rate of major or life-threatening bleeding events (10.8% vs. 3.6% in the aspirin group, p=0.038). The composite of death, MI, stroke, transient ischaemic attack, or major/life-threatening bleeding tended to occur more frequently in the DAPT group (15.3% vs. 7.2%, p = 0.065)8. In the randomised POPular TAVI cohort B (n=326)), there was a higher one-year incidence of bleeding among TAVI patients receiving oral anticoagulation plus clopidogrel than among those receiving oral anticoagulation alone (34.6% vs. 21.7%, p=0.01)9. Finally, the GALILEO trial (N=1,644) of rivaroxaban plus three months of aspirin as compared with clopidogrel plus three months of aspirin after TAVI was stopped prematurely because of excess mortality in the rivaroxaban group10.

TAVI patient populations, technology and procedural simplifications have expanded dramatically over the past decade. As these recent trials demonstrate, it is time for post TAVI pharmacology to similarly grow and clarify. The high burden of bleeding will continue to be a challenge in the severe aortic stenosis population. While methods to safely prevent valve failure, thrombosis and stroke continue to be unclear,  the clarity of these recent trials regarding bleeding risks and TAVI pharmacology have already changed our practice: we currently use aspirin alone following TAVI, unless patients have had recent coronary stenting or indications for oral anticoagulation. We believe that the POPular TAVI trial will heighten clinical awareness of bleeding risks with routine intensive antiplatelet therapy after TAVI and lead to a future modification of both guidelines and clinical practice with respect to optimal post TAVI pharmacology.

References

  1. De Larochelliere H, Puri R, Eikelboom JW, Rodes-Cabau J. Blood Disorders in Patients Undergoing Transcatheter Aortic Valve Replacement: A Review. JACC Cardiovasc Interv 2019;12:1-11.
  2. Kibler M, Marchandot B, Messas N, et al. Primary Hemostatic Disorders and Late Major Bleeding After Transcatheter Aortic Valve Replacement. J Am Coll Cardiol 2018;72:2139-48.
  3. Jimenez Diaz VA, Tello-Montoliu A, Moreno R, et al. Assessment of Platelet REACtivity After Transcatheter Aortic Valve Replacement: The REAC-TAVI Trial. JACC Cardiovasc Interv 2019;12:22-32.
  4. Baumgartner H, Falk V, Bax JJ, et al. 2017 ESC/EACTS Guidelines for the management of valvular heart disease. Eur Heart J 2017;38:2739-91.
  5. Nishimura RA, Otto CM, Bonow RO, et al. 2017 AHA/ACC Focused Update of the 2014 AHA/ACC Guideline for the Management of Patients With Valvular Heart Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2017;70:252-89.
  6. Dauerman HL, DeStephan CM, Sommer HT, et al. Prolonged Clotting Time Among Patients Undergoing Transcatheter Aortic Valve Replacement. J Am Coll Cardiol 2019;74:820-1.
  7. Brouwer J, Nijenhuis VJ, Delewi R, et al. Aspirin with or without Clopidogrel after Transcatheter Aortic-Valve Implantation. N Engl J Med 2020;383:1447-57.
  8. Rodes-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;10:1357-65.
  9. Nijenhuis VJ, Brouwer J, Delewi R, et al. Anticoagulation with or without Clopidogrel after Transcatheter Aortic-Valve Implantation. N Engl J Med 2020;382:1696-707.
  10. Dangas GD, Tijssen JGP, Wohrle J, et al. A Controlled Trial of Rivaroxaban after Transcatheter Aortic-Valve Replacement. N Engl J Med 2020;382:120-9.

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