Antithrombotic Regimens in Low-Risk Patients Undergoing Transcatheter Aortic Valve Replacement
2021; Lippincott Williams & Wilkins; Volume: 14; Issue: 1 Linguagem: Inglês
10.1161/circinterventions.120.010331
ISSN1941-7632
AutoresAlexander C. Fanaroff, Renato D. Lópes,
Tópico(s)Antiplatelet Therapy and Cardiovascular Diseases
ResumoHomeCirculation: Cardiovascular InterventionsVol. 14, No. 1Antithrombotic Regimens in Low-Risk Patients Undergoing Transcatheter Aortic Valve Replacement Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyRedditDiggEmail Jump toFree AccessEditorialPDF/EPUBAntithrombotic Regimens in Low-Risk Patients Undergoing Transcatheter Aortic Valve ReplacementTrials Evaluating Patient-Centered Outcomes Needed Alexander C. Fanaroff, MD, MHS Renato D. LopesMD, PhD, MHS Alexander C. FanaroffAlexander C. Fanaroff Penn Cardiovascular Outcomes, Quality and Evaluative Research Center, Leonard Davis Institute, and Cardiovascular Medicine Division, University of Pennsylvania, Philadelphia (A.C.F). , Renato D. LopesRenato D. Lopes Correspondence to: Renato D. Lopes, MD, PhD, Duke Clinical Research Institute, P.O. Box 17969, Durham, NC 27715. Email E-mail Address: [email protected] https://orcid.org/0000-0003-2999-4961 Foundation for Cardiovascular Medicine, San Diego, CA.Duke Clinical Research Institute, and Division of Cardiology, Duke University School of Medicine, Durham, NC (R.D.L.). Originally published11 Jan 2021https://doi.org/10.1161/CIRCINTERVENTIONS.120.010331Circulation: Cardiovascular Interventions. 2021;14:e010331This article is a commentary on the followingRandomized Trial of Aspirin Versus Warfarin After Transcatheter Aortic Valve Replacement in Low-Risk PatientsSee Article by Rogers et alChoice of antithrombotic therapy following transcatheter aortic valve replacement (TAVR) has been evaluated in several recent clinical trials. Initially, consensus guidelines recommended dual antiplatelet therapy with aspirin plus clopidogrel based on expert opinion. Responding to concerns regarding subclinical leaflet thrombosis raised in observational studies, GALILEO (Global Study Comparing a Rivaroxaban-Based Antithrombotic Strategy to an Antiplatelet-Based Strategy After Transcatheter Aortic Valve Replacement to Optimize Clinical Outcomes) studied the efficacy and safety of rivaroxaban 10 mg daily compared with dual antiplatelet therapy. Although rivaroxaban reduced the incidence of subclinical leaflet thrombosis as compared with dual antiplatelet therapy, it increased major bleeding and all-cause mortality, and the study was stopped prematurely.1,2 Subsequently, the POPular-TAVI trial (Antiplatelet Therapy for Patients Undergoing Transcatheter Aortic-Valve Implantation), confirming results from a smaller trial, demonstrated that aspirin monotherapy caused fewer major bleeding events than dual antiplatelet therapy, with a similar number of ischemic events, in patients without a formal indication for oral anticoagulation.3 Overall, the current state of the evidence suggests that aspirin alone is the optimal antithrombotic regimen in the population of patients undergoing TAVR.However, the population of patients undergoing TAVR continues to evolve. Pivotal clinical trials conducted over the past 10 years demonstrated the safety and efficacy of TAVR as compared with surgical aortic valve replacement in increasingly younger and lower-risk patients.4,5 Patients enrolled in GALILEO and POPular-TAVI had a mean age of 80 and a mean predicted surgical mortality >2.5%; patients enrolled in the low-risk TAVR trials had a mean age of 73 and a mean predicted surgical mortality <2%.1,3–5 As TAVR is increasingly used in younger patients with long expected post-procedure lifespans, long-term valve durability becomes an important consideration. The phenomenon of subclinical leaflet thrombosis was identified serendipitously on post-TAVR cardiac computed tomography obtained as part of a clinical trial protocol and was subsequently observed in a systematic registry of patients undergoing both TAVR and surgical aortic valve replacement with bioprosthetic valves.6 These observational studies showed that patients treated with oral anticoagulation were less likely to develop subclinical leaflet thrombosis and that computed tomography findings of subclinical leaflet thrombosis—including hypoattenuated leaflet thickening and reduced leaflet motion—resolved with anticoagulant treatment.6 There is limited data on the effect of early subclinical leaflet thrombosis on long-term valve durability, but a single-center study of 83 patients with surgical bioprosthetic valve leaflet thrombosis showed an association between valve thrombosis and need for valve replacement at 10-year follow-up.7 The optimal antithrombotic therapy to strike the appropriate balance between short-term major bleeding and the long-term risk of subclinical leaflet thrombosis and early valve degeneration is likely to differ based on the age and projected post-TAVR lifespan of individual patients, with short-term bleeding a more important consideration in older patients and long-term durability a more important consideration in younger patients.In this issue of Circulation: Cardiovascular Interventions, Rogers et al8 present the results of an open-label randomized controlled trial that informs the balance between bleeding and subclinical leaflet thrombosis in younger, low-risk patients. In the low-risk TAVR (LRT) 2.0 trial, low-risk patients undergoing transfemoral TAVR for aortic stenosis with no indication for anticoagulation were randomized 1:1 to 30 days of treatment with low-dose aspirin or low-dose aspirin plus warfarin dose adjusted to achieve an international normalized ratio of 2.5. Enrolled patients had a mean age of 73 and predicted surgical mortality risk of 1.5%, similar to the pivotal trials assessing TAVR versus surgical aortic valve replacement in low-risk patients. The trial was intended to enroll 100 patients in each arm but was stopped prematurely, at approximately half of its target enrollment (50 patients randomized to aspirin and 44 to aspirin plus warfarin), when the US Food and Drug Administration–approved TAVR for low-risk patients in August 2019. Nevertheless, the trial met its primary end point—the composite of hypoattenuated leaflet thickening on computed tomography, moderately reduced leaflet motion on computed tomography, hemodynamic aortic valve dysfunction on echocardiography (mean gradient ≥20 mm Hg, effective orifice area ≤1 cm2, dimensionless index <0.35, or moderate or severe aortic regurgitation), and stroke or transient ischemic attack at 30 days—with 26.5% (n=13) of patients in the aspirin arm having an end point event and 7.0% (n=3) in the warfarin plus aspirin arm (P=0.014). Hypoattenuated leaflet thickening was the most common end point event, occurring in 8 patients in the aspirin arm and 2 in the warfarin plus aspirin arm. All components of the primary end point numerically favored the warfarin plus aspirin arm, but just 6 patients had moderate or severely reduced leaflet motion (5 in the aspirin arm, 1 in the warfarin plus aspirin arm) and 2 had stroke or transient ischemic attack (both in the aspirin arm). Two patients in the warfarin plus aspirin arm had major bleeding compared with 1 in the aspirin arm.Although this trial provides interesting hypothesis-generating data about the role of anticoagulation in low-risk patients undergoing TAVR, it must be interpreted with caution for several reasons. Most importantly, the trial was designed and powered to detect a difference in a composite end point that was comprised mostly of imaging findings, rather than outcomes important to patients. Trials employing such surrogate end points are at best hypothesis-generating, especially when the association between the surrogate end point and relevant clinical outcomes is not well-established, as is the case for the association between subclinical leaflet thrombosis and early valve degeneration, short-term valve hemodynamics, and cerebral ischemic events. It is especially unclear whether short-term treatment with oral anticoagulation, as used in LRT 2.0, would affect long-term valve durability, or if longer-term anticoagulation (with attendant increased risks of major bleeding) is necessary.Second, LRT 2.0 was stopped early before accruing its planned sample size and it is possible that the observed effect of warfarin on subclinical leaflet thrombosis is overly optimistic. Third, the imaging results in LRT 2.0 mirror the results in GALILEO without the effect on bleeding. It is possible, as the authors hypothesize, that anticoagulation is better tolerated in a population of younger patients at lower surgical risk than in GALILEO's older, higher-risk population; however, it is also possible that the present trial was simply too small to observe a difference in bleeding rates. Moreover, it is possible that anticoagulation was subtherapeutic in some proportion of the warfarin-treated study population, which would reduce the rate of bleeding. The investigators did not systematically capture or report international normalized ratio values, but prior studies have shown that international normalized ratio values are frequently nontherapeutic shortly after warfarin initiation.9 Lastly, LRT 2.0 used warfarin for oral anticoagulation rather than one of the non–vitamin K antagonist oral anticoagulants. Although warfarin was chosen because it has an Food and Drug Administration–approved indication for the prophylaxis and treatment of thromboembolic complications from cardiac valve replacement, non–vitamin K antagonist oral anticoagulants generally have a favorable safety profile compared with warfarin. Furthermore, the recent RIVER trial (Rivaroxaban for Valvular Heart Disease and Atrial Fibrillation) showed that rivaroxaban reduced both stroke and major bleeding compared with warfarin in patients with bioprosthetic heart valves and atrial fibrillation.10There are ongoing trials of non–vitamin K antagonist oral anticoagulants versus antiplatelet therapy in patients undergoing TAVR (https://www.clinicaltrials.gov; Unique identifiers: NCT03284827, NCT02943785, NCT02664649); however, none are specifically designed to determine whether anticoagulation, with warfarin or non–vitamin K antagonist oral anticoagulants, is superior to antiplatelet therapy for the prevention of clinical events related to leaflet thrombosis in patients undergoing TAVR without another indication for anticoagulation. With the expansion of TAVR into increasingly younger patients, determining the precise association between imaging findings of early subclinical valve thrombosis and longer-term valve durability is critical, as are questions surrounding the utility of anticoagulation to prevent early valve degeneration and the optimal antithrombotic therapy and treatment duration for low-risk TAVR patients. Trials to answer these questions would necessarily require long follow-up, but with an end point like death or repeat valve replacement, would be well-suited for pragmatic (and low-cost) methods of end point ascertainment. GALILEO showed that treatment with rivaroxaban at a specific dose following TAVR is not appropriate in the intermediate and higher-risk population; however, other anticoagulants may be useful in different patient populations. When considering a trial of anticoagulation to prevent TAVR leaflet thrombosis and valve degeneration over long-term follow-up, anticoagulant choice, dose, duration, concomitant treatment, and patient population will all need to be taken into account. Though LRT 2.0 showed that short-term warfarin treatment may safely reduce subclinical leaflet thrombosis in a low-risk population undergoing TAVR, clinical trials powered for patient-centered clinical outcomes are needed to change the standard of care.Disclosures Dr Fanaroff reported grant funding and honoraria from the American Heart Association and grant funding from Boston Scientific. Dr Lopes reported grants and personal fees from Bristol-Myers Squibb and Pfizer, personal fees from Boehringer Ingelheim and Bayer AG, and grants from Amgen, Inc, GlaxoSmithKline, Medtronic PLC, and Sanofi AventisFootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.For Disclosures, see page 97.Correspondence to: Renato D. Lopes, MD, PhD, Duke Clinical Research Institute, P.O. Box 17969, Durham, NC 27715. Email renato.[email protected]eduReferences1. Dangas GD, Tijssen JGP, Wöhrle J, Søndergaard L, Gilard M, Möllmann H, Makkar RR, Herrmann HC, Giustino G, Baldus S, et al.; GALILEO Investigators. A controlled trial of rivaroxaban after transcatheter aortic-valve replacement.N Engl J Med. 2020; 382:120–129. doi: 10.1056/NEJMoa1911425CrossrefMedlineGoogle Scholar2. De Backer O, Dangas GD, Jilaihawi H, Leipsic JA, Terkelsen CJ, Makkar R, Kini AS, Veien KT, Abdel-Wahab M, Kim WK, et al.; GALILEO-4D Investigators. Reduced leaflet motion after transcatheter aortic-valve replacement.N Engl J Med. 2020; 382:130–139. doi: 10.1056/NEJMoa1911426CrossrefMedlineGoogle Scholar3. Brouwer J, Nijenhuis VJ, Delewi R, Hermanides RS, Holvoet W, Dubois CLF, Frambach P, De Bruyne B, van Houwelingen GK, Van Der Heyden JAS, et al.. Aspirin with or without clopidogrel after transcatheter aortic-valve implantation.N Engl J Med. 2020; 383:1447–1457. doi: 10.1056/NEJMoa2017815CrossrefMedlineGoogle Scholar4. Mack MJ, Leon MB, Thourani VH, Makkar R, Kodali SK, Russo M, Kapadia SR, Malaisrie SC, Cohen DJ, Pibarot P, et al.; PARTNER 3 Investigators. Transcatheter aortic-valve replacement with a balloon-expandable valve in low-risk patients.N Engl J Med. 2019; 380:1695–1705. doi: 10.1056/NEJMoa1814052CrossrefMedlineGoogle Scholar5. Popma JJ, Deeb GM, Yakubov SJ, Mumtaz M, Gada H, O'Hair D, Bajwa T, Heiser JC, Merhi W, Kleiman NS, et al.; Evolut Low Risk Trial Investigators. Transcatheter aortic-valve replacement with a self-expanding valve in low-risk patients.N Engl J Med. 2019; 380:1706–1715. doi: 10.1056/NEJMoa1816885CrossrefMedlineGoogle Scholar6. Chakravarty T, Søndergaard L, Friedman J, De Backer O, Berman D, Kofoed KF, Jilaihawi H, Shiota T, Abramowitz Y, Jørgensen TH, et al.; RESOLVE; SAVORY Investigators. Subclinical leaflet thrombosis in surgical and transcatheter bioprosthetic aortic valves: an observational study.Lancet. 2017; 389:2383–2392. doi: 10.1016/S0140-6736(17)30757-2CrossrefMedlineGoogle Scholar7. Petrescu I, Egbe AC, Ionescu F, Nkomo VT, Greason KL, Pislaru C, Pellikka PA, Connolly HM, Pislaru SV. Long-term outcomes of anticoagulation for bioprosthetic valve thrombosis.J Am Coll Cardiol. 2020; 75:857–866. doi: 10.1016/j.jacc.2019.12.037CrossrefMedlineGoogle Scholar8. Rogers T, Shults C, Torguson R, Shea C, Parikh P, Bilfinger T, Cocke T, Brizzio ME, Levitt R, Hahn C, et al.. Randomized trial of aspirin versus warfarin after transcatheter aortic valve replacement in low-risk patients.Circ Cardiovasc Interv. 2021; 14:e009983. doi: 10.1161/CIRCINTERVENTIONS.120.009983LinkGoogle Scholar9. Rose AJ, Hylek EM, Ozonoff A, Ash AS, Reisman JI, Berlowitz DR. Patient characteristics associated with oral anticoagulation control: results of the Veterans AffaiRs Study to Improve Anticoagulation (VARIA).J Thromb Haemost. 2010; 8:2182–2191. doi: 10.1111/j.1538-7836.2010.03996.xCrossrefMedlineGoogle Scholar10. Guimarães HP, Lopes RD, de Barros E Silva PGM, Liporace IL, Sampaio RO, Tarasoutchi F, Hoffmann-Filho CR, de Lemos Soares Patriota R, Leiria TLL, Lamprea D, et al.; RIVER Trial Investigators. Rivaroxaban in patients with atrial fibrillation and a bioprosthetic mitral valve.N Engl J Med. 2020; 383:2117–2126. doi: 10.1056/NEJMoa2029603CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsRelated articlesRandomized Trial of Aspirin Versus Warfarin After Transcatheter Aortic Valve Replacement in Low-Risk PatientsToby Rogers, et al. Circulation: Cardiovascular Interventions. 2021;14 January 2021Vol 14, Issue 1Article InformationMetrics Download: 82 © 2020 American Heart Association, Inc.https://doi.org/10.1161/CIRCINTERVENTIONS.120.010331PMID: 33423539 Originally publishedJanuary 11, 2021 Keywordssurrogate end pointEditorialsanticoagulantstranscatheter aortic valve replacementprosthesis failurePDF download SubjectsAortic Valve Replacement/Transcatheter Aortic Valve ImplantationValvular Heart DiseaseAnticoagulants
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