TAVR and DAPT: Are We Any Closer to the Answer?

The antiplatelet medication of choice for patients undergoing transcatheter aortic valve replacement (TAVR) has been derived empirically. Periprocedural stroke and adverse cardiac events have been associated with worse outcomes at 30 days and 1 year after TAVR, with half of these events occurring after 24 hours.1Kodali SK Williams MR Smith CR et al.for the PARTNER trial investigators. Two-year outcomes after transcatheter or surgical aortic-valve replacement.N Engl J Med. 2012; 366: 1686-1695Google Scholar, 2Stortecky S Windecker S Pilgrim T et al.Cerebrovascular accidents complicating transcatheter aortic valve implantation: frequency, timing and impact on outcomes.EuroIntervention. 2012; 8 (doi: 10.4244/EIJV8I1A11.): 62-70Google Scholar, 3Smith CR Leon MB Mack MJ et al.for the PARTNER trial investgators. Transcatheter versus surgical aortic-valve replacement in high-risk patients.N Engl J Med. 2011; 364 (doi: 10.1056/NEJMoa1007994.): 2187-2198Google Scholar Dual antiplatelet therapy (DAPT), consisting of a thienopyridine and aspirin, improves clinical outcomes following coronary artery stenting through reductions in stent thrombosis and myocardial infarction.4Bhatt DL Fox KA Hacke W et al.for the CHARISMA investigators. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events.N Engl J Med. 2006; 354 (doi: 10.1056/NEJMoa060989.): 1706-1717Google Scholar,5Valgimigli M Campo G Monti M et al.Short-versus long-term duration of dual-antiplatelet therapy after coronary stenting: a randomized multicenter trial.Circulation. 2012; 125 (doi: 10.1161/CIRCULATIONAHA.111.071589.): 2015-2026Google Scholar The mechanism of cardiac event rate reduction in coronary artery disease may be significantly different to that of TAVR. Platelet-mediated stent thrombosis, the antiproliferative effects of drug-eluting stents, and small caliber arteries are clearly a different milieu compared to TAVR procedures. The TAVR prosthesis has a greater metallic burden and greater flow turbulence across the valve, in coronary sinuses and paravalvular spaces, compared to drug-eluting coronary stents. The TAVR patient tends to be older and more likely to have peripheral vascular disease, and due to a higher rate of comorbidities, may have a higher risk of bleeding. The benefit of DAPT in coronary artery disease, weighed against the risk of bleeding, has been extrapolated to TAVR, without clear prior evidence to support this. The ACCF/AATS/SCAI/STS panel recommends DAPT with aspirin and clopidogrel after TAVR.6Holmes Jr, DR Mack MJ Kaul S et al.2012 ACCF/AATS/SCAI/STS expert consensus document on transcatheter aortic valve replacement.J Am Coll Cardiol. 2012; 59 (doi: 10.1016/j.jacc.2012.01.002.): 1200-1254Google Scholar The Canadian Cardiovascular Society recommends aspirin indefinitely and clopidogrel for 3 months in patients undergoing TAVR.7Webb J Rodés-Cabau J Fremes S et al.Transcatheter aortic valve implantation: a Canadian cardiovascular society position statement.Can J Cardiol. 2012; 28 (doi: 10.1016/j.cjca.2012.04.015.): 520-552Google Scholar Similarly to the duration of DAPT after coronary stenting, the necessary duration of clopidogrel remains unclear. In the meta-analysis by Abuzaid and colleagues (this issue), single antiplatelet therapy (SAPT) was compared to DAPT following TAVR.8Abuzaid A, Pragya Ranjan P, Fabrizio C, et al. Single anti-platelet therapy versus dual anti-platelet therapy after transcatheter aortic valve replacement: a meta-analysis. Struct Heart. 2018;this issue. doi: 10.1080/24748706.2018.1491082.Google Scholar Previous meta-analyses on this subject have had variable conclusions, especially with regard to major bleeding complications. This analysis is the most current, comprehensive evaluation of this topic, comparing aspirin as SAPT versus dual antiplatelet therapy. The STS data registry is not included in this analysis due to a lack of clarity of SAPT as aspirin alone. Clinical trials that included anticoagulant therapy were also not included. There were 10 studies that met selection criteria with 2412 patients included. There were no differences in all-cause mortality, myocardial infarction or stroke, but the risk of major bleeding was greater with DAPT. The length of follow-up was approximately 6 months, which limits long-term conclusions. The increase in bleeding was driven largely by the observational studies rather than the randomized trials included in the meta-analysis. Major bleeding has been associated with an increase in overall mortality in randomized TAVR clinical trials.4Bhatt DL Fox KA Hacke W et al.for the CHARISMA investigators. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events.N Engl J Med. 2006; 354 (doi: 10.1056/NEJMoa060989.): 1706-1717Google Scholar This publication contributes to a better understanding of necessary antiplatelet therapy, with more focus on safety. Several clinical scenarios require further clarification regarding DAPT strategies in TAVR patients, such as concomitant atrial fibrillation. As many as a third of extreme and high-risk TAVR patients have atrial fibrillation.3Smith CR Leon MB Mack MJ et al.for the PARTNER trial investgators. Transcatheter versus surgical aortic-valve replacement in high-risk patients.N Engl J Med. 2011; 364 (doi: 10.1056/NEJMoa1007994.): 2187-2198Google Scholar Although many of these patients are already on anticoagulant therapy, there is an increased risk of cerebrovascular events in follow-up for 1 year after TAVR.9Nombela-Franco L Webb JG De Jaegere PP et al.Timing, predictive factors, and prognostic value of cerebrovascular events in a large cohort of patients undergoing transcatheter aortic valve implantation.Circulation. 2012; 126 (doi: 10.1161/CIRCULATIONAHA.112.110981.): 3041-3053Google Scholar As in PCI, adding antiplatelet therapy to existing anticoagulation increases bleeding risk. Anticoagulation with warfarin has been recommended (Class I, LOE B-NR) for stroke prevention in TAVR patients with atrial fibrillation, since the direct oral anticoagulants (apixaban, rivaroxaban, edoxaban or dabigatran) are not approved specifically for these patients. One such trial, Global Study Comparing a Rivaroxaban-based Antithrombotic Strategy to an Antiplatelet-based Strategy After Transcatheter Aortic Valve Replacement to Optimize Clinical Outcomes (GALILEO), should shed light on the efficacy and safety of rivaroxaban in TAVR patients who develop atrial fibrillation after the procedure. Determining the most appropriate anticoagulant and antiplatelet strategies is essential due to high clinical event rate and bleeding complication rate following development of atrial fibrillation on dual or triple therapy. Another clinical situation following TAVR is the development of leaflet thrombosis following TAVR. Thrombosis of valve leaflets may result in reduced leaflet motion, elevated valvular gradient and potentially decreased valve durability. Often computed tomography (CT) is necessary for confirmation of the diagnosis. The occurrence of leaflet thrombosis occurs more commonly in TAVR patients who received antiplatelet therapy compared to those on anticoagulation, although routine oral anticoagulation is not certain to prevent leaflet thrombosis. There may not be a difference in those taking warfarin compared to those on a direct oral anticoagulant. The treatment of leaflet thrombosis is anticoagulation, with no clear difference in efficacy between warfarin or direct oral anticoagulants. Leaflet thrombosis may also occur in patients who have received surgical bioprosthetic aortic valves. Guideline recommendations for anticoagulation following surgical bioprosthetic aortic valve replacement have been modified, with greater short-term use of anticoagulation with warfarin for 3–6 months after surgery.10Nishimura 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 (doi: 10.1016/j.jacc.2017.04.053.): 252-289Google Scholar Moreover, a vitamin K antagonist for at least 3-months is also recommended (class IIa) after TAVR in patients at low risk for bleeding10Nishimura 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 (doi: 10.1016/j.jacc.2017.04.053.): 252-289Google Scholar The incidence of leaflet thrombosis is being studied in the low risk clinical trials with the Sapien 3 bioprosthesis as well as CoreValve. Patients in the leaflet thrombosis substudies, both in the TAVR arm and surgical AVR arm, will have routine 30-day CT to determine if there is any evidence of leaflet thrombosis. Clinical treatment is not dictated by the findings on the CT, but anticoagulation is usually recommended if there are findings of clinical symptoms or elevated gradients on echocardiography. In summary, this meta-analysis by Abuzaid and colleagues demonstrates there may be no difference in efficacy (stroke, all-cause mortality or myocardial infarction) using a SAPT versus DAPT strategy in patients receiving TAVR. There was a decrease in bleeding events with SAPT. The clinical characteristics of patients undergoing TAVR provide a unique challenge for tailoring the correct antithrombotic and antiplatelet strategies. As procedural devices improve and indication expansion progresses to lower risk patients with the expectation of less bleeding and lower stroke rates, any adverse complications will be expected to decrease significantly. Future, large-scale randomized trials will be necessary to adequately answer definitively the need for SAPT, DAPT, oral anticoagulation, or a combination (antiplatelets and anticoagulants) in routine TAVR and those with atrial fibrillation. The authors report no conflicts of interest in this work.

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