Anticoagulation in TAVR
Transcatheter aortic valve replacement (TAVR) has become an increasingly prevalent and effective means of treating severe aortic stenosis. Adjunctive pharmacologic therapy primarily consists of heparin during the procedure and dual antiplatelet therapy with aspirin and clopidogrel for 6 months after implantation. This regimen adheres to the protocol used in the first randomized control trial of TAVR, The Placement of Aortic Transcatheter Valves (PARTNER).1-4 Patients in the PARTNER trial were treated only with the balloon-expandable Sapien valve, but studies of the self-expandable CoreValve have employed a similar antithrombotic strategy.5 The rationale for this regimen is extrapolated from prior experience with stenting in percutaneous coronary intervention (PCI), strategies employed in bioprosthetic surgical aortic valve replacement, and early observational studies of percutaneous valve implantation.6-12 Furthermore, many patients undergoing TAVR have comorbidities that require anticoagulation therapy.1-4,13,14 What combination of antiplatelet and anticoagulant therapy is best in these patients has not been studied in a rigorous fashion. Hence, despite its increasing use, the optimal antithrombotic management of patients undergoing TAVR remains uncertain.
Insight into the role of anticoagulation in aortic valve replacement (AVR) can be taken from decades of experience with surgical implantation of mechanical and bioprosthetic valves. Similar to many bioprosthetic surgical valves, the Sapien valve consists of three bovine pericardial leaflets mounted on a cobalt chromium stent frame. The CoreValve is comprised of porcine pericardial tissue attached to a self expanding nitinol frame.9 In surgical AVR, original mechanical prostheses were shown to have a high risk of thromboembolism, and anticoagulation with a vitamin K antagonist (VKA) was accepted as standard of care.15-17 Tissue valves were developed partly in response to this embolic risk and early studies showed very low rates of thromboembolism.18,19 In light of this improved safety profile, controversy existed regarding the role, if any, of anticoagulation following bioprosthetic valve replacement. Anticoagulant regimens in early studies of AVR ranged from no routine therapy to two months routine treatment with a VKA and continued treatment based on additional risk factors.20,21 Since then, various reports have reached different conclusions on the risks and benefits, optimal timing, INR goals, and adjunctive use of antiplatelets with anticoagulation after bioprosthetic AVR. Notably, patients with atrial fibrillation and a history of cerebrovascular accident have consistently shown to be at increased risk of future embolic events.22-34
Recent guidelines for antithrombotic therapy after bioprosthetic AVR have become more conservative regarding anticoagulation. The newly released American College of Cardiology (ACC)/American Heart Association (AHA) 2014 guidelines on valvular heart disease give a Class IIb recommendation for anticoagulation with a VKA titrated to an INR of 2.5 for the first three months after bioprosthetic AVR (level of evidence of B). Aspirin 75 mg to 100 mg is given a Class IIa recommendation (level of evidence B).35 The 2012 European Society of Cardiology (ESC) guidelines on valvular disease also give a Class IIb recommendation for oral anticoagulation in the first three months after bioprosthetic AVR (level of evidence C), with a Class IIa recommendation for low dose aspirin (level of evidence C).10 Of note, both guidelines call for life-long anticoagulation in patients with other risk factors such as atrial fibrillation. In practice, actual use of anticoagulation following bioprosthetic AVR is highly variable and a recent registry study showed 38% of all patients and 49% of those at high risk were given anticoagulation.36
After TAVR, atrial fibrillation is likely to be the most common reason a patient will require anticoagulation. Other potential indications include history of deep vein thrombosis/pulmonary embolism, left ventricular thrombus, pulmonary hypertension, and other prosthetic valves and clotting disorders. In the PARTNER trial, 41% of patients in the inoperable cohort and 42% of the patients in the high risk cohort had atrial fibrillation.1,4 Other potential indications for anticoagulation were not reported nor was the percentage of patients on anticoagulation prior to receiving a valve. More recent studies have shown the average CHADS2 score of TAVR patients to be approximately 3, making it likely that a substantial proportion of patients being considered for the procedure will benefit from anticoagulation.37 Additional registry data since PARTNER support the presence of a large percentage of patients with a potential indication for anticoagulation.13,14,38-49
Current guidelines suggest different approaches to managing patients undergoing TAVR while on anticoagulation. A 2012 multi-society expert consensus document supported by the ACC and AHA suggests continuing anticoagulation and adding low dose aspirin without clopidogrel.9 The 2014 ACC/AHA valvular disease guidelines give a Class IIb recommendation for aspirin and clopidogrel for six months after TAVR (level of evidence C), but do not comment on anticoagulation.35 A position statement from the Canadian Cardiovascular Society says triple antithrombotic therapy should be avoided unless definite indications exist, but offers no specific strategy.50 Guidelines on the management of valvular heart disease issued by the ESC and European Association for Cardio-Thoracic Surgery state that in patients with atrial fibrillation, a VKA in combination with either aspirin or a thienopyridine is generally used but should be weighed against increased risk of bleeding.10
Few small studies have specifically addressed the use of anticoagulation in TAVR. A 2013 study by Czerwinska-Jelonkiewicz et al. assessed bleeding complications in 83 patients after TAVR in the context of antithrombotic management.51 After TAVR, 10% of patients were given aspirin, clopidogrel, and a VKA (triple therapy), 18.7% were given aspirin plus a VKA, and 6.2% of patients were given clopidogrel plus a VKA. In this study, bleeding complications were lowest with a VKA and clopidogrel. Nijenhuis et al. sent a survey to 14 centers in the Netherlands that perform TAVR asking about patterns of antithrombotic treatment.52 All centers used unfractionated heparin during the procedure, three centers administered bolus doses according to weight, and 11 centers gave a standard fixed initial dose. Activated clotting time (ACT) was measured in 13 centers with a target >300 seconds used by three centers, a target >250 seconds used by nine centers, and a target >200 seconds used by two centers. In patients already on anticoagulation, three centers continued oral medication periprocedurally with a goal INR of 2-2.5, and 11 centers discontinued oral anticoagulation (OAC). Of these 11 centers, one never performed bridging therapy, three always performed bridging therapy, and seven only bridged patients at high thrombotic risk. For patients with an indication for OAC, nine centers added only clopidogrel after the procedure, four added only aspirin, and one did not add any antiplatelet. In two of these centers, patients already on aspirin were continued on aspirin, but were otherwise given clopidogrel. A 300 mg loading dose of clopidogrel was used in five centers, and 600 mg loading dose was used in four centers with a 75 mg maintenance dose used for one month (one center), three months (six centers), or six months (two centers). For aspirin, loading doses between 200-600 mg were given one day before the procedure in one center and the day of the procedure in another. One center continued aspirin for six months and three centers placed patients on lifelong therapy. Patients who were receiving triple therapy pre-TAVR had their regimen continued in one center, discontinued in six centers (aspirin omitted in four, clopidogrel omitted in one, no routine in one), or continued for one to two weeks in two centers (the five remaining centers had no specified protocol for this scenario). Though small, this study illustrates the many decision points involved in determining an anticoagulant regimen for TAVR patients already on an OAC.
A study evaluating the frequency and causes of stroke during and 30 days after TAVR looked at the role of anticoagulation in relation to cerebrovascular accidents.53 In this cohort of 214 patients, patients on OACs stopped treatment three days before the procedure, received enoxaparin until the day before TAVR, were given IV heparin during the procedure to an ACT of 250-350, and were bridged with heparin back to an OAC following completion of the procedure. Patients on an OAC received only clopidogrel for antiplatelet therapy. With this strategy, 63 patients on an OAC did not have a stroke (33% of total patients without stroke), while four did have a stroke (21% of total patients with a stroke). Seventeen of the no stroke patients had chronic atrial fibrillation (9% of total no stroke patients) while six of the stroke patients had chronic atrial fibrillation (33% of total stroke patients). New onset atrial fibrillation after TAVR was noted in 17 no stroke patients (9% of total) and five stroke patients (26% of total). The authors note that none of the five patients with new onset atrial fibrillation were anticoagulated.
Many patients undergoing TAVR have multiple thromboses and bleeding-related comorbidities that make optimal antiplatelet and anticoagulant management complex. Furthermore, the optimal antithrombotic strategy following implantation of any bioprosthetic valve in the aortic position is not entirely clear. Guidelines differ on anticoagulation strategies in TAVR, most without a strong evidence base for their recommendations. Practice variation in the real world is high. Given the focus on stroke following TAVR, the role of anticoagulation, in particular in patients with atrial fibrillation, is likely to be important for the ongoing assessment of transcatheter versus surgical aortic valve replacement. Further studies in this domain are needed to guide appropriate management of this growing patient cohort.
- Leon MB, Smith CR, Mack M, et al. Transcatheter aortic-valve implantation for aortic stenosis in patients who cannot undergo surgery. N Engl J Med 2010;363:1597-1607.
- Kodali SK, Williams MR, Smith CR, et al. Two-year outcomes after transcatheter or surgical aortic-valve replacement. N Engl J Med 2012;366:1686-1695.
- Makkar RR, Fontana GP, Jilaihawi H, et al. Transcatheter aortic-valve replacement for inoperable severe aortic stenosis. N Engl J Med 2012;366:1696-1704.
- Smith CR, Leon MB, Mack MJ, et al. Transcatheter versus surgical aortic-valve replacement in high-risk patients. N Engl J Med 2011;364:2187-2198.
- Tamburino C, Capodanno D, Ramondo A, et al. Incidence and predictors of early and late mortality after transcatheter aortic valve implantation in 663 patients with severe aortic stenosis. Circulation 2011;123:299-308.
- Cribier A, Eltchaninoff H, Tron C, et al. Early experience with percutaneous transcatheter implantation of heart valve prosthesis for the treatment of end-stage inoperable patients with calcific aortic stenosis. J Am Coll Cardiol 2004;43:698-703.
- Dunning J, Versteegh M, Fabbri A, et al. Guideline on antiplatelet and anticoagulation management in cardiac surgery. Eur J Cardiothorac Surg 2008;34:73-92.
- Whitlock RP, Sun JC, Fremes SE, Rubens FD, Teoh KH, American College of Chest P. Antithrombotic and thrombolytic therapy for valvular disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141(2 Suppl):e576S-600S.
- Holmes DR, Jr., Mack MJ, Kaul S, et al. 2012 ACCF/AATS/SCAI/STS expert consensus document on transcatheter aortic valve replacement. J Am Coll Cardiol 2012;59:1200-1254.
- Joint Task Force on the Management of Valvular Heart Disease of the European Society of C, European Association for Cardio-Thoracic S, Vahanian A, et al. Guidelines on the management of valvular heart disease (version 2012). Eur Heart J 2012;33:2451-2496.
- American College of Cardiology/American Heart Association Task Force on Practice G, Society of Cardiovascular A, Society for Cardiovascular A, et al. ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (writing committee to revise the 1998 Guidelines for the Management of Patients With Valvular Heart Disease): developed in collaboration with the Society of Cardiovascular Anesthesiologists: endorsed by the Society for Cardiovascular Angiography and Interventions and the Society of Thoracic Surgeons. Circulation 2006;114:e84-231.
- Cribier A, Eltchaninoff H, Tron C, et al. Treatment of calcific aortic stenosis with the percutaneous heart valve: mid-term follow-up from the initial feasibility studies: the French experience. J Am Coll Cardiol 2006;47:1214-1223.
- Mack MJ, Brennan JM, Brindis R, et al. Outcomes following transcatheter aortic valve replacement in the United States. JAMA 2013;310:2069-2077.
- Gilard M, Eltchaninoff H, Iung B, et al. Registry of transcatheter aortic-valve implantation in high-risk patients. N Engl J Med 2012;366:1705-1715.
- Starr A, Bonchek LI, Anderson RP, Wood JA, Chapman RD. Late complications of aortic valve replacement with cloth-covered, composite-seat prostheses. A six-year appraisal. Ann Thorac Surg 1975;19:289-300.
- Andersen PV, Alstrup P. Long-term survival and complications in patients with mechanical aortic valves without anticoagulation. A follow-up study from 1 to 15 years. Eur J Cardiothorac Surg 1992;6:62-65.
- Cannegieter SC, Rosendaal FR, Briet E. Thromboembolic and bleeding complications in patients with mechanical heart valve prostheses. Circulation 1994;89:635-641.
- Stinson EB, Griepp RB, Oyer PE, Shumway NE. Long-term experience with porcine aortic valve xenografts. J Thorac Cardiovasc Surg 1977;73:54-63.
- Cohn LH, Lambert JJ, Castaneda AR, Collins JJ, Jr. Cardiac valve replacement with the stabilized glutaraldehyde porcine aortic valve: indications, operative results, and followup. Chest 1975;68:162-165.
- Cohn LH, Mudge GH, Pratter F, Collins JJ, Jr. Five to eight-year follow-up of patients undergoing porcine heart-valve replacement. N Engl J Med 1981;304:258-262.
- Bloomfield P, Wheatley DJ, Prescott RJ, Miller HC. Twelve-year comparison of a Bjork-Shiley mechanical heart valve with porcine bioprostheses. N Engl J Med 1991;324:573-579.
- Babin-Ebell J, Schmidt W, Eigel P, Elert O. Aortic bioprosthesis without early anticoagulation--risk of thromboembolism. Thorac Cardiovasc Surg 1995;43:212-214.
- Heras M, Chesebro JH, Fuster V, et al. High risk of thromboemboli early after bioprosthetic cardiac valve replacement. J Am Coll Cardiol 1995;25:1111-1119.
- Orszulak TA, Schaff HV, Mullany CJ, et al. Risk of thromboembolism with the aortic Carpentier-Edwards bioprosthesis. Ann Thorac Surg 1995;59:462-468.
- Massel D, Little SH. Risks and benefits of adding anti-platelet therapy to warfarin among patients with prosthetic heart valves: a meta-analysis. J Am Coll Cardiol 2001;37:569-578.
- Gherli T, Colli A, Fragnito C, et al. Comparing warfarin with aspirin after biological aortic valve replacement: a prospective study. Circulation 2004;110:496-500.
- Mistiaen W, Van Cauwelaert P, Muylaert P, Sys SU, Harrisson F, Bortier H. Thromboembolic events after aortic valve replacement in elderly patients with a Carpentier-Edwards Perimount pericardial bioprosthesis. J Thorac Cardiovasc Surg 2004;127:1166-1170.
- Sundt TM, Zehr KJ, Dearani JA, et al. Is early anticoagulation with warfarin necessary after bioprosthetic aortic valve replacement? J Thorac Cardiovasc Surg 2005;129:1024-1031.
- Colli A, Mestres CA, Castella M, Gherli T. Comparing warfarin to aspirin (WoA) after aortic valve replacement with the St. Jude Medical Epic heart valve bioprosthesis: results of the WoA Epic pilot trial. J Heart Valve Dis 2007;16:667-671.
- Jamieson WR, Moffatt-Bruce SD, Skarsgard P, et al. Early antithrombotic therapy for aortic valve bioprostheses: is there an indication for routine use? Ann Thorac Surg 2007;83:549-556; discussion 556-547.
- ElBardissi AW, DiBardino DJ, Chen FY, Yamashita MH, Cohn LH. Is early antithrombotic therapy necessary in patients with bioprosthetic aortic valves in normal sinus rhythm? J Thorac Cardiovasc Surg 2010;139:1137-1145.
- Al-Atassi T, Lam K, Forgie M, et al. Cerebral microembolization after bioprosthetic aortic valve replacement: comparison of warfarin plus aspirin versus aspirin only. Circulation 2012;126(11 Suppl 1):S239-244.
- Brennan JM, Edwards FH, Zhao Y, et al. Early anticoagulation of bioprosthetic aortic valves in older patients: results from the Society of Thoracic Surgeons Adult Cardiac Surgery National Database. J Am Coll Cardiol 2012;60:971-977.
- Merie C, Kober L, Skov Olsen P, et al. Association of warfarin therapy duration after bioprosthetic aortic valve replacement with risk of mortality, thromboembolic complications, and bleeding. JAMA 2012;308:2118-2125.
- Nishimura RA, Otto CM, Bonow RO, et al. 2014 AHA/ACC Guidelines for the Management of Patient With Valvular Heart Disease. J Am Coll Cardiol 2014. [Epub Ahead of Print].
- Brennan JM, Alexander KP, Wallace A, et al. Patterns of anticoagulation following bioprosthetic valve implantation: observations from ANSWER. J Heart Valve Dis 2012;21:78-87.
- Nombela-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;126:3041-3053.
- Bosmans JM, Kefer J, De Bruyne B, et al. Procedural, 30-day and one year outcome following CoreValve or Edwards transcatheter aortic valve implantation: results of the Belgian national registry. Interact Cardiovasc Thorac Surg 2011;12:762-767.
- Rodes-Cabau J, Webb JG, Cheung A, et al. Long-term outcomes after transcatheter aortic valve implantation: insights on prognostic factors and valve durability from the Canadian multicenter experience. J Am Coll Cardiol 2012;60:1864-1875.
- Dager AE, Nuis RJ, Caicedo B, et al. Colombian experience with transcatheter aortic valve implantation of medtronic CoreValve. Texas Heart Inst J 2012;39:351-358.
- Piazza N, Grube E, Gerckens U, et al. Procedural and 30-day outcomes following transcatheter aortic valve implantation using the third generation (18 Fr) corevalve revalving system: results from the multicentre, expanded evaluation registry 1-year following CE mark approval. EuroIntervention 2008;4:242-249.
- Di Mario C, Eltchaninoff H, Moat N, et al. The 2011-12 pilot European Sentinel Registry of Transcatheter Aortic Valve Implantation: in-hospital results in 4,571 patients. EuroIntervention 2013;8:1362-1371.
- Hamm CW, Mollmann H, Holzhey D, et al. The German Aortic Valve Registry (GARY): in-hospital outcome. Eur Heart J. Sep 10 2013. [Epub Ahead of Print].
- Zahn R, Gerckens U, Grube E, et al. Transcatheter aortic valve implantation: first results from a multi-centre real-world registry. Eur Heart J 2011;32:198-204.
- Ussia GP, Barbanti M, Petronio AS, et al. Transcatheter aortic valve implantation: 3-year outcomes of self-expanding CoreValve prosthesis. Eur Heart J 2012;33:969-976.
- Lefevre T, Kappetein AP, Wolner E, et al. One year follow-up of the multi-centre European PARTNER transcatheter heart valve study. Eur Heart J 2011;32:148-157.
- Thomas M, Schymik G, Walther T, et al. One-year outcomes of cohort 1 in the Edwards SAPIEN Aortic Bioprosthesis European Outcome (SOURCE) registry: the European registry of transcatheter aortic valve implantation using the Edwards SAPIEN valve. Circulation 2011;124(4):425-433.
- Windecker S. One-Year Outcomes from the Source XT Post Approval Study. Paper presented at: EuroPCR; May 21, 2013; Paris, France.
- Moat NE, Ludman P, de Belder MA, et al. Long-term outcomes after transcatheter aortic valve implantation in high-risk patients with severe aortic stenosis: the U.K. TAVI (United Kingdom Transcatheter Aortic Valve Implantation) Registry. J Am Coll Cardiol 2011;58:2130-2138.
- Webb J, Rodes-Cabau J, Fremes S, et al. Transcatheter aortic valve implantation: a Canadian Cardiovascular Society position statement. Can J Cardiol 2012;28:520-528.
- Czerwinska-Jelonkiewicz K, Witkowski A, Dabrowski M, et al. Antithrombotic therapy - predictor of early and long-term bleeding complications after transcatheter aortic valve implantation. Arch Med Sci 2013;9:1062-1070.
- Nijenhuis VJ, Stella PR, Baan J, et al. Antithrombotic therapy in patients undergoing TAVI: an overview of Dutch hospitals. Neth Heart J 2014;22:64-69.
- Nuis RJ, Van Mieghem NM, Schultz CJ, et al. Frequency and causes of stroke during or after transcatheter aortic valve implantation. Am J Cardiol 2012;109:1637-1643.
Clinical Topics: Anticoagulation Management, Cardiac Surgery, Invasive Cardiovascular Angiography and Intervention, Valvular Heart Disease, Aortic Surgery, Cardiac Surgery and VHD, Interventions and Structural Heart Disease
Keywords: Anticoagulants, Aortic Valve, Aortic Valve Stenosis, Aspirin, Bioprosthesis, Comorbidity, Heart Valve Prosthesis, Heparin, Percutaneous Coronary Intervention, Ticlopidine, Transcatheter Aortic Valve Replacement
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