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.
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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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