Antithrombotic Therapy After TAVI: Insights Provided by the POPULAR-TAVI Trial
Transcatheter aortic valve implantation (TAVI) has been a revolutionary therapeutic modality for the treatment of severe symptomatic aortic stenosis. Recently, as reported in the Journal of the American College of Cardiology, TAVI volume has surpassed surgical aortic valve replacement in the United States (72,991 versus 57,626).1 Extrapolating from experience with intra-coronary stents, the early TAVI trial protocols used 3-6 months of dual antiplatelet therapy (DAPT) with aspirin and clopidogrel followed by daily low-dose aspirin.2-5 Although outcomes from TAVI continue to improve, patients remain at risk for both thromboembolic events and bleeding events in the post-procedure time period, making optimal antiplatelet and anticoagulation strategies of the utmost importance. Current guidelines recommend low-dose aspirin monotherapy (Class IIa) or DAPT for 3-6 months (Class IIb) post-TAVI.6 However, it has never been proven whether DAPT or single antiplatelet therapy is superior, and optimal anticoagulation strategies remain under investigation.
An early, small trial by Ussia et al. raised the question of whether DAPT was necessary.7 This was followed by the SAT-TAVI (Single Antiplatelet Therapy for TAVI; 2014) and ARTE (Aspirin Versus Aspirin + Clopidogrel Following Transcatheter Aortic Valve Implantation; 2017) trials, both of which failed to show benefit for DAPT and demonstrated increased risk of bleeding, although these trials were too small to draw firm conclusions from.8,9 Based on these data, the European Society of Cardiology did update TAVI guidelines making single antiplatelet therapy a Class IIb recommendation over DAPT in high-bleed-risk patients.10 This is consistent with recently published meta-analyses showing no benefit to DAPT over single antiplatelet therapy, with increased bleeding complications.11 The US guidelines then followed with a Class IIa recommendation for single antiplatelet therapy and a Class IIB recommendation for DAPT as noted.6
GALILEO (Global Study Comparing a Rivaroxaban-based Antithrombotic Strategy to an Antiplatelet-based Strategy After TAVR to Optimize Clinical Outcomes), published in 2020, randomized patients without any additional indication for anticoagulation to receive either rivaroxaban (10 mg daily) plus aspirin or aspirin plus clopidogrel for 3 months.12 Routine use of rivaroxaban anticoagulation was associated with worse outcomes including increased risk of death, increased risk of major bleeding events, and no reduction in thromboembolic events, earning a Class III recommendation for harm in the recent guideline update.6 However, although GALILEO suggests routine anticoagulation should not be used in all TAVI patients, questions remain regarding the best strategy in TAVI patients who do have an independent indication for oral anticoagulation. A recent meta-analysis suggested that anticoagulation alone without addition of antiplatelet therapy may be preferred.13
The POPULAR-TAVI (Antiplatelet Therapy for Patients Undergoing Transcatheter Aortic-Valve Implantation) trial is a parallel-design trial involving 2 cohorts. Cohort A included patients without an indication for anticoagulation and compared DAPT with clopidogrel versus single antiplatelet therapy with low-dose aspirin. Cohort B, which was published first, included patients with an indication for anticoagulation and enrolled 313 patients undergoing TAVI to receive oral anticoagulation alone or anticoagulation plus clopidogrel for 3 months.14 The vast majority of patients were indicated for anticoagulation due to atrial fibrillation. The majority of patients in the anticoagulation-alone group (75%) and the anticoagulation plus clopidogrel group (71%) were treated with vitamin K antagonists (VKA), with 2 patients treated with low molecular weight heparin and the remainder treated with direct oral anticoagulants (DOAC). Transfemoral TAVI was performed in the majority of patients in both arms (87% and 85%) with transapical being the next most-common access strategy (10% and 12%). In both cohorts, the investigators could use the valve platform of choice. The results showed a bleeding event in 21.7% of the oral anticoagulation-alone group versus 34.6% of the anticoagulation plus clopidogrel group (p = 0.01). The secondary composite outcome of cardiovascular death, non-procedure-related bleeding, stroke, or myocardial infarction in 12 months occurred in 31.2% of the oral anticoagulation-alone group versus 45.5% in the oral anticoagulation plus clopidogrel group. Oral anticoagulation alone was also equal or superior to oral anticoagulation plus clopidogrel for all individual secondary outcomes. The authors concluded that the use of oral anticoagulation alone without addition of clopidogrel in patients indicated for anticoagulation undergoing TAVI would lead to decreased bleeding events and improved outcomes.
Cohort A of the POPULAR-TAVI trial was just recently published in The New England Journal of Medicine in October 2020.15 Cohort A included 331 patients without an indication for anticoagulation who were undergoing TAVI. The subjects were randomized to single antiplatelet therapy with low-dose aspirin alone versus DAPT with aspirin plus clopidogrel. Recent percutaneous coronary intervention (PCI) with a drug-eluting stent within 3 months or a bare-metal stent within 1 month was a major exclusion criterion. The primary endpoint of a bleeding event occurred in 15.1% of the single antiplatelet therapy group versus 26.6% of the DAPT group (p = 0.001). The secondary composite outcome of cardiovascular death, non-procedure-related bleeding, stroke, or myocardial infarction in 12 months occurred in 23% of subjects in the single antiplatelet therapy group versus 31.1% in the DAPT group. There was no statistically significant difference between groups for death, cardiovascular death, stroke, or myocardial infarction. The authors concluded that for patients without an indication for anticoagulation, the use of DAPT post-TAVI lead to increased bleeding complications.
Consider the following three possible clinical scenarios that clinicians will encounter:
- Patient undergoing TAVI with no recent PCI and no indication for anticoagulation
In patients without a concurrent indication for DAPT or anticoagulation, we can now recommend single antiplatelet therapy indefinitely as the only anticoagulation or antithrombotic agent needed. For the majority of patients, this will be low-dose aspirin. For those with aspirin allergy, however, clopidogrel monotherapy is preferred.
- Patient undergoing TAVI with recent PCI and no indication for anticoagulation
In this circumstance, the antiplatelet therapy will be determined based on the PCI: DAPT with shorter duration in accordance with existing PCI guidelines (12 months for acute coronary syndromes, 6 months if at higher risk of bleeding); for elective PCI, DAPT for 6 months or 3 months if high bleeding risk.16 After completion of DAPT, low-dose aspirin should then be continued indefinitely.
- Patient undergoing TAVI with an indication for anticoagulation
Given that the POPULAR-TAVI trial results suggest that the addition of clopidogrel worsens bleeding, we recommend anticoagulation without routine antiplatelet therapy in patients undergoing TAVI with an independent indication for anticoagulation.12-14 Although the majority of patients receiving anticoagulation in the POPULAR-TAVI trial were treated with VKA, monotherapy is preferred with DOAC or VKA alike.
The POPULAR-TAVI trial has provided important clarification for the routine management of antithrombotic therapy after TAVI. Single antiplatelet therapy in routine cases is preferred. Questions remain regarding the use of DOAC versus VKA, concurrent use of aspirin in the setting of anticoagulation, and whether certain high-risk groups may benefit from routine anticoagulation. However, for the majority of patients undergoing TAVI, routine antithrombotic management has been simplified.
Table 1: Summary of Antithrombotic Therapy Recommendations for Patients Undergoing TAVI
|Single Antiplatelet Therapy||DAPT||VKA or DOAC|
|No recent interventions and no indication for anticoagulation||+|
|Recent PCI or other independent indication for DAPT||+|
|Independent indication for anticoagulation||+|
|*In patients with high ischemic risk due to recent acute coronary syndrome or other anatomical/procedural characteristic who are also indicated for anticoagulation, triple therapy may be considered on an individual basis after carefully considering bleeding risk.10|
- Carroll JD, Mack MJ, Vemulapalli S, et al. STS-ACC TVT Registry of Transcatheter Aortic Valve Replacement. J Am Coll Cardiol 2020;76:2492-516.
- 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;363:1597-607.
- Smith CR, Leon MB, Mack M, et al. Transcatheter versus surgical aortic-valve replacement in high-risk patients. N Engl J Med 2011;364:2187-98.
- Popma JJ, Adams DH, Reardon MJ, et al. Transcatheter aortic valve replacement using a self-expanding bioprosthesis in patients with severe aortic stenosis at extreme risk for surgery. J Am Coll Cardiol 2014;63:1972-81.
- Adams DH, Popma JJ, Reardon MJ. Transcatheter aortic-valve replacement with a self-expanding prosthesis. N Engl J Med 2014;371:967-8.
- Writing Committee Members, Otto CM, Nishimura RA, et al. 2020 ACC/AHA Guideline for the Management of Patients With Valvular Heart Disease: Executive Summary: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. J Am Coll Cardiol 2020;77:450-500.
- Ussia GP, Scarabelli M, Mulè M, et al. Dual antiplatelet therapy versus aspirin alone in patients undergoing transcatheter aortic valve implantation. Am J Cardiol 2011;108:1772-6.
- Stabile E, Pucciarelli A, Cota L, et al. SAT-TAVI (single antiplatelet therapy for TAVI) study: a pilot randomized study comparing double to single antiplatelet therapy for transcatheter aortic valve implantation. Int J Cardiol 2014;174:624-7.
- Rodés-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.
- 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.
- Kuno T, Takagi H, Sugiyama T, et al. Antithrombotic strategies after transcatheter aortic valve implantation: Insights from a network meta-analysis. Catheter Cardiovasc Interv 2020;96:E177-E186.
- Dangas GD, Tijssen JGP, Wöhrle J, et al. A Controlled Trial of Rivaroxaban after Transcatheter Aortic-Valve Replacement. N Engl J Med 2020;382:120-9.
- Zhu Y, Meng S, Chen M, et al. Comparing anticoagulation therapy alone versus anticoagulation plus single antiplatelet drug therapy after transcatheter aortic valve implantation in patients with an indication for anticoagulation: a systematic review and meta-analysis. Cardiovasc Drugs Ther 2020;Oct 8:[Epub ahead of print].
- 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.
- 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.
- Levine GN, Bates ER, Bittl JA, et al. 2016 ACC/AHA Guideline Focused Update on Duration of Dual Antiplatelet Therapy in Patients With Coronary Artery Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2016;68:1082-115.
Clinical Topics: Acute Coronary Syndromes, Anticoagulation Management, Arrhythmias and Clinical EP, Cardiac Surgery, Cardiovascular Care Team, Invasive Cardiovascular Angiography and Intervention, Valvular Heart Disease, Anticoagulation Management and ACS, Anticoagulation Management and Atrial Fibrillation, Atrial Fibrillation/Supraventricular Arrhythmias, Aortic Surgery, Cardiac Surgery and Arrhythmias, Cardiac Surgery and VHD, Interventions and ACS, Interventions and Structural Heart Disease
Keywords: Heart Valve Diseases, Fibrinolytic Agents, Platelet Aggregation Inhibitors, Transcatheter Aortic Valve Replacement, Drug-Eluting Stents, Aspirin, Aortic Valve, Heparin, Low-Molecular-Weight, Atrial Fibrillation, Percutaneous Coronary Intervention, Acute Coronary Syndrome, Myocardial Infarction, Thromboembolism, Hemorrhage, Anticoagulants, Stroke, Aortic Valve Stenosis, Vitamin K, Hypersensitivity
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