Transcatheter aortic valve replacement (TAVR) is a validated therapeutic option for patients with symptomatic severe aortic valve stenosis and moderate or high surgical risk.^1,2 The progressive extension to patients with lower operative risk is causing an exponential increase in the number of patients treated with this technique.³ Stemming from the experience of intracoronary stents, the first trials evaluating TAVR used dual antiplatelet therapy (DAPT) with aspirin and clopidogrel up to 6 months as an antiplatelet regimen after the procedure.^4,5 The rationale was to prevent device-related thromboembolic complications while neointimal tissue growth and endothelialization of the metallic valve frame are ongoing. Thromboembolic events after TAVR, such as stroke, may occur in up to 7 ± 1.7% of the patients within the first years of TAVR and is associated with considerable morbidity and mortality.⁶ However, the majority of patients undergoing TAVR are frail and at high risk of major or life-threatening bleeding, which may affect up to 16 ± 0.9% of the subjects within the first year of the procedure.⁶ As a consequence, the risk-benefit trade-off of DAPT has been the subject of debate in recent years.

The safety and efficacy of a single antiplatelet therapy (SAPT) strategy after TAVR has been tested in three small randomized trials.^7-9 None found significant differences regarding ischemic events, such as death, myocardial infarction, or stroke. The most recent, the ARTE (Aspirin Versus Aspirin + Clopidogrel Following Transcatheter Aortic Valve Implantation) trial, albeit underpowered, described an increased risk of major or life-threatening bleeding within 3 months of TAVR with DAPT compared with aspirin.⁹ In a recent patient-level meta-analysis of these 3 trials, Maes et al. found a significant increase of the 30-day risk of major or life-threatening bleeding with DAPT over SAPT (odds ratio 2.24; 95% confidence interval, 1.12-4.46; p = 0.022). Of note, there was no difference between DAPT and SAPT regarding the risk of 30-day mortality (5.2 vs. 3.8% respectively, p = 0.447) and global ischemic events (3.8 vs. 3.8%, p = 0.999).¹⁰ This is consistent with results from numerous real-life observational studies.¹¹ Although insufficient to allow a definite conclusion regarding antithrombotic treatment after TAVR, these data have led to a change in the 2017 recommendations of the European Society of Cardiology. In patients with high bleeding risk, SAPT with aspirin or clopidogrel alone may now be considered (Class IIb).²

Furthermore, the increasing quality of the imaging surveillance after TAVR with computed tomography or transesophageal echocardiography is highlighting the higher-than-expected risk for subclinical leaflet thrombosis in such patients. With a systematic use of four-dimensional volume-rendered computed tomography, Makkar et al. documented "hypoattenuated leaflet thickening" with or without reduced leaflet motion in 22 of 55 patients undergoing TAVR implant.¹² Similar findings where observed in a pooled analysis from the SAVORY (Subclinical Aortic Valve Bioprosthesis Thrombosis Assessed With 4D CT) and RESOLVE (Assessment of Transcatheter and Surgical Aortic Bioprosthetic Valve Thrombosis and Its Treatment With Anticoagulation) registries, with 17 of 115 patients presenting with reduced leaflet motion. This phenomenon may affect up to 13% of patients within months of the procedure and has been associated with an increase of stroke or transient ischemic attack.¹³ Interestingly, there was no difference in the prevalence of hypoattenuated leaflet thickening between SAPT and DAPT. Conversely, oral anticoagulation (OAC) with either vitamin K antagonists (VKA) or novel oral anticoagulants has been shown to prevent and treat this complication.^13,14 The 2017 focused update of the American Heart Association and American College of Cardiology have granted a Level IIb recommendation to the use of VKA within the first 3 months post-TAVR in patients without high risk of bleeding.¹

Although patients in need of OAC represent a sizable part of the population undergoing TAVR, data supporting antithrombotic strategies in these patients are even more scarce compared with the rest of the population. The most common indication for OAC use is atrial fibrillation (AF), representing up to one third of the population undergoing TAVR. Moreover, 14% (95% confidence interval, 10-18%) of the remaining patients may develop new-onset of AF within 30 days of TAVR¹⁵ with a high risk for subsequent stroke. A combination of aspirin or clopidogrel in addition to VKA is currently recommended based on expert consensus.¹⁶ However, this regimen has been associated in recent retrospective studies with increased rates of major or life-threatening bleeding without significant reduction of thromboembolic events.¹⁷

Observational studies have described the use of novel oral anticoagulants to be safe after TAVR.^13,18 Particularly, Seeger et al. recently described a reduced rate of bleeding events with apixaban compared with VKA in patients with AF after successful transfemoral TAVR.¹⁸ Several ongoing randomized trials are evaluating different antithrombotic regimens after TAVR, as detailed in Table 1.

Table 1: Main Ongoing Randomized Trials Evaluating Antithrombotic Regimen After Successful TAVR

Trials	Antithrombotic Regimen	Target Population	Estimated Enrollment	Anticipated Completion Date
POPular-TAVI (Antiplatelet Therapy for Patients Undergoing Transcatheter Aortic Valve Implantation) (NCT02247128)	Acetylsalicylic acid (ASA) vs. ASA + clopidogrel or VKA vs. clopidogrel + VKA	All-comer	1,000	December 2019
GALILEO (Global Study Comparing a Rivaroxaban-based Antithrombotic Strategy to an Antiplatelet-based Strategy After Transcatheter Aortic Valve Replacement to Optimize Clinical Outcomes) (NCT02556203)	Rivaroxaban + ASA (3 months) followed by rivaroxaban vs. Clopidogrel + ASA (3 months) followed by ASA	Patients without underlying indication for chronic OAC	1,644	December 2018
ATLANTIS (Anti-Thrombotic Strategy After Trans-Aortic Valve Implantation for Aortic Stenosis) (NCT02664649)	Apixaban vs. standard of care (VKA or SAPT/DAPT)	All-comer	1,510	April 2019
ENVISAGE-TAVI AF (Edoxaban Compared to Standard Care After Heart Valve Replacement Using a Catheter in Patients With Atrial Fibrillation) (NCT02943785)	Edoxaban vs. VKA	Patients with AF	1,400	November 2020
AUREA (Dual Antiplatelet Therapy Versus Oral Anticoagulation for a Short Time to Prevent Cerebral Embolism After TAVI) (NCT01642134)	ASA + clopidogrel vs. VKA	Patients without underlying indication for chronic OAC	124	2018
AVATAR (Anticoagulation Alone Versus Anticoagulation and Aspirin Following Transcatheter Aortic Valve Interventions (1:1)) (NCT02735902)	ASA + VKA vs. VKA	Patients with underlying indication for chronic OAC	170	April 2020

Specific Situations: PCI in the Setting of TAVR

Coronary artery disease is frequent in the setting of TAVR, affecting 40-70% of the patients. Currently, guidelines state a Class IIa recommendation to achieve coronary revascularization in case of ≥70% reduction in luminal diameter in major coronary artery and ≥50% in the left main artery, with a level of evidence C.^2,19

Patients without underlying indication for OAC who received a stent in the setting of TAVR should be treated with a combination of aspirin and clopidogrel for a total duration of 6-12 months, which will overlap with the antithrombotic treatment recommended for the TAVR itself.

Patients with underlying indication for OAC represent a greater therapeutic challenge. Triple therapy with aspirin, clopidogrel, and VKA is recommended for at least 1 month after stenting.²⁰ In case of high ischemic risk (acute clinical presentation or anatomical/procedural features), triple therapy should be prolonged up to 6 months after stenting. After this initial treatment, VKA and clopidogrel can be prescribed for an overall 12-month duration after stenting. In case of high bleeding risk, VKA and clopidogrel for 12 months may be an alternative to triple therapy.

Future trials to evaluate the optimal antithrombotic regimen among this high-risk population are warranted, particularly because patients with recent stent implantation are usually excluded from randomized pharmacological trials in TAVR.^21,22

Take-Home Messages

Specific guidelines are detailed in Table 2.²³

Table 2: Summary of Guidelines and Expert Consensus on Antithrombotic Treatment Following TAVR

Guidelines and Expert Consensus	Recommendations	Class – level of evidence
American College of Cardiology / American Heart Association 2017 Updated Recommendations1	Patients without underlying indication for chronic OAC
	Anticoagulation with a VKA to achieve an international normalized ratio of 2.5 may be reasonable in patients at low risk of bleeding for at least 3 months.	IIb – B NR
	Clopidogrel 75 mg the first 6 months after TAVR may be reasonable in addition to lifelong aspirin 75-100 mg daily.	IIb – C
	Patients with underlying indication for chronic OAC
	No specific recommendation.	-
European Society of Cardiology / European Association for Cardio-Thoracic Surgery 2017 Guidelines2	Patients without underlying indication for chronic OAC
	DAPT should be considered for the first 3-6 months after TAVR, followed by lifelong SAPT in patients who do not need OAC for other reasons.	IIa – C
	SAPT may be considered after TAVR in the case of high bleeding risk.	IIb - C
	Patients with underlying indication for chronic OAC
	Despite the lack of evidence, a combination of VKA and aspirin or thienopyridine is generally used but should be weighed against increased risk of bleeding.	Expert consensus
American College of Cardiology Foundation / American Association for Thoracic Surgery / Society for Cardiovascular Angiography and Interventions / Society of Thoracic Surgeons 2012 Expert Consensus24	Patients without underlying indication for chronic OAC
	Antiplatelet therapy for at least 3-6 months after TAVR is recommended to decrease the risk of thrombotic or thromboembolic complications.	Expert consensus
	Patients with underlying indication for chronic OAC
	In patients treated with warfarin, a direct thrombin inhibitor, or factor Xa inhibitor, it is reasonable to continue low-dose aspirin but other antiplatelet therapy should be avoided if possible.	Expert consensus
Canadian Cardiovascular Society 2012 Position Statement25	Patients without underlying indication for chronic OAC
	In general, indefinite low-dose aspirin is recommended along with 1-3 months of a thienopyridine.	Expert consensus
	Patients with underlying indication for chronic OAC
	The need for adjunctive antiplatelet agents is controversial, and triple therapy should be avoided unless definite indications exist.	Expert consensus

The following antithrombotic regimen may be used after TAVR:

• In the absence of underlying indication for OAC:
  • SAPT (aspirin 75-100 mg or clopidogrel 75 mg once daily).
  • Aspirin and clopidogrel should be prescribed for an overall duration of 6-12 months in case of coronary stenting in the setting of TAVR.
• In the presence of underlying indication for OAC:
  • Oral anticoagulation alone without concomitant antiplatelet treatment. Patients already treated with novel oral anticoagulants before TAVR may continue the treatment after the procedure.
  • Triple therapy, with VKA, aspirin, and clopidogrel for 1-6 months in case of coronary stenting in the setting of TAVR, followed by VKA and clopidogrel for an overall duration of 12 months. In case of high bleeding risk, VKA and clopidogrel for 12 months after stenting may be prescribed.

References

1. Nishimura 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;70:252-89.
2. 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.
3. Durko AP, Osnabrugge RL, Van Mieghem NM, et al. Annual number of candidates for transcatheter aortic valve implantation per country: current estimates and future projections. Eur Heart J 2018;Mar 12:[Epub ahead of print].
4. 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.
5. 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.
6. Vranckx P, Windecker S, Welsh RC, Valgimigli M, Mehran R, Dangas G. Thrombo-embolic prevention after transcatheter aortic valve implantation. Eur Heart J 2017;38:3341-50.
7. 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.
8. 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.
9. 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.
10. Maes F, Stabile E, Ussia GP, et al. Meta-Analysis Comparing Single Versus Dual Antiplatelet Therapy Following Transcatheter Aortic Valve Implantation. Am J Cardiol 2018;122:310-5.
11. Vavuranakis M, Kalogeras K, Kolokathis AM, et al. Antithrombotic therapy in TAVI. J Geriatr Cardiol 2018;15:66-75.
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13. Chakravarty T, Søndergaard L, Friedman J, et al. Subclinical leaflet thrombosis in surgical and transcatheter bioprosthetic aortic valves: an observational study. Lancet 2017;389:2383-92.
14. Del Trigo M, Muñoz-Garcia AJ, Wijeysundera HC, et al. Incidence, Timing, and Predictors of Valve Hemodynamic Deterioration After Transcatheter Aortic Valve Replacement: Multicenter Registry. J Am Coll Cardiol 2016;67:644-55.
15. Siontis GCM, Praz F, Lanz J, et al. New-onset arrhythmias following transcatheter aortic valve implantation: a systematic review and meta-analysis. Heart 2017;104:1208-15.
16. Vahanian A, Alfieri O, Andreotti F, et al. Guidelines on the management of valvular heart disease (version 2012): the Joint Task Force on the Management of Valvular Heart Disease of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS). Eur J Cardiothorac Surg 2012;42:S1-44.
17. Abdul-Jawad Altisent O, Durand E, Muñoz-García AJ, et al. Warfarin and Antiplatelet Therapy Versus Warfarin Alone for Treating Patients With Atrial Fibrillation Undergoing Transcatheter Aortic Valve Replacement. JACC Cardiovasc Interv 2016;9:1706-17.
18. Seeger J, Gonska B, Rodewald C, Rottbauer W, Wöhrle J. Apixaban in Patients With Atrial Fibrillation After Transfemoral Aortic Valve Replacement. JACC Cardiovasc Interv 2017;10:66-74.
19. Ramee S, Anwaruddin S, Kumar G, et al. The Rationale for Performance of Coronary Angiography and Stenting Before Transcatheter Aortic Valve Replacement: From the Interventional Section Leadership Council of the American College of Cardiology. JACC Cardiovasc Interv 2016;9:2371-5.
20. Kirchhof P, Benussi S, Kotecha D, et al. 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Eur Heart J 2016;37:2893-962.
21. Nijenhuis VJ, Bennaghmouch N, Hassell M, et al. Rationale and design of POPular-TAVI: antiPlatelet therapy fOr Patients undergoing Transcatheter Aortic Valve Implantation. Am Heart J 2016;173:77-85.
22. Windecker S, Tijssen J, Giustino G, et al. Trial design: Rivaroxaban for the prevention of major cardiovascular events after transcatheter aortic valve replacement: Rationale and design of the GALILEO study. Am Heart J 2017;184:81-7.
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Keywords: Transcatheter Aortic Valve Replacement, Aspirin, Ischemic Attack, Transient, Atrial Fibrillation, Coronary Artery Disease, Aortic Valve, Echocardiography, Transesophageal, Satureja, Bioprosthesis, Four-Dimensional Computed Tomography, Retrospective Studies, Confidence Intervals, Ticlopidine, Pyridones, Pyrazoles, Thromboembolism, Myocardial Infarction, Stroke, Thrombosis, Anticoagulants, Stents, Registries, Percutaneous Coronary Intervention, Vitamin K, Aortic Valve Stenosis, Heart Valve Diseases

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