Your activity: 10 p.v.

Transcatheter aortic valve implantation: Antithrombotic therapy

Transcatheter aortic valve implantation: Antithrombotic therapy
Author:
Stephen JD Brecker, MD, FRCP, FESC, FACC
Section Editors:
Donald Cutlip, MD
Jeroen J Bax, MD, PhD
Deputy Editor:
Susan B Yeon, MD, JD, FACC
Literature review current through: Nov 2022. | This topic last updated: Aug 03, 2021.

INTRODUCTION — Aortic valve replacement (AVR) is the mainstay of treatment for symptomatic severe aortic stenosis (AS). The role of transcatheter aortic valve implantation (TAVI; also known as transcatheter aortic valve replacement or TAVR) as an alternative to surgical aortic valve replacement (SAVR) is established, and in 2019, the number of TAVIs exceeded SAVRs in the US for the first time [1]. A multidisciplinary team approach is recommended in approaching patients with symptomatic AS. (See "Choice of intervention for severe calcific aortic stenosis".)

This topic will review antithrombotic therapy post-TAVI. Indications for AVR, choice of aortic valve intervention (TAVI versus SAVR), TAVI periprocedural care (including anticoagulation during the procedure), medical therapy for symptomatic AS, and percutaneous aortic valvuloplasty are discussed separately. (See "Indications for valve replacement for high gradient aortic stenosis in adults" and "Choice of intervention for severe calcific aortic stenosis" and "Transcatheter aortic valve implantation: Periprocedural and postprocedural management" and "Estimating the risk of valvular procedures" and "Medical management of symptomatic aortic stenosis" and "Percutaneous balloon aortic valvotomy for native aortic stenosis in adults".)

GENERAL APPROACH — Post-TAVI antithrombotic therapy varies depending upon the following factors (algorithm 1):

Presence of a concurrent indication for anticoagulation (such as atrial fibrillation [AF] with criteria for anticoagulation).

Presence of a concurrent indication for antiplatelet therapy (such as the indication for dual antiplatelet therapy with recent coronary artery stent implantation).

WITHOUT CONCURRENT INDICATION FOR THERAPEUTIC ANTICOAGULATION — Patients without a concurrent indication for anticoagulation are generally treated with chronic antiplatelet therapy post-TAVI (in the intermediate and long term) (algorithm 1); a role for routine anticoagulation in this setting has not been established [2].

Thus, antithrombotic therapy in the intermediate term (initial three to six months) following transcatheter bioprosthetic aortic valve implantation differs from that for surgically implanted bioprosthetic valves (which includes intermediate-term anticoagulation). (See "Antithrombotic therapy for surgical bioprosthetic valves and surgical valve repair", section on 'Approach for surgical bioprosthetic valves'.)

Without concurrent indication for dual antiplatelet therapy

For patients post-TAVI without a concurrent indication for therapeutic anticoagulation and no concurrent indication for dual antiplatelet therapy (DAPT), we suggest treatment with a single antiplatelet therapy (SAPT; generally aspirin 75 to 100 mg daily; if aspirin is contraindicated, clopidogrel 75 mg daily is an alternative) for life. In the available clinical trials, the risk of stroke appears to be similar with SAPT and DAPT, but SAPT is associated with lower bleeding risk.

A reasonable alternative for patients with no concurrent indication for anticoagulation is to use DAPT (aspirin 75 to 100 mg daily plus clopidogrel 75 mg daily) in the intermediate term (during the initial three to six months depending upon valve type) followed by lifelong SAPT, which is the approach used in the pivotal TAVI trials. If intermediate-term DAPT is chosen, it is continued for the first six months (for the SAPIEN valve) or for the first three months (for the Evolut R/PRO/PRO-PLUS valve).

For patients post-TAVI with an indication for subtherapeutic anticoagulation (eg, low-dose heparin for prophylaxis against deep vein thrombosis) and no concurrent indication for DAPT, we suggest SAPT rather than DAPT.

The SAPT approach is based upon evidence that post-TAVI DAPT increases bleeding risk without improving clinical outcomes compared with SAPT. Support for this approach comes from a randomized controlled trial in patients undergoing TAVI without a concurrent indication for anticoagulation at the time of the procedure [3]. This trial found lower bleeding risk and similar stroke risk at one year with SAPT compared with DAPT for the three months following the procedure. A bleeding event occurred less frequently in the 331 patients receiving aspirin alone compared with the 334 patients receiving aspirin plus clopidogrel (15.1 versus 26.6 percent; risk ratio [RR] 0.57, 95% CI 0.42-0.77). The frequency of stroke was similar in the two groups (5.1 versus 5.7 percent; RR 0.90, 95% CI 0.50-1.82). A secondary composite 1 event (composite of death from cardiovascular causes, non–procedure-related bleeding, stroke, or myocardial infarction) occurred less frequently in patients receiving aspirin alone compared with those receiving aspirin plus clopidogrel (23.0 versus 31.1 percent; 95% CI for superiority 0.57-0.95). A secondary composite 2 event (a composite of death from cardiovascular causes, ischemic stroke, or myocardial infarction) occurred at similar rates in the two groups (9.7 versus 9.9 percent; 95% CI for superiority 0.62-1.55). The risk of subclinical valve thrombosis was not assessed. Oral anticoagulation was started during the trial (most commonly for AF) in 13.3 percent of the aspirin-alone group and 9.6 percent in the aspirin-clopidogrel group.

Outcomes post-TAVI with SAPT versus DAPT were also compared in a network meta-analysis including three earlier randomized controlled trials and 10 observational studies with a total of 20,548 post-TAVI patients [4]. SAPT was associated with lower rates of major and/or life-threatening bleeding compared with other antithrombotic regimens (hazard ratio [HR] 0.59, 95% CI 0.46-0.77 compared with DAPT). Mortality and stroke rates were similar with DAPT and SAPT. However, this analysis included limited adjustment for differences in risk.

With concurrent indication for dual antiplatelet therapy — If there is a concurrent indication for DAPT (eg, recent coronary artery stenting) but no concurrent indication for anticoagulation, the duration of DAPT is dictated by the concurrent indication. After this period, we suggest daily SAPT (generally aspirin 75 to 100 mg daily; if aspirin is contraindicated, clopidogrel 75 mg daily is an alternative) for life rather than anticoagulation. This approach is based upon protocols in randomized trials comparing TAVI with other therapy and is reflected in major society guidelines [2,5]. (See "Choice of intervention for severe calcific aortic stenosis", section on 'Outcomes'.)

Uncertain role of anticoagulation (without a concurrent indication) — For patients post-TAVI who lack a concurrent indication for anticoagulation, the efficacy and safety of anticoagulation are uncertain and are under investigation. A possible role for anticoagulation is being studied given concern about the risk of bioprosthetic valve thrombosis post-TAVI with standard antiplatelet therapy and some observational data suggesting that the risk of bioprosthetic valve thrombosis is reduced with anticoagulation. (See "Transcatheter aortic valve implantation: Complications", section on 'Valve thrombosis'.)

The 2020 American College of Cardiology/American Heart Association (ACC/AHA) valvular disease guideline suggested that for patients post-TAVI who lack an established indication for anticoagulation and who have a low risk of bleeding, treatment with a vitamin K antagonist (VKA) to achieve an international normalized ratio of 2.5 for three months or more may be reasonable [2]; however, the limited available evidence is not sufficient to support routine VKA use in this setting.

Limited data are available on the effects of anticoagulation in patients post-TAVI with no concurrent indication for anticoagulation. An analysis of data of 4832 patients undergoing bioprosthetic aortic valve replacement (3889 TAVI and 943 SAVR) in the pooled cohort of the PARTNER 2 randomized trial and nonrandomized registries found that discharge without anticoagulant therapy was associated with a higher frequency of a >10 mmHg increase in mean transvalvular gradient from 30 days to one year compared with discharge with an anticoagulant (2.3 versus 1.1 percent) [6]. There were similar rates of prosthetic valve dysfunction without and with anticoagulation (1.3 and 1.70 percent). There was no independent association between post-TAVI anticoagulation and death or rehospitalization. Anticoagulation post-TAVI was associated with greater minor bleeding (8.5 versus 5.0 percent; adjusted HR 1.72, 95% CI 1.13-2.61).

Patients post-TAVI should not be routinely treated with the combination of a direct oral anticoagulant plus antiplatelet agent in the absence of a concurrent indication for anticoagulation, given adverse outcomes with rivaroxaban plus aspirin use in the GALILEO trial [7], although this antithrombotic regimen reduced subclinical prosthetic valve abnormalities in an imaging substudy [8]. In the GALILEO trial, 1644 patients without an established indication for oral anticoagulation after TAVI were randomly assigned to receive rivaroxaban 10 mg daily (with aspirin 75 to 100 mg daily for the first three months) or aspirin 75 to 100 mg daily (with clopidogrel 75 mg daily for the first three months).

The trial was stopped early, at a median follow-up of 17 months, because of safety concerns. In the rivaroxaban group, there were higher rates of death or first thromboembolic event (105 versus 78 patients; 9.8 versus 7.2 per 100 person-years; HR 1.35, 95% CI 1.01-1.81) and all-cause mortality (64 versus 38 deaths; 5.8 versus 3.4 per 100 person-years; HR 1.69, 95% CI 1.13-2.53) compared with the antiplatelet-only group. Major bleeding was more frequent in the rivaroxaban group (2.8 versus 1.4 person-years; HR 2.02, 95% CI 1.09-3.76), but rates of life-threatening or disabling bleeding were similar in the two groups (1.6 versus 1.5 person-years; HR 1.06, 95% CI 0.55-2.06).

In a 231 patient substudy of this trial, four-dimensional computed tomography was performed at a mean of 90 days after randomization [8]. In the rivaroxaban group, there was a lower rate of subclinical leaflet motion abnormalities (grade 3 or higher motion reduction; 2.1 versus 10.9 percent in the antiplatelet group; difference -8.8 percentage points, 95% CI -16.5 to -1.9), as well as a lower rate of hypoattenuated thickening of one or more bioprosthetic leaflets (12.4 versus 32.4 percent; difference -20.0 percentage points, 95% CI -30.9 to -8.5) compared with the antiplatelet group. There were few clinical events in the imaging substudy, so the relation between subclinical leaflet abnormalities and clinical events could not be assessed.

WITH CONCURRENT INDICATION FOR THERAPEUTIC ANTICOAGULATION — The optimal post-TAVI antithrombotic regimen for patients with a concurrent indication for therapeutic anticoagulation (eg, AF with risk factors favoring anticoagulation) has not been established, and clinical practice varies [2,5,9-11]. Given the limited available evidence, we base antithrombotic therapy in this setting on whether there is a concurrent indication for antiplatelet therapy (algorithm 1), as discussed in the following sections.

Anticoagulation without antiplatelet therapy — For a patient post-TAVI with a concurrent indication for therapeutic anticoagulation (eg, AF with CHA2DS2-VASc score ≥2 in males or ≥3 in females) and no concurrent indication for antiplatelet therapy, anticoagulation is prescribed and no additional antithrombotic therapy for TAVI is required.

The selection of anticoagulant (vitamin K antagonist [VKA] or direct oral anticoagulant [DOAC]) is based upon the indication for anticoagulation and other clinical factors. For most patients post-TAVI with a concurrent indication for anticoagulation (including most patients with AF), we prefer a DOAC to VKA therapy. This approach is supported by the following studies:

An open-label trial randomly assigned 1426 post-TAVI patients (mean age 82 years) with AF to edoxaban or VKA with median follow-up of approximately 1.5 years [12]. During the trial period, the trial drug was discontinued by 30.2 percent in the edoxaban group and 40.5 percent in the VKA group. Mortality rates (7.8 and 9.1 percent respectively; hazard ratio [HR] 0.86, 95% CI 0.64-1.15) and ischemic stroke rates (2.1 and 2.8 percent; HR 0.75, 95% CI 0.43-1.30) were similar in the two groups. The rate of major bleeding was higher in the edoxaban group (9.7 and 7.0 percent; HR 1.40, 95% CI 1.03-1.91) but rates of intracranial hemorrhage (1.5 and 2.1 percent; HR 0.72, 95% CI 0.38-1.39) were similar in the two groups.

An observational study of patients post-TAVI found higher rates of death and major bleeding in patients treated with VKAs compared with those treated with DOACs. Of 24,581 patients (mean age 83 years) in French TAVI registries linked to the national health claims database, 36.5 percent of the patients were treated with an oral anticoagulant [13]. Among those anticoagulated, over two-thirds had AF. Propensity-matched comparisons at three years between patients receiving VKAs (n = 1093) and those receiving DOACs (n = 1378) identified higher rates of mortality (HR 1.37, 95% CI 1.12-1.67) and major bleeding including hemorrhagic stroke (HR 1.64, 95% CI 1.17-2.29) in patients on VKAs. Rates of ischemic stroke and acute coronary syndrome were similar in the two groups.

Evidence on use of DOAC versus warfarin in patients with AF is discussed separately. (See "Atrial fibrillation in adults: Use of oral anticoagulants".)

Anticoagulation with antiplatelet therapy — A patient post-TAVI with a concurrent indication for therapeutic anticoagulation (eg, AF) and a concurrent indication for antiplatelet therapy (eg, recent coronary artery stent) is treated with anticoagulant plus antiplatelet therapy. Long-term triple antithrombotic therapy (anticoagulation plus dual antiplatelet therapy [DAPT]) is generally avoided. (See 'Avoid triple antithrombotic therapy' below.)

The above described approach of using combined anticoagulant and antiplatelet therapy only when specific indications are present is supported by the results of the POPular TAVI trial performed in patients receiving oral anticoagulants for appropriate indications [14]. The patients were randomly assigned to not receive clopidogrel or receive clopidogrel for three months after TAVI, and outcomes were assessed at one year. Bleeding occurred less frequently in the 157 patients receiving an oral anticoagulant alone than in the 156 patients receiving an oral anticoagulant plus clopidogrel (21.7 versus 34.6 percent; relative risk [RR] 0.63, 95% CI 0.43-0.90). Major, life-threatening, or disabling bleeding was less frequent in the oral anticoagulant only group (8.9 versus 16.7 percent; RR 0.54, 95% CI 0.29-0.99). Most bleeding occurred in the first month and was minor. Rates of ischemic stroke were similar in the two groups, but were based upon few events (8 events or 5.1 percent in the oral anticoagulant only group and 9 events or 5.8 percent in the oral anticoagulant plus clopidogrel group). There was one hemorrhagic stroke in the oral anticoagulant only group and none in the oral anticoagulant plus clopidogrel group. Mortality rates were similar in the two groups (13.4 versus 15.4 percent; RR 0.87, 95% CI 0.51-1.50).

A potential clinical benefit of antiplatelet therapy in reducing the risk of stroke in patients post-TAVI with AF was suggested by an analysis of data from the PARTNER 2 trial and associated registries [15]. In an adjusted analysis of data on 1621 patients with prior AF and CHA2DS2-VASc score ≥2, antiplatelet therapy (for at least 6 months or until an endpoint event) with or without anticoagulation was associated with reduced rate of stroke at two years compared with no antithrombotic therapy (HR for anticoagulant plus antiplatelet therapy 0.44, 95% CI 0.22-0.87; HR for antiplatelet therapy alone 0.32, 95% CI 0.16-0.65), while anticoagulation alone was not (HR 0.61, 95% CI 0.31-1.21). In this adjusted analysis, the risk of death or stroke was lower with antiplatelet therapy with or without anticoagulation, as well as with anticoagulation alone, compared with no antithrombotic therapy. Indications for antiplatelet therapy in the study subjects were not provided.

Avoid triple antithrombotic therapy — We generally avoid triple antithrombotic therapy (DAPT plus anticoagulation) post-TAVI. The above cited network meta-analysis evaluating antithrombotic therapy post-TAVI found that triple antithrombotic therapy was associated with a higher mortality rate than each of the other antithrombotic regimens (including anticoagulation plus single antiplatelet therapy) [4]. Although this network meta-analysis has several limitations, this finding is consistent with indirect evidence of adverse effects of triple antithrombotic therapy from studies of patients with AF and acute coronary syndrome or percutaneous coronary intervention. (See "Coronary artery disease patients requiring combined anticoagulant and antiplatelet therapy", section on 'Efficacy and safety'.)

Management of antithrombotic therapy for patients with coronary artery disease requiring anticoagulant and antiplatelet therapy is discussed separately. (See "Coronary artery disease patients requiring combined anticoagulant and antiplatelet therapy".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Cardiac valve disease" and "Society guideline links: Transcatheter aortic valve implantation".)

SUMMARY AND RECOMMENDATIONS

Post-transcatheter aortic valve implantation (TAVI) antithrombotic therapy varies depending upon whether there is a concurrent indication for anticoagulation (such as atrial fibrillation [AF] with criteria for anticoagulation) (algorithm 1).

For patients post-TAVI without a concurrent indication for therapeutic anticoagulation (algorithm 1) (see 'Without concurrent indication for therapeutic anticoagulation' above):

If there is no concurrent indication for dual antiplatelet therapy (DAPT), we suggest lifelong treatment with single antiplatelet therapy (SAPT) rather than DAPT (Grade 2B). SAPT generally consists of aspirin 75 to 100 mg daily; if aspirin is contraindicated, clopidogrel 75 mg daily is an alternative. In the available clinical trials, the risk of stroke appears to be similar with SAPT and DAPT, but SAPT is associated with lower bleeding risk. (See 'Without concurrent indication for dual antiplatelet therapy' above.)

A reasonable alternative for patients with no indication for anticoagulation is to use DAPT in the intermediate term (during the initial three to six months depending upon valve type) followed by lifelong SAPT, which is the approach used in the pivotal TAVI trials. If intermediate-term DAPT is chosen, it is continued for the first six months (for the SAPIEN valve) or for the first three months (for the Evolut R/PRO/PRO-PLUS valve).

If there is a concurrent indication for DAPT (eg, recent coronary artery stenting), the selection of agents and duration of DAPT is dictated by the concurrent indication. After this period, we suggest daily SAPT for life rather than anticoagulation (Grade 2C). (See 'With concurrent indication for dual antiplatelet therapy' above.)

Patients post-TAVI without a concurrent indication for therapeutic anticoagulation should not be routinely treated with a direct oral anticoagulant (DOAC) plus antiplatelet agent, given adverse outcomes observed in a randomized trial. (See 'Uncertain role of anticoagulation (without a concurrent indication)' above.)

For patients post-TAVI with a concurrent indication for therapeutic anticoagulation (algorithm 1) (see 'With concurrent indication for therapeutic anticoagulation' above):

If there is no concurrent indication for antiplatelet therapy, we suggest no additional antithrombotic therapy for TAVI other than anticoagulation (Grade 2C). The selection of anticoagulant (vitamin K antagonist [VKA] or DOAC) is generally based upon the indication for anticoagulation and other clinical factors. For example, a DOAC is generally preferred for patients with AF with risk factors favoring anticoagulation, as discussed separately. (See 'With concurrent indication for therapeutic anticoagulation' above and "Atrial fibrillation in adults: Use of oral anticoagulants", section on 'Approach to anticoagulation'.)

If there is a concurrent indication for antiplatelet therapy, the patient is treated with anticoagulant plus antiplatelet therapy. The selection of anticoagulant and antiplatelet agents and duration of use is based upon the indications for these agents. Long-term triple antithrombotic therapy (anticoagulation plus DAPT) is generally avoided. (See 'Avoid triple antithrombotic therapy' above.)

  1. Carroll JD, Mack MJ, Vemulapalli S, et al. STS-ACC TVT Registry of Transcatheter Aortic Valve Replacement. J Am Coll Cardiol 2020; 76:2492.
  2. Otto CM, Nishimura RA, Bonow RO, et al. 2020 ACC/AHA Guideline for the Management of Patients With Valvular Heart Disease: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation 2021; 143:e72.
  3. 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.
  4. 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.
  5. 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.
  6. Chakravarty T, Patel A, Kapadia S, et al. Anticoagulation After Surgical or Transcatheter Bioprosthetic Aortic Valve Replacement. J Am Coll Cardiol 2019; 74:1190.
  7. 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.
  8. De Backer O, Dangas GD, Jilaihawi H, et al. Reduced Leaflet Motion after Transcatheter Aortic-Valve Replacement. N Engl J Med 2020; 382:130.
  9. Nijenhuis VJ, Brouwer J, Søndergaard L, et al. Antithrombotic therapy in patients undergoing transcatheter aortic valve implantation. Heart 2019; 105:742.
  10. Saito Y, Nazif T, Baumbach A, et al. Adjunctive Antithrombotic Therapy for Patients With Aortic Stenosis Undergoing Transcatheter Aortic Valve Replacement. JAMA Cardiol 2020; 5:92.
  11. Ranasinghe MP, Peter K, McFadyen JD. Thromboembolic and Bleeding Complications in Transcatheter Aortic Valve Implantation: Insights on Mechanisms, Prophylaxis and Therapy. J Clin Med 2019; 8.
  12. Van Mieghem NM, Unverdorben M, Hengstenberg C, et al. Edoxaban versus Vitamin K Antagonist for Atrial Fibrillation after TAVR. N Engl J Med 2021; 385:2150.
  13. Didier R, Lhermusier T, Auffret V, et al. TAVR Patients Requiring Anticoagulation: Direct Oral Anticoagulant or Vitamin K Antagonist? JACC Cardiovasc Interv 2021; 14:1704.
  14. 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.
  15. Kosmidou I, Liu Y, Alu MC, et al. Antithrombotic Therapy and Cardiovascular Outcomes After Transcatheter Aortic Valve Replacement in Patients With Atrial Fibrillation. JACC Cardiovasc Interv 2019; 12:1580.
Topic 131939 Version 7.0

References