Evidence review for anticoagulant and/or antiplatelet therapy for biological prosthetic valves and after valve repair

National Guideline Centre (UK)

Evidence review for anticoagulant and/or antiplatelet therapy for biological prosthetic valves and after valve repair

Heart valve disease presenting in adults: investigation and management

Evidence review J

NICE Guideline, No. 208

Authors

National Guideline Centre (UK).

London: National Institute for Health and Care Excellence (NICE); 2021 Nov.

ISBN-13: 978-1-4731-4301-2

1. Anticoagulant and antiplatelet use after biological valve replacement and valve repair

1.1. Review question: What is the clinical and cost effectiveness of anticoagulant and/or antiplatelet therapy for adults with transcatheter or surgical biological prosthetic valves or after valve repair?

1.2. Introduction

Anticoagulation is essential for patients with mechanical prosthetic heart valves. However, controversy exists in clinical practice regarding the use of anticoagulant and/or antiplatelet therapy for transcatheter or surgical prosthetic valves. Consequently, it is important to determine the clinical and cost effectiveness of anticoagulant and/or antiplatelet therapy in this setting, examining the associated risks and benefits.

1.3. PICO table

For full details see the review protocol in Appendix A:.

Table 1

PICO characteristics of review question.

1.4. Clinical evidence

1.4.1. Included studies

A search was conducted for randomised controlled trials (RCTs) comparing the effectiveness of antithrombotic agents (including anticoagulants and antiplatelet therapies) against other antithrombotic agents, placebo or no treatment with antithrombotic agents.

Ten RCTs reported in 11 publications were included in the review;¹⁵^, ¹⁸^, ¹⁹^, ²³^, ³¹^, ⁵⁰^, ⁵⁷^, ⁶²^, ⁶⁸^, ⁷³^, ⁷⁵ these are summarised in Table 2 below. Evidence from these studies is summarised in the clinical evidence summary tables below (Table 3, Table 4, Table 5, Table 6, Table 7 and Table 8).

The evidence covered the following populations and comparisons:

Surgical valve replacement

DOAC versus VKA: 1 study²³
VKA versus SAPT: 2 studies¹⁸^, ⁵⁷
VKA and SAPT versus VKA alone: 1 study⁷³

Transcatheter valve implantation

SAPT versus DAPT: 3 primary RCTs⁶²^, ⁶⁸^, ⁷⁵, and 1 individual patient data meta analysis³¹
direct-acting oral anticoagulant (+single antiplatelet therapy for 3 months) vs. single antiplatelet therapy alone (+clopidogrel for 3 months): 1 RCT¹⁹
oral anticoagulant + single antiplatelet therapy vs. oral anticoagulant alone: 1 RCT⁵⁰

One individual patient data (IPD) meta-analysis³¹ was included, which contained two RCTs identified during the search⁶⁸^, ⁷⁵. The risk of bias for this systematic review was assessed using the ROBIS checklist, and the primary RCTs were also assessed. Only additional outcomes (not included in the IPD) were extracted from the individual RCTs.

No RCTs were included that discussed antithrombotic therapy in heart valve repair.

See also the study selection flow chart in Appendix C:, study evidence tables in Appendix D:, forest plots in Appendix E: and GRADE tables in Appendix F:.

1.4.2. Excluded studies

See the excluded studies list in Table 20.

A Cochrane review⁴⁶ was identified but could not be included as it included studies with people who had mechanical prosthetic valves and biological prosthetic valves. The studies did not separate the people with mechanical prosthetic valves and biological prosthetic valves and so were not applicable to our protocol. All included studies were cross-checked for inclusion in this review.

1.4.3. Summary of clinical studies included in the evidence review

Table 2

Summary of studies included in the evidence review.

See Appendix D:for full evidence tables.

1.4.4. Quality assessment of clinical studies included in the evidence review

1.4.4.1. Surgical valve replacement

Table 3

Clinical evidence summary: DOAC versus VKA in surgical valve replacement.

Table 4

Clinical evidence summary: VKA versus SAPT in surgical valve replacement.

Table 5

Clinical evidence summary: VKA and SAPT versus VKA alone in surgical valve replacement.

1.4.4.2. Transcatheter valve implantation

Table 6

Clinical evidence summary: SAPT versus DAPT in biological transcatheter valve implantation.

Table 7

Clinical evidence summary: DOAC (+ aspirin for 3 months) versus aspirin (+ clopidogrel for 3 months) in biological transcatheter valve implantation.

Table 8

Clinical evidence summary: Anticoagulant (VKA or DOAC) + SAPT (clopidogrel) versus anticoagulant (VKA or DOAC) alone in biological transcatheter valve implantation.

1.4.4.3. Valve repair

No information available.

See Appendix F: for full GRADE tables.

1.5. Economic evidence

1.5.1. Included studies

No health economic studies were included.

1.5.2. Excluded studies

No relevant health economic studies were excluded due to assessment of limited applicability or methodological limitations.

See also the health economic study selection flow chart in Appendix G:.

1.5.3. Summary of studies included in the economic evidence review

No economic evidence identified.

1.5.4. Health economic modelling

This question was not prioritised for economic modelling.

1.5.5. Unit costs

Relevant unit costs are provided below to aid consideration of cost effectiveness.

Table 9

UK costs of anticoagulant and antiplatelet drugs.

1.5.5.1. Monitoring

For warfarin there is also the cost of monitoring. In the previous update of the guideline (CG178), the annual cost of warfarin monitoring (anticoagulation clinic) was reported in the costing template as £241.54 a year (2014 cost year). This equates to a daily cost of £0.66, or £0.67 when including the drug cost of warfarin as well.

1.6. Evidence statements

1.6.1. Clinical evidence statements

See the summary of evidence in Table 3, Table 4, Table 5, Table 6, Table 7 and Table 8.

1.6.2. Health economic evidence statements

No relevant economic evaluations were identified.

1.7. The committee’s discussion of the evidence

1.7.1. Interpreting the evidence

1.7.1.1. The outcomes that matter most

The critical outcomes were all-cause mortality, health-related quality of life, major bleeding, minor bleeding and arterial thromboembolic events (including myocardial infarction, stroke and transient ischaemic attack). These events were considered critical due to their consequences to people with heart valve disease. The important outcomes were hospital re-admission, withdrawal from the study due to adverse events, thrombus on imaging of the valve, need for re-intervention and valve degeneration.

Thrombus on valve imaging was considered important by the committee as this is believed to reduce valve durability by provoking earlier valve degeneration (measured by transvalvular gradient). This will affect patients in the long-term as it will mean they require re-intervention earlier. Valve degeneration can present in multiple ways, including a drop in mean calculated effective valve area and development of valvular regurgitation, but valve degeneration as measured by transvalvular gradient was prioritised for inclusion in this review.

Health-related quality of life, need for re-intervention and valve degeneration were not reported in any of the studies, possibly because the length of follow-up in the studies was short and studies did not aim to measure these types of outcomes where any effects would take longer to occur, with the longest follow-up being ~12 months.

1.7.1.2. The quality of the evidence

Eleven studies, including one systematic review (with individual patient data) and ten randomised controlled trials were included in this review. No relevant clinical studies for antithrombotic therapy in valve repair were identified. Evidence was available for the following comparisons:

Biological surgical valve replacement
- DOAC versus VKA
- VKA versus SAPT
- VKA and SAPT versus VKA alone
Transcatheter valve implantation
- SAPT versus DAPT
- DOAC (+SAPT for 3 months) versus SAPT (DAPT for 3 months)
- Anticoagulant (VKA or DOAC) + SAPT versus anticoagulant alone (VKA or DOAC)

Most of the evidence ranged from low to very low quality. Three outcomes in the transcatheter valve group were of moderate quality: major bleeding and mean aortic valve gradient at short term time points for SAPT versus DAPT, major bleeding at >12 months for DOAC (+ aspirin for 3 months) versus aspirin (+ clopidogrel for 3 months). Evidence quality was often downgraded due to the risk of bias and imprecision. Common problems leading to risk of bias were issues with selection bias, including groups not being comparable at baseline for all reported factors in some studies and some studies where allocation concealment was not described, and incomplete outcome data due to missing data rates being high or not well reported.. The majority of the analyses were based on data from a small number of participants and some outcomes had low event rates resulting in uncertainty. One study was downgraded for indirectness because participants were given a mixture of medications included in our protocol and a medication excluded from our protocol without a way to separate out the cases affected.

Based on the limitations of the evidence, including the population being limited to older adults, lack of a placebo comparison and a lack of data longer than 12 months follow-up, the strength of the recommendation made for single antiplatelet therapy after transcatheter intervention was limited to consider. A strong do not offer recommendation was made against the use of anticoagulation after surgical biological valve replacement supported by evidence of very low quality, but also based on the clinical experience of the committee.

1.7.1.3. Benefits and harms

Direct acting oral anticoagulants compared to vitamin K antagonists following surgical biological valve replacement

For the comparison of direct acting oral anticoagulants compared to vitamin K antagonists after surgical biological valve replacement, the committee agreed that there were no clinically significant differences for major bleeding, arterial thromboembolic events, hospital readmission and thrombus on imaging. A small benefit of direct acting oral anticoagulants was seen for reduced all-cause mortality. However, this effect estimate was based on a very small sample size (27 people) and a very low event rate reported during the follow up period of 3 months, and so the committee did not have confidence in this finding. The population of the study consisted of people who had atrial fibrillation post-operatively. This would alter the risk of arterial thromboembolic events compared to the population without atrial fibrillation and it was likely that the anti-thrombotic treatment was primarily used to manage the atrial fibrillation rather than the valve disease.

Based on this information and the lack of applicable evidence the committee agreed that they could not make a recommendation on the choice between vitamin K antagonists and direct acting oral anticoagulants for biological surgical valve replacement, and have included these treatment options in a recommendation for research (see Appendix J.2.1 for details), including long term outcomes. However, a recommendation was made on the use of anticoagulants in general based on the evidence discussed in the paragraph below and the experience of the committee.

Vitamin K antagonists compared to single antiplatelet therapy following surgical biological valve replacement

For the comparison of vitamin K antagonists with single antiplatelet therapy after surgical biological valve replacement, a clinically important benefit was seen for single antiplatelet therapy in reducing major bleeding events. The evidence also suggested a possible small benefit of single antiplatelet therapy in reducing all-cause mortality but there was too much uncertainty in the effect estimate to conclude whether or not this was a clinically important effect. This was associated with no clinically important difference between the two interventions for arterial thromboembolic events, hospital re-admission and thrombus on imaging.

One of the included studies compared four treatment arms, where two groups had simultaneous coronary artery bypass grafting surgery and surgical valve replacement, while the others did not. The population who had coronary artery bypass grafting surgery would be at a greater risk of adverse events compared to the population having valve replacement alone, which made the evidence more difficult to interpret.

Both studies consisted of people without atrial fibrillation taking warfarin for three months. In one study, the people taking warfarin switched to aspirin after this time and continued this for three months while the other study concluded after three months. Therefore, the committee could not assess the long-term efficacy of treatment and made a research recommendation (see Appendix J.2.1 for details). The committee could not make a consensus recommendation.

Based on the evidence of an increased bleeding risk with vitamin K antagonists and no apparent reduction in risk for other outcomes, such as mortality or thromboembolic events, the lack of clinical difference between vitamin K antagonists and direct acting oral anticoagulants (as discussed in the paragraph above) and supported by clinical experience, the committee made a recommendation not to use anticoagulants after surgical biological valve replacement unless there are other indications for anticoagulant therapy. Where this is the case, the committee recommended following the existing guidelines for the relevant indication.

Combined anticoagulant and antiplatelet therapy compared to anticoagulant therapy alone following surgical biological valve replacement

For the comparison of combined vitamin K antagonists and single antiplatelet therapy compared to single antiplatelet therapy alone following surgical biological valve replacement, the evidence suggested a reduction in the composite outcome of major systemic embolism or death from vascular causes with the combination therapy, although there was great uncertainty around the effect estimate. However, the committee discussed that this study was not relevant to the population based on the target INR being much higher than that used in standard practice and the fact that all participants had to have atrial fibrillation or a thromboembolic event prior to surgery. Most importantly, the study was conducted in patients with mechanical and biological valve replacement. The populations were combined for all outcomes apart from “major systemic embolism or death from vascular causes”. Due to the indirectness of this outcome and the imprecision of the effect size based on one study with a small sample size, the committee agreed that it was not possible to make any recommendations based on this evidence. Additionally, given limited evidence for whether any form of anticoagulation/antiplatelet is needed, research recommendations were prioritised to compare treatments with placebo rather than to each other or combinations. It was not possible to make a consensus recommendation.

Single antiplatelet therapy compared to dual antiplatelet therapy following transcatheter valve implantation

For the comparison of single antiplatelet therapy to dual antiplatelet therapy after transcatheter aortic valve implantation a clinically important benefit was seen with single antiplatelet in reducing major and minor bleeding events. A small but clinically significant effect of single antiplatelet therapy in reducing mortality compared to dual antiplatelet therapy was also observed, however there was uncertainty in this effect estimate and the difference was very small so the committee were not confident in this finding. Arterial thromboembolic events were reported as a range of odds ratios due to heterogeneity on inspection of the forest plot, with large effect estimates in opposite directions between the included studies, and the inability to form adequate subgroups with the limited number of studies. A separate study also reported only small differences between the two groups in terms of stroke, myocardial infarction, symptomatic clinical aortic valve thrombosis and valve degeneration (mean aortic valve gradient), with uncertainty in the direction of effect present for all of these outcomes. Therefore, in addition to the uncertainty around the effect estimates, it was not possible to determine whether there was a benefit to either treatment for these outcomes.

The committee noted that all the included studies were conducted in an older population (people aged over 70 years), who may already be at a higher risk of major bleeding and arterial thromboembolic events, with a lower window for benefit, than a younger population. This included people with comorbidities, including chronic kidney disease. While this may influence the results, the committee felt that this was applicable to people in the United Kingdom.

The committee raised the lack of comparison to placebo, which meant that, while they could say there was a benefit of taking single antiplatelet therapy rather than dual antiplatelet therapy, they could not say that single antiplatelet therapy was preferable to no antiplatelet therapy.

There was no evidence for long-term outcomes, with the studies included having a duration of up to 12 months. This meant that the committee were uncertain on the long-term efficacy of the treatment. The committee noted that antiplatelet agents used over the long term may reduce the risk of valve thrombosis and have a positive effect on valve durability. Some evidence for this may come from observational studies that were excluded in this protocol. These factors contributed to the research recommendations.

Based on the higher bleeding risk observed with dual antiplatelet therapy compared to single antiplatelet therapy, especially in the elderly population, and supported by clinical experience, the committee made a recommendation to consider single antiplatelet therapy following transcatheter aortic valve implantation. The recommendation was specifically for aspirin, as this was the drug usually used in practice and was used in all of the studies. Clopidogrel was included in the recommendation as the alternative if aspirin was not tolerated, in line with current practice. However, given the lack of evidence, clopidogrel was also included within the research recommendation (see Appendix J.1.1 for details).

The committee agreed that in practice it would be normal for the majority of patients having transcatheter aortic valve implantation to have at least a single antiplatelet agent, with many receiving dual antiplatelet therapy. The committee noted that there is limited experience of implanting TAVI without any antiplatelet therapy

Rivaroxaban (+aspirin for 3 months) compared to aspirin (+clopidogrel for 3 months) following transcatheter valve implantation

One study with 1644 participants was included that compared outcomes with rivaroxaban (a DOAC) to aspirin, with a median treatment duration of 428 days in the rivaroxban group. In both groups, the first 3 months involved a combined treatment, with aspirin taken alongside rivaroxban and clopidogrel taken alongside aspirin in those randomised to rivaroxaban and aspirin, respectively.

The absolute effects for the majority of the outcomes favoured the aspirin group, with a clinically important harm of rivaroxaban demonstrated for mortality, major bleeding and withdrawal due to adverse events. The same direction of effect was seen for the outcomes of minor bleeding, stroke, myocardial infarction and pulmonary embolism, though there was more uncertainty in these results and the effect sizes were smaller.

The only outcome that favoured the rivaroxaban group was symptomatic valve thrombosis; however, the effect was small and there was uncertainty in this result.

Evidence from this study, including moderate quality evidence for major bleeding being higher in the DOAC group, further supports the recommendation made to consider single antiplatelet therapy (aspirin) following transcatheter valve implantation as rivaroxaban did not appear to be a better option based on this study.

Anticoagulant (VKA or DOAC) + clopidogrel compared to anticoagulant (VKA or DOAC) alone following transcatheter valve implantation

One study compared outcomes between an anticoagulant + single antiplatelet therapy in the form of clopidogrel and an anticoagulant alone in those with an existing indication for long-term oral anticoagulation. The results suggested a clinically significant harm of anticoagulant plus clopidogrel for mortality and major and minor bleeding, though there was uncertainty in these results. No clinically significant differences were identified for the other reported outcomes of stroke, myocardial infarction and mean aortic valve gradient (valve degeneration), with uncertainty in the direction of the effect.

This evidence did not contribute to any recommendations made as it was based on a single, moderately sized study with uncertainty in the effects for all of the reported outcomes. In addition, recommendations for anticoagulants following transcatheter valve implantation were not made due to the limited evidence and this study assessing whether an anticoagulant combined with clopidogrel is preferable to an anticoagulant alone did not add anything further that could be used to inform recommendations on anticoagulants following transcatheter valve implantation. However, the population of this study was covered by one of the recommendations made, as it was agreed that for those with other indications for anticoagulation or antiplatelet therapy, such as atrial fibrillation or chronic heart failure, the respective NICE guidelines should be followed.

Key uncertainties

There is no evidence comparing anticoagulant or antiplatelet therapy to placebo, which means there was no clear evidence that antithrombotic therapy is required after surgical biological valve replacement or valve repair. Therefore, there was insufficient evidence to make a recommendation based on this. The committee agreed that this is an area that requires more research as there is a large variance in clinical practice across the country and currently no high-quality evidence to support any consensus recommendation on antithrombotic therapy. This led to a research recommendation (see Appendix J.1.1 for details). The committee noted the reasonable clinical rationale for single antiplatelet therapy after surgical biological and transcatheter valve implantation, as well as surgical valve repair, but the requirement for antithrombotic therapy has not been tested in a clinical trial.

No evidence was available to assess the long-term efficacy of any antithrombotic therapy after any surgical or transcatheter procedure. Currently the duration of antithrombotic therapy in this population is unclear with no high-quality evidence to support a consensus recommendation. This led to a research recommendation (see Appendix J.2.1 for details).

1.7.2. Cost effectiveness and resource use

No economic evidence was found for this review. The unit costs of drugs were presented. The committee noted that the daily cost of these interventions was typically low but that the price varied between different drugs. Aspirin and clopidogrel, for example, have a daily cost of £0.05 whilst ticagrelor has a daily cost of £1.90. According to committee consensus, broad current practice is to give dual antiplatelet therapy after valve intervention but some clinics may choose other interventions or give no treatment.

For vitamin K antagonists compared to single antiplatelet therapy following surgical biological valve replacement, a do not use recommendation was made for vitamin K antagonists. This was based on the evidence of an increased bleeding risk with vitamin K antagonists and no apparent reduction in risk for other outcomes, such as mortality or thromboembolic events. Savings are possible from reduced use of anticoagulation clinics and fewer bleeding events. The recommendation does not specify exactly which drugs should be given as the evidence concerned broader drug classes. It was therefore not possible to make more detailed recommendation for particular drugs.

The committee also recommended single antiplatelet therapy over dual antiplatelet therapy for transcatheter aortic valve implantation. The resource impact of this recommendation will depend on the type of single antiplatelet therapy used. Although most of current practice is to use dual antiplatelet therapy, for the smaller number of clinics that do not currently give any treatment there will be an initial cost in procurement of drugs. However, these costs might be offset by a reduction in major and minor bleeding events, although no evidence was found that included placebo or no treatment as a comparator.

1.7.3. Other factors the committee took into account

The committee discussed that while there may be no evidence to support anticoagulant therapy after surgical biological valve replacement that clinicians should still provide anticoagulant therapy for other indications (for example, atrial fibrillation) as appropriate according to the relevant guidance.

The committee recognised that the BNF states that dabigatran is contraindicated for prosthetic heart valves. However, they believed that this contraindication is based on evidence from the mechanical valve population and does not necessarily apply to people with biological prosthetic heart valves. The evidence found in this review did not support or oppose this.

The committee noted that guidelines for direct oral anticoagulation medication for atrial fibrillation use the term “non-valvular atrial fibrillation” to refer to atrial fibrillation that is not coexistent with mitral stenosis. Atrial fibrillation coexistent with mitral stenosis is named “valvular atrial fibrillation”. Furthermore, the committee noted that in the presence of mechanical prosthetic valves with coexistent atrial fibrillation the anticoagulation requirements for the mechanical prosthetic valves prevails.

Although not the subject of this review, the committee noted the widespread use of warfarin or antiplatelets for 3 months after biological valve replacement, which was thought to be based on a clinical rationale but limited evidence.

No evidence was identified as part of this review that could be used to inform recommendations specifically in pregnant women with heart valve disease or women who may become pregnant in the future.

1.8. Recommendations supported by this evidence review

This evidence review supports recommendations 1.7.1-1.7.3 and the 2 research recommendations for antithrombotic therapy.

References

1.: Abuzaid A, Ranjan P, Fabrizio C, Felpel K, Chawla R, Topic A et al. Single anti-platelet therapy versus dual anti-platelet therapy after transcatheter aortic valve replacement: A meta-analysis. Structural Heart. 2018; 2(5):408–418

2.: Ahmad Y, Demir O, Rajkumar C, Howard JP, Shun-Shin M, Cook C et al. Optimal antiplatelet strategy after transcatheter aortic valve implantation: a meta-analysis. Open Heart. 2018; 5(1):e000748 [PMC free article: PMC5786926] [PubMed: 29387433]

3.: Al-Atassi T, Lam K, Forgie M, Boodhwani M, Rubens F, Hendry P 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 [PubMed: 22965989]

4.: Al Halabi S, Newman J, Farkouh ME, Fortuin D, Leya F, Sweeney J et al. Meta-analysis of studies comparing dual- versus mono-antiplatelet therapy following transcatheter aortic valve implantation. American Journal of Cardiology. 2018; 122(1):141–148 [PubMed: 29779587]

5.: Alrifai A, Soud M, Kabach A, Jobanputra Y, Masrani A, El Dassouki S et al. Dual antiplatelet therapy versus single antiplatelet therapy after transaortic valve replacement: Meta-analysis. Cardiovascular Revascularization Medicine. 2018; 19(6S):47–52 [PubMed: 29580827]

6.: Altman R, Boullon F, Rouvier J, Raca R, de la Fuente L, Favaloro R. Aspirin and prophylaxis of thromboembolic complications in patients with substitute heart valves. Journal of Thoracic and Cardiovascular Surgery. 1976; 72(1):127–129 [PubMed: 1084448]

7.: An KR, Belley-Cote EP, Um KJ, Gupta S, McClure GR, Jaffer IH et al. Antiplatelet therapy versus anticoagulation after surgical bioprosthetic aortic valve replacement: A systematic review and meta-analysis. Thrombosis and Haemostasis. 2019; 119(2):328–339 [PubMed: 30616247]

8.: Ando T, Takagi H, Briasoulis A, Afonso L. Single versus dual anti-platelet therapy post transcatheter aortic valve implantation: a meta-analysis of randomized controlled trials. Journal of Thrombosis and Thrombolysis. 2017; 44(4):448–456 [PubMed: 28905178]

9.: Aramendi JI, Mestres CA, Martinez-Leon J, Campos V, Munoz G, Navas C. Erratum: Triflusal versus oral anticoagulation for primary prevention of thromboembolism after bioprosthetic valve replacement (trac): Prospective, randomized, co-operative trial (European Journal of Cardio-thoracic Surgery (2005) 27 (854-860) PII: S1010794005001284 and DOI: 10.1016/j.ejcts.2004.12.064). European Journal of Cardio-Thoracic Surgery. 2005; 28(1):188 [PubMed: 15848326]

10.: Aramendi JI, Mestres CA, Martinez-Leon J, Campos V, Munoz G, Navas C. Triflusal versus oral anticoagulation for primary prevention of thromboembolism after bioprosthetic valve replacement (trac): prospective, randomized, co-operative trial. European Journal of Cardio-Thoracic Surgery. 2005; 27(5):854–860 [PubMed: 15848326]

11.: Aramendi JL, Agredo J, Llorente A, Larrarte C, Pijoan J. Prevention of thromboembolism with ticlopidine shortly after valve repair or replacement with a bioprosthesis. Journal of Heart Valve Disease. 1998; 7(6):610–614 [PubMed: 9870193]

12.: Aryal MR, Karmacharya P, Pandit A, Hakim F, Pathak R, Mainali NR et al. Dual versus single antiplatelet therapy in patients undergoing transcatheter aortic valve replacement: a systematic review and meta-analysis. Heart, Lung & Circulation. 2015; 24(2):185–192 [PubMed: 25240570]

13.: Avezum A, Lopes RD, Schulte PJ, Lanas F, Hanna M, Pais P. Apixaban versus warfarin in patients with atrial fibrillation and valvular heart disease: findings from the ARISTOTLE trial. European Heart Journal. 2013; 34(Suppl 1):809

14.: Banerjee K, Poddar K, Mick S, White J, Krishnaswamy A, Johnston D et al. Meta-analysis of usefulness of anticoagulation after transcatheter aortic valve implantation. American Journal of Cardiology. 2017; 120(9):1612–1617 [PubMed: 28844512]

15.: Brouwer J, Nijenhuis VJ, Delewi R, Hermanides RS, Holvoet W, Dubois CLF et al. Aspirin with or without clopidogrel after transcatheter aortic-valve implantation. New England Journal of Medicine. 2020; 383(15):1447–1457 [PubMed: 32865376]

16.: Burke H, Boron A, Lee JH, Kahlon KR. Exploring the difference in post-procedural stroke rates between patients with aortic stenosis who undergo transcatheter aortic valve replacement versus surgical aortic valve replacement. Cureus. 2018; 10(4):e2494 [PMC free article: PMC6003804] [PubMed: 29922535]

17.: Caldeira D, David C, Costa J, Ferreira JJ, Pinto FJ. Non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation and valvular heart disease: systematic review and meta-analysis. European Heart Journal Cardiovascular Pharmacotherapy. 2018; 4(2):111–118 [PubMed: 28950374]

18.: 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. Journal of Heart Valve Disease. 2007; 16(6):667–671 [PubMed: 18095518]

19.: Dangas GD, Tijssen JGP, Wohrle J, Sondergaard L, Gilard M, Mollmann H et al. A controlled trial of rivaroxaban after transcatheter aortic-valve replacement. New England Journal of Medicine. 2020; 382(2):120–129 [PubMed: 31733180]

20.: De Caterina R, Renda G, Carnicelli AP, Nordio F, Trevisan M, Mercuri MF et al. Valvular heart disease patients on edoxaban or warfarin in the ENGAGE AF-TIMI 48 trial. Journal of the American College of Cardiology. 2017; 69(11):1372–1382 [PubMed: 28302288]

21.: de Souza Lima Bitar Y, Neto MG, Filho JAL, Pereira LV, Travassos KSO, Akrami KM et al. Comparison of the new oral anticoagulants and warfarin in patients with atrial fibrillation and valvular heart disease: Systematic review and meta-analysis. Drugs in R & D. 2019; 19(2):117–126 [PMC free article: PMC6544604] [PubMed: 31055767]

22.: Dong MF, Ma ZS, Ma SJ, Chai SD, Tang PZ, Yao DK et al. Anticoagulation therapy with combined low dose aspirin and warfarin following mechanical heart valve replacement. Thrombosis Research. 2011; 128(5):e91–94 [PubMed: 21813162]

23.: Duraes AR, de Souza Roriz P, de Almeida Nunes B, Albuquerque FP, de Bulhoes FV, de Souza Fernandes AM et al. Dabigatran versus warfarin after bioprosthesis valve replacement for the management of atrial fibrillation postoperatively: DAWA pilot study. Drugs in R & D. 2016; 16(2):149–154 [PMC free article: PMC4875919] [PubMed: 26892845]

24.: Ezekowitz MD, Nagarakanti R, Noack H, Brueckmann M, Litherland C, Jacobs M et al. Comparison of dabigatran and warfarin in patients with atrial fibrillation and valvular heart disease: The RE-LY trial (Randomized Evaluation of Long-Term Anticoagulant Therapy). Circulation. 2016; 134(8):589–598 [PubMed: 27496855]

25.: Farah E, Cadhilac M, Boubaker A. Thromboembolic risk in prosthetic valve carriers. Scandinavian Journal of Haematology. 1981; 27(Suppl.38):96–119 [PubMed: 6950503]

26.: Gandhi S, Schwalm JD, Velianou JL, Natarajan MK, Farkouh ME. Comparison of dual-antiplatelet therapy to mono-antiplatelet therapy after transcatheter aortic valve implantation: Systematic review and meta-analysis. Canadian Journal of Cardiology. 2015; 31(6):775–784 [PubMed: 25913473]

27.: Geisler T, Droppa M, Muller K, Borst O. Antithrombotic therapy after TAVR. Current Vascular Pharmacology. 2018; 16(5):437–445 [PubMed: 29345593]

28.: Gherli T, Colli A, Fragnito C, Nicolini F, Borrello B, Saccani S et al. Comparing warfarin with aspirin after biological aortic valve replacement: a prospective study. Circulation. 2004; 110(5):496–500 [PubMed: 15289387]

29.: Guedeney P, Mehran R, Collet JP, Claessen BE, Ten Berg J, Dangas GD. Antithrombotic therapy after transcatheter aortic valve replacement. Circulation: Cardiovascular Interventions. 2019; 12(1):e007411 [PubMed: 30630354]

30.: Guimaraes PO, Pokorney SD, Lopes RD, Wojdyla DM, Gersh BJ, Giczewska A et al. Efficacy and safety of apixaban vs warfarin in patients with atrial fibrillation and prior bioprosthetic valve replacement or valve repair: Insights from the ARISTOTLE trial. Clinical Cardiology. 2019; 42(5):568–571 [PMC free article: PMC6522998] [PubMed: 30907005]

31.: Hassell ME, Hildick-Smith D, Durand E, Kikkert WJ, Wiegerinck EM, Stabile E et al. Antiplatelet therapy following transcatheter aortic valve implantation. Heart. 2015; 101(14):1118–1125 [PubMed: 25948421]

32.: He Q, Sze CY, Shum TY, Hao G, Wong NB, Sin TH et al. Comparing clinical outcomes of NOACs with warfarin on atrial fibrillation with Valvular heart diseases: a meta-analysis. BMC Cardiovascular Disorders. 2019; 19:113 [PMC free article: PMC6521383] [PubMed: 31092194]

33.: Herold J, Herold-Vlanti V, Sherif M, Luani B, Breyer C, Bonaventura K et al. Analysis of cardiovascular mortality, bleeding, vascular and cerebrovascular events in patients with atrial fibrillation vs. sinus rhythm undergoing transfemoral Transcatheter Aortic Valve Implantation (TAVR). BMC Cardiovascular Disorders. 2017; 17:298 [PMC free article: PMC5738713] [PubMed: 29262768]

34.: Hu X, Yang FY, Wang Y, Zhang Y, Chen M. Single versus dual antiplatelet therapy after transcatheter aortic valve implantation: A systematic review and meta-analysis. Cardiology. 2018; 141(1):52–65 [PubMed: 30368490]

35.: Ichibori Y, Mizote I, Maeda K, Onishi T, Ohtani T, Yamaguchi O et al. Clinical outcomes and bioprosthetic valve function after transcatheter aortic valve implantation under dual antiplatelet therapy vs. Aspirin alone. Circulation Journal. 2017; 81(3):397–404 [PubMed: 28123149]

36.: Jamieson WR, Moffatt-Bruce SD, Skarsgard P, Hadi MA, Ye J, Fradet GJ et al. Early antithrombotic therapy for aortic valve bioprostheses: is there an indication for routine use? Annals of Thoracic Surgery. 2007; 83(2):549–556; discussion 556-547 [PubMed: 17257986]

37.: Joint Formulary Committee. British National Formulary (BNF). 77th ed. London. British Medical Association and The Royal Pharmaceutical Society of Great Britain,. 2019. Available from: https://bnf.nice.org.uk/

38.: Kawazoe K, Fujita T, Manabe H. Dipyridamole combined with anticoagulant in prevention of early postoperative thromboembolism after cardiac valve replacement. Thrombosis Research Supplement. 1990; 57(Suppl 3):27–33 [PubMed: 2082485]

39.: Kuno T, Takagi H, Sugiyama T, Ando T, Miyashita S, Valentin N et al. Antithrombotic strategies after transcatheter aortic valve implantation: Insights from a network meta-analysis. Catheterization and Cardiovascular Interventions. 2020; 96(2):E177–E186 [PubMed: 31609071]

40.: Lawley CM, Lain SJ, Algert CS, Ford JB, Figtree GA, Roberts CL. Prosthetic heart valves in pregnancy, outcomes for women and their babies: A systematic review and meta-analysis. BJOG: An International Journal of Obstetrics and Gynaecology. 2015; 122(11):1446–1455 [PubMed: 26119028]

41.: Liang H, He Q, Zhang Q, Liu X, Cui K, Chen G et al. Efficacy and safety outcomes in novel oral anticoagulants versus vitamin-K antagonist on post-TAVI patients: a meta-analysis. BMC Cardiovascular Disorders. 2020; 20:307 [PMC free article: PMC7318737] [PubMed: 32586273]

42.: Ma X, Xu Z, Li J, Zhao D, Kong X, Ma J et al. Antiplatelet strategy after transcatheter aortic valve replacement: an updated meta-analysis. Journal of Cardiovascular Surgery. 2019; 60(5):624–632 [PubMed: 31486613]

43.: Maes F, Stabile E, Ussia GP, Tamburino C, Pucciarelli A, Masson JB et al. Meta-analysis comparing single versus dual antiplatelet therapy following transcatheter aortic valve implantation. American Journal of Cardiology. 2018; 122(2):310–315 [PubMed: 29861051]

44.: Malik AH, Yandrapalli S, Aronow WS, Panza JA, Cooper HA. Oral anticoagulants in atrial fibrillation with valvular heart disease and bioprosthetic heart valves. Heart. 2019; 105(18):1432–1436 [PubMed: 31203254]

45.: Masri A, Gillinov AM, Johnston DM, Sabik JF, Svensson LG, Rodriguez LL et al. Anticoagulation versus antiplatelet or no therapy in patients undergoing bioprosthetic valve implantation: a systematic review and meta-analysis. Heart. 2017; 103(1):40–48 [PubMed: 27487810]

46.: Massel D, Little S. Antiplatelet and anticoagulation for patients with prosthetic heart valves. Cochrane Database of Systematic Reviews 2013, Issue 7. Art. No.: CD003464. DOI: 10.1002/14651858.CD003464.pub2. [PMC free article: PMC8094423] [PubMed: 23839768] [CrossRef]

47.: Massel D, Little SH. Risks and benefits of adding anti-platelet therapy to warfarin among patients with prosthetic heart valves: a meta-analysis. Journal of the American College of Cardiology. 2001; 37(2):569–578 [PubMed: 11216981]

48.: Mok CK, Boey J, Wang R, Chan TK, Cheung KL, Lee PK et al. Warfarin versus dipyridamole-aspirin and pentoxifylline-aspirin for the prevention of prosthetic heart valve thromboembolism: a prospective randomized clinical trial. Circulation. 1985; 72(5):1059–1063 [PubMed: 3899404]

49.: National Institute for Health and Care Excellence. Developing NICE guidelines: the manual [updated 2020]. London. National Institute for Health and Care Excellence, 2014. Available from: http://www.nice.org.uk/article/PMG20/chapter/1%20Introduction%20and%20overview [PubMed: 26677490]

50.: Nijenhuis VJ, Brouwer J, Delewi R, Hermanides RS, Holvoet W, Dubois CLF et al. Anticoagulation with or without clopidogrel after transcatheter aortic-valve implantation. New England Journal of Medicine. 2020; 382(18):1696–1707 [PubMed: 32223116]

51.: Nijenhuis VJ, Brouwer J, Sondergaard L, Collet JP, Grove EL, Ten Berg JM. Antithrombotic therapy in patients undergoing transcatheter aortic valve implantation. Heart. 2019; 105(10):742–748 [PubMed: 30867148]

52.: Nowell J, Wilton E, Markus H, Jahangiri M. Antithrombotic therapy following bioprosthetic aortic valve replacement. European Journal of Cardio-Thoracic Surgery. 2007; 31(4):578–585 [PubMed: 17267235]

53.: Owais T, Rouman M, Breuer M, Huter L, Fuchs J, Lauer B et al. Anticoagulation after biological aortic valve replacement: Is there an optimal regimen? Journal of Heart Valve Disease. 2016; 25(2):139–144 [PubMed: 27989055]

54.: Pan KL, Singer DE, Ovbiagele B, Wu YL, Ahmed MA, Lee M. Effects of non-vitamin k antagonist oral anticoagulants versus warfarin in patients with atrial fibrillation and valvular heart disease: A systematic review and meta-analysis. Journal of the American Heart Association. 2017; 6(7):e005835 [PMC free article: PMC5586302] [PubMed: 28720644]

55.: Paparella D, Di Mauro M, Bitton Worms K, Bolotin G, Russo C, Trunfio S et al. Antiplatelet versus oral anticoagulant therapy as antithrombotic prophylaxis after mitral valve repair. Journal of Thoracic and Cardiovascular Surgery. 2016; 151(5):1302–1308.e1301 [PubMed: 26832208]

56.: Perleth M, Busse R. Health technology assessment of oral anticoagulation following heart valve replacement. European Heart Journal, Supplement. 2001; 3(Q):Q60–Q64

57.: Rafiq S, Steinbruchel DA, Lilleor NB, Moller CH, Lund JT, Thiis JJ et al. Antithrombotic therapy after bioprosthetic aortic valve implantation: Warfarin versus aspirin, a randomized controlled trial. Thrombosis Research. 2017; 150:104–110 [PubMed: 27914653]

58.: Raheja H, Garg A, Goel S, Banerjee K, Hollander G, Shani J et al. Comparison of single versus dual antiplatelet therapy after TAVR: A systematic review and meta-analysis. Catheterization and Cardiovascular Interventions. 2018; 92(4):783–791 [PubMed: 29516608]

59.: Rajah SM, Sreeharan N, Rao S, Watson DA. Warfarin versus warfarin and dipyridamole on the incidence of arterial thromboembolism in prosthetic heart valve patients. Thrombosis and Haemostasis. 1979; 42(1):160

60.: Renda G, Ricci F, Giugliano RP, De Caterina R. Non-vitamin k antagonist oral anticoagulants in patients with atrial fibrillation and valvular heart disease. Journal of the American College of Cardiology. 2017; 69(11):1363–1371 [PubMed: 28302287]

61.: Riaz H, Alansari SAR, Khan MS, Riaz T, Raza S, Luni FK et al. Safety and use of anticoagulation after aortic valve replacement with bioprostheses. Circulation: Cardiovascular Quality and Outcomes. 2016; 9(3):294–302 [PMC free article: PMC5124764] [PubMed: 27166205]

62.: Rodes-Cabau J, Masson JB, Welsh RC, Garcia Del Blanco B, Pelletier M, Webb JG 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: Cardiovascular Interventions. 2017; 10(13):1357–1365 [PubMed: 28527771]

63.: Russmann S, Gohlke-Barwolf C, Jahnchen E, Trenk D, Roskamm H. Age-dependent differences in the anticoagulant effect of phenprocoumon in patients after heart valve surgery. European Journal of Clinical Pharmacology. 1997; 52(1):31–35 [PubMed: 9143864]

64.: Sharma A, Goel S, Lavie CJ, Arbab-Zadeh A, Mukherjee D, Lazar J. Antithrombotic therapy before, during and after transcatheter aortic valve replacement (TAVR). Journal of Thrombosis and Thrombolysis. 2015; 39(4):467–473 [PubMed: 25103613]

65.: Sharma R. Review: Evidence is inconclusive on dual- vs mono-antiplatelet therapy after transcatheter aortic valve implantation. Annals of Internal Medicine. 2018; 169(8):JC42 [PubMed: 30326086]

66.: Sherwood MW, Vora AN. Challenges in aortic stenosis: Review of antiplatelet/anticoagulant therapy management with transcatheter aortic valve replacement (TAVR): TAVR with recent PCI, TAVR in the Patient with atrial fibrillation, and TAVR thrombosis management. Current Cardiology Reports. 2018; 20:130 [PubMed: 30311013]

67.: Siddamsetti S, Balasubramanian S, Yandrapalli S, Vij A, Joshi U, Tang G et al. Meta-analysis comparing dual antiplatelet therapy versus single antiplatelet therapy following transcatheter aortic valve implantation. American Journal of Cardiology. 2018; 122(8):1401–1408 [PubMed: 30340696]

68.: Stabile E, Pucciarelli A, Cota L, Sorropago G, Tesorio T, Salemme 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. International Journal of Cardiology. 2014; 174(3):624–627 [PubMed: 24809922]

69.: Sterling LH, Windle SB, Filion KB, Eisenberg MJ. Pharmacological management strategies for stroke prevention following transcatheter aortic valve replacement: A systematic review. International Journal of Cardiology. 2015; 191:303–311 [PubMed: 26001285]

70.: Taguchi K, Matsumura H, Washizu T, Harao M, Kato K, Kato E et al. Effect of athrombogenic therapy, especially high dose therapy of dipyridamole, after prosthetic valve replacement. Journal of Cardiovascular Surgery. 1975; 16(1):8–15 [PubMed: 1126989]

71.: Thourani VH, Gunter RL, Hurst S, Kilgo P, Padala M, Puskas JD et al. Postoperative warfarin following mitral valve repair or bioprosthetic valve replacement. Journal of Heart Valve Disease. 2013; 22(5):716–723 [PubMed: 24383387]

72.: Turgeon RD, Barry AR. Single vs dual antiplatelet therapy following transcatheter aortic valve implantation: A systematic review. Clinical Cardiology. 2015; 38(10):629–634 [PMC free article: PMC6490860] [PubMed: 26239886]

73.: Turpie AG, Gent M, Laupacis A, Latour Y, Gunstensen J, Basile F et al. A comparison of aspirin with placebo in patients treated with warfarin after heart-valve replacement. New England Journal of Medicine. 1993; 329(8):524–529 [PubMed: 8336751]

74.: Ueyama H, Kuno T, Ando T, Briasoulis A, Fox J, Hayashida K et al. Meta-analysis comparing direct oral anticoagulants versus vitamin k antagonists after transcatheter aortic valve implantation. American Journal of Cardiology. 2020; 125(7):1102–1107 [PubMed: 31964500]

75.: Ussia GP, Scarabelli M, Mule M, Barbanti M, Sarkar K, Cammalleri V et al. Dual antiplatelet therapy versus aspirin alone in patients undergoing transcatheter aortic valve implantation. American Journal of Cardiology. 2011; 108(12):1772–1776 [PubMed: 21907949]

76.: Vavuranakis M, Kalogeras K, Kolokathis AM, Vrachatis D, Magkoutis N, Siasos G et al. Antithrombotic therapy in TAVI. Journal of Geriatric Cardiology. 2018; 15(1):66–75 [PMC free article: PMC5803540] [PubMed: 29434628]

77.: Vavuranakis M, Siasos G, Zografos T, Oikonomou E, Vrachatis D, Kalogeras K et al. Dual or single antiplatelet therapy after transcatheter aortic valve implantation? A systematic review and meta-analysis. Current Pharmaceutical Design. 2016; 22(29):4596–4603 [PubMed: 27262328]

78.: Verdoia M, Barbieri L, Nardin M, Suryapranata H, De Luca G. Dual versus single antiplatelet regimen with or without anticoagulation in transcatheter aortic valve replacement: Indirect comparison and meta-analysis. Revista Española de Cardiología. 2018; 71(4):257–266 [PubMed: 28734880]

79.: Zhou M, Chan EW, Hai JJ, Wong CK, Lau YM, Huang D et al. Protocol, rationale and design of DAbigatran for Stroke PreVention In Atrial Fibrillation in MoDerate or Severe Mitral Stenosis (DAVID-MS): a randomised, open-label study. BMJ Open. 2020; 10(9):e038194 [PMC free article: PMC7520829] [PubMed: 32978200]

80.: Zhu Y, Zou Z, Huang Y, Zhang L, Chen H, Li Y et al. Comparative efficacy and safety of antithrombotic therapy for transcatheter aortic valve replacement: a systematic review and network meta-analysis. European Journal of Cardio-Thoracic Surgery. 2020; 57(5):965–976 [PubMed: 31883333]

81.: Zuo W, Yang M, He Y, Hao C, Chen L, Ma G. Single or dual antiplatelet therapy after transcatheter aortic valve replacement: an updated systemic review and meta-analysis. Journal of Thoracic Disease. 2019; 11(3):959–968 [PMC free article: PMC6462726] [PubMed: 31019786]

Appendices

Appendix A. Review protocols

Table 10. Review protocol: Clinical protocol for anticoagulant and/or antiplatelet therapy for biological prosthetic valves (PDF, 227K)

Table 11. Health economic review protocol (PDF, 188K)

Appendix B. Literature search strategies

Heart valve disease – search strategy 10 - anticoagulant and/or antiplatelet therapy for biological prosthetic valves and after valve repair

This literature search strategy was used for the following review:

What is the clinical and cost effectiveness of anticoagulant and/or antiplatelet therapy for adults with transcatheter or surgical biological prosthetic valves or after valve repair?

The literature searches for this review are detailed below and complied with the methodology outlined in Developing NICE guidelines: the manual.⁴⁹

For more information, please see the Methodology review published as part of the accompanying documents for this guideline.

B.1. Clinical search literature search strategy (PDF, 349K)

B.2. Health Economics literature search strategy (PDF, 290K)

Appendix C. Clinical evidence selection

Figure 1. Flow chart of clinical study selection for the review anticoagulation and antiplatelet use after biological valve replacement and valve repair (PDF, 147K)

Appendix D. Clinical evidence tables

Download PDF (456K)

Appendix E. Forest plots

E.1. Surgical Valve Replacement

Download PDF (208K)

E.2. Transcatheter valve implantation

Download PDF (242K)

E.3. Valve repair

No information available.

Appendix F. GRADE tables

F.1. Surgical valve replacement

Download PDF (286K)

F.2. Transcatheter valve implantation

Download PDF (400K)

F.3. Valve repair

No information available.

Appendix G. Health economic evidence selection

Download PDF (250K)

Appendix H. Health economic evidence tables

No economic studies were identified.

Appendix I. Excluded studies

I.1. Excluded clinical studies

Download PDF (169K)

I.2. Excluded health economic studies

Published health economic studies that met the inclusion criteria (relevant population, comparators, economic study design, published 2004 or later and not from non-OECD country or USA) but that were excluded following appraisal of applicability and methodological quality are listed below. See the health economic protocol for more details.

None.

Appendix J. Research recommendations

J.1. Anticoagulation and antiplatelet therapy (PDF, 197K)

J.2. Anticoagulation and antiplatelet therapy: long-term valve function and outcomes (PDF, 193K)

Final

Intervention evidence review underpinning recommendations 1.7.1 to 1.7.3 and research recommendations in the NICE guideline

This evidence review was developed by the National Guideline Centre

Disclaimer: The recommendations in this guideline represent the view of NICE, arrived at after careful consideration of the evidence available. When exercising their judgement, professionals are expected to take this guideline fully into account, alongside the individual needs, preferences and values of their patients or service users. The recommendations in this guideline are not mandatory and the guideline does not override the responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and, where appropriate, their carer or guardian.

Local commissioners and providers have a responsibility to enable the guideline to be applied when individual health professionals and their patients or service users wish to use it. They should do so in the context of local and national priorities for funding and developing services, and in light of their duties to have due regard to the need to eliminate unlawful discrimination, to advance equality of opportunity and to reduce health inequalities. Nothing in this guideline should be interpreted in a way that would be inconsistent with compliance with those duties.

NICE guidelines cover health and care in England. Decisions on how they apply in other UK countries are made by ministers in the Welsh Government, Scottish Government, and Northern Ireland Executive. All NICE guidance is subject to regular review and may be updated or withdrawn.

Bookshelf ID: NBK577829PMID: 35143139

Table 1PICO characteristics of review question

Population	Adults aged 18 years and over with repaired valves or biological prosthetic valves stratified by type of intervention: Transcatheter intervention Surgical intervention. Exclusion: Children (aged <18 years). Adults with congenital heart disease (excluding bicuspid aortic valves). Tricuspid stenosis and pulmonary valve disease. Adults who have had a mechanical valve replacement.
Interventions	Oral anticoagulation therapy: Vitamin K antagonists (VKA) (including: warfarin, acenocoumarol and phenindione) Direct acting oral anticoagulants (DOAC) (including: dabigatran, rivaroxaban, apixaban and edoxaban) Oral antiplatelet therapy: Single antiplatelet therapy (SAPT) (including: aspirin, clopidogrel, ticagrelor or prasugrel) Dual antiplatelet therapy (DAPT) (the combination of aspirin with either clopidogrel, ticagrelor or prasugrel) Combined oral anticoagulation and oral antiplatelet therapy.
Comparisons	Other active comparator listed above. Placebo. No treatment or standard care (for example, treatment with all other required medication post-valve replacement apart from anticoagulants/antiplatelets).
Outcomes	Primary outcomes: All-cause mortality at ≤12 months and >1 year (dichotomous) Health-related quality of life at ≤12 months and >1 year (continuous) Major bleeding at ≤12 months and >1 year (dichotomous) Minor bleeding at ≤12 months and >1 year (dichotomous) Arterial thromboembolic events at ≤12 months and >1 year (dichotomous) Secondary outcomes: Hospital re-admission at 12 months (dichotomous) Withdrawal due to adverse events at 12 months (dichotomous) Thrombus on imaging at <12 months (dichotomous) Need for intervention at medium term (6 months to 1 year) and long term (>1 year) (time-to-event) Valve degeneration (mean transvalvular gradient) at ≥1 year (continuous)
Study design	RCTs or Systematic Reviews of RCTs

Table 2Summary of studies included in the evidence review

Study

Intervention and comparison

Population

Outcomes

Comments

Surgical valve replacement, direct-acting oral anticoagulant vs. vitamin K antagonist

Duraes 2016 ²³

N=27

RCT

Conducted in Brazil

Dabigatran

110mg orally twice daily. If on warfarin prior they underwent a washout period and dabigatran was introduced when INR <2.5. For up to 3 months.

Warfarin

Oral. Target INR between 2.0 and 3.0. For up to 3 months.

Adults 18-64 years old (mean age in dabigatran arm: 48.8±10.4 mean age in warfarin arm: 45.7±6) who underwent mitral and/or aortic bioprosthetic valve replacement (underlying preoperative valve disease not discussed) in the 3 months prior to entering the study and had documented atrial fibrillation postoperatively.

1 patient had diabetes mellitus.

Preoperatively 8 patients were classified as NYHA class III-IV. Mean LVEF was 40±12 in the dabigatran arm and 50±10 in the warfarin arm.

All-cause mortality at 3 months

Bleeding at 3 months

Arterial thromboembolic events at 3 months

Hospital re-admission at 3 months

Thrombus on imaging at 3 months

DAWA trial

No funding noted

Surgical valve replacement, vitamin K antagonist vs. single antiplatelet therapy

Colli 2007 ¹⁸

N=69

RCT

Conducted in Spain

Warfarin, followed by aspirin

Oral. Warfarin for up to 3 months. Target INR between 2.0 and 3.0.

After 3 months the warfarin was stopped and aspirin (100mg/day) was started for up to a further 3 months.

Aspirin

100mg/day orally for up to 6 months.

Adults (mean age in aspirin arm: 70.7±3.7, mean age in warfarin arm: 69.5±3.3) who required, for the first time, isolated aortic valve replacement (50 people had preoperative aortic stenosis, 8 had aortic insufficiency, 11 had mixed aortic valve disease) and were in sinus rhythm before implantation.

No patients had atrial fibrillation at the start of the study. 22 patients had diabetes mellitus. 20 patients had dyslipidaemia.

Preoperatively, 53 (78%) people were classified as New York Heart Association (NYHA) class III-IV. Mean left ventricular ejection fraction (LVEF) was 53.6±11.6 in the aspirin arm and 52.5±10.2 in the warfarin arm.

All-cause mortality at 6 months

Major bleeding at 6 months

Arterial thromboembolic events at 3 months and 6 months

WoA Epic trial

Principle author funded by industry (Andrea Colli was a clinical investigator for St. Jude Medical, Minneapolis, MN, USA).

Rafiq 2017 ⁵⁷

N=328

RCT

Conducted in Denmark

Warfarin

5mg orally initial dose. Target INR between 2.0 and 3.0.

Aspirin

150mg orally

Patients who underwent a coronary artery bypass grafting (CABG) surgery at the same time as intervention received warfarin and aspirin 75mg or aspirin 150mg only.

Adults aged ≥60 years (mean age in warfarin arm: 73.1±6.4, mean age in aspirin arm: 72.7±7.2) referred for first time aortic valve replacement (underlying preoperative valve disease not discussed) with or without CABG surgery in sinus rhythm.

People were excluded from the study if they had a history of AF or atrial flutter, liver cirrhosis or were on renal dialysis. 67 (20.4%) had diabetes mellitus. 187 (57.0%) had dyslipidaemia.

The median NYHA score for both arms was 2 (ranging from 1 to 4). The mean LVEF was 51.4±12.5 for the warfarin arm and 52.6±10.5 in the aspirin arm.

All-cause mortality at 3 months

Major bleeding at 3 months

Arterial thromboembolic events at 3 months

Hospital re-admission at 3 months

Thrombus on imaging at 3 months

No funding noted.

Surgical valve replacement, vitamin K antagonist + single antiplatelet therapy vs. vitamin K antagonist alone

Turpie 1993 ⁷³

N=89 with bioprosthetic valves (n=370 in whole trial)

RCT

Conducted in Canada

Warfarin and aspirin

Warfarin orally. Target INR 3.0-4.5.

Aspirin 100mg/day orally.

Warfarin and placebo

Warfarin orally. Target INR 3.0-4.5.

Adults with mechanical or tissue replacement valves and preoperative atrial fibrillation or a history of thromboembolism. 172 (46%) patients had aortic valve replacement, 162 (44%) patients had mitral valve replacement and 36 (10%) had multiple valves replaced.

Arterial thromboembolic event/Vascular mortality at 6 months.

Reports major systemic embolism or death from vascular causes for mechanical and bioprosthetic valves separately.

Transcatheter valve implantation, single antiplatelet therapy vs. dual antiplatelet therapy

Brouwer 2020 ¹⁵

N=690

RCT

Conducted in Belgium, Czech Republic, Luxembourg, Netherlands

Aspirin only

80-100 mg daily for duration of trial and advised to take it on a lifelong basis.

Loading dose of 300 mg aspirin prior to TAVI procedure for those that had not previously taken aspirin.

Aspirin and clopidogrel

Aspirin at a dose of 80-100 mg daily with 75 mg clopidogrel daily for 3 months, followed by aspirin alone at dose of 80-100 mg daily for rest of trial duration. Patients were advised to take aspirin on a lifelong basis.

Loading dose of 300 mg aspirin prior to TAVI procedure for those that had not previously taken aspirin. An initial single loading dose of 300 mg clopidogrel was given the day before or on the day of the TAVI procedure.

Adults (mean age ~80 years in both groups) scheduled to undergo TAVI (majority for normal-flow high-gradient or low-flow low-gradient aortic stenosis) and no current indication for long-term oral anticoagulation.

Details of number with atrial fibrillation not clear, but likely excluded as this group only included those with no current indication for oral anticoagulation.

Mean estimated glomerular filtration rate was ~58 ml/min/1.73 m² in both groups. 24-25% had diabetes mellitus and >70% had hypertension in both groups.

Ejection fraction was >31-50% in 22% vs. 20% and ≤30% in 4% vs. 7%.

All-cause mortality at 12 months

Major bleeding at 12 months

Minor bleeding at 12 months

Arterial thromboembolic events at 12 months (stroke, myocardial infarction and lung embolism reported separately)

Valve thrombosis at 12 months

Mean aortic valve gradient (valve degeneration) at 6 months

POPular TAVI trial cohort A

Said to be no industry involvement in the trial.

Hassell 2015 ³¹

N=199 across two studies

Systematic review with individual patient data

Aspirin only

81-100mg orally for up to 3-6 months.

Aspirin and clopidogrel

Aspirin 81-100mg orally for up to 3-6 months.

Clopidogrel 75mg orally for up to 3-6 months.

Studies including patients with aortic stenosis treated by TAVI (transcatheter aortic valve implantation) with a clear explanation of postprocedural antithrombotic treatment including one group treated with single antiplatelet therapy and another treated with dual antiplatelet therapy for a minimum follow-up of 1 month.

Mean age of patients in the Stabile study was 80±5.2 and in the Ussia study was 81±5.1. No patients had AF in the Stabile study, while 10 (12.7%) had preoperative AF in the Ussia study.

54 (45%) patients had renal disease in the Stabile study, while 11 (13.9%) had renal disease in the Ussia study.

34 (28.3%) patients had diabetes mellitus in the Stabile study, while 21 (26.6%) had diabetes mellitus in the Ussia study.

All patients in the Stabile study classified as NYHA class III-IV preoperatively, while 60 (75.9%) patients were classified as such in the Ussia study. In the Stabile study, LVEF was 30-50% in 46 (38.3%) patients and <30% in 5 (4.2%) patients. In the Ussia study, LVEF was 30-50% in 50 (63.3%) patients, and <30% in 4 (5.1%) patients.

All-cause mortality at 6 months

Major bleeding at 6 months

Arterial thromboembolic events at 6 months

Systematic review with pooled analysis of individual patient data.

Includes 2 RCTs (Stabile 2014⁶⁸ and Ussia 2011⁷⁵) and 2 observational studies, which were analysed separately in their study (and not included in the analysis of this guideline as per the protocol (Appendix A)).

No funding noted.

All relevant studies were included.

Rodes-Cabau 2017 ⁶²

N=222

RCT

Conducted in Canada, Chile, Spain, Switzerland

Aspirin alone

80-100mg/day orally.

Aspirin and clopidogrel

Aspirin 80-100mg/day orally. Clopidogrel 75mg/day orally.

Adults (mean age: 79±9) with clinical indications for TAVR (does not explicitly express the type of valve disease. However, 41 (19%) people had moderate aortic regurgitation) with a balloon-expandable Edwards SAPIEN XT or SAPIEN 3 valve.

No patients had atrial fibrillation at the start of the study.140 (63%) patients (63%) had chronic renal failure (GFR <60mL/min). 173 (78%) patients had hypertension. 77 (35%) patients had diabetes mellitus.

Preoperative ejection fraction was 55±12 in the clopidogrel and aspirin arm and 54±13 in the aspirin only arm.

All-cause mortality at 3 months

Major bleeding at 3 months

Arterial thromboembolic events at 3 months

The ARTE trial

Principle author and several other authors were funded by industry and the study was funded by industry (a grant from Edwards Lifesciences) and from academic sources.

Stabile 2014 ⁶⁸

N=120

RCT

Conducted in Italy

Aspirin only

81mg orally for 3 months.

Aspirin and clopidogrel or ticlopidine

Aspirin 81mg orally for 3 months.

Clopidogrel 75mg orally or Ticlopidine 500mg twice a day orally for 3 months.

Unable to determine how many patients had clopidogrel and how many had ticlopidine.

Adults (mean age in single antiplatelet arm: 81.1±4.8, mean age in dual antiplatelet arm: 80.2±5.7) with severe aortic stenosis treated with TAVI.

No patients had atrial fibrillation at the start of the study.

Please see Hassell 2015 for further information.

As in Hassell³¹ study (no additional outcomes)

SAT-TAVI trial

Included in Hassell 2015³¹ – the outcomes reported for this study are not included in the systematic review³¹.

Non-principle authors were funded by industry (G. Sorropago and P. Rubino were proctors for Edwards Lifesciences).

Ussia 2011 ⁷⁵

N=79

RCT

Conducted in Italy

Aspirin only

100mg orally for 6 months.

Aspirin and clopidogrel

Aspirin 100mg orally for 6 months.

Clopidogrel 75mg orally for up to 6 months.

Adults (mean age 81±4) with severe aortic stenosis treated with TAVI.

10 patients (13%) had permanent atrial fibrillation.

1 patient had liver cirrhosis.

11 patients (14%) had chronic kidney disease.

Please see Hassell 2015 for further information.

Minor bleeding at 6 months

Included in Hassell 2015³¹ – the outcomes reported for this study are not included in the systematic review³¹.

Principle author funded by industry (Dr Ussia was a proctor physician for Medtronic Incorporation).

Transcatheter valve implantation, direct-acting oral anticoagulant (+single antiplatelet therapy for 3 months) vs. single antiplatelet therapy alone (+clopidogrel for 3 months)

Dangas 2020 ¹⁹

N=1644

RCT

Conducted in Austria, Belgium, Canada, Czech Republic, Denmark, France, Germany, Italy, Netherlands, Norway, Poland, Spain, Sweden, Switzerland, United Kingdom, USA

Rivaroxaban (+aspirin for 3 months)

Rivaroxaban at 10 mg daily with aspirin at 75-100 mg daily for 3 months, followed by rivaroxaban monotherapy at 10 mg daily.

In those that developed atrial fibrillation, rivaroxaban received at 20 mg once daily (or 15 mg if eGFR 30-50 ml/min/1.73 m²).

Median treatment duration with rivaroxaban was 428 days and with aspirin was 90 days.

Aspirin (+clopidogrel for 3 months)

Aspirin at 75-100 mg daily with clopidogrel at 75 mg daily for 3 months, followed by aspirin monotherapy at 75-100 mg daily. Initial loading dose of ≥300 mg clopidogrel recommended for those that had not previously received it.

Patients that developed atrial fibrillation received vitamin K antagonists (INR 2-3) to replace clopidogrel within 3 months or to replace aspirin thereafter.

Median treatment duration with aspirin was 474 days and with clopidogrel was 90 days.

Adults (mean age: 80-81 years in the two groups) that underwent successful TAVI for aortic stenosis.

Current or previous atrial fibrillation with ongoing indication for oral anticoagulant treatment was an exclusion criterion. Mean estimated glomerular filtration rate was 73 ml/min/1.73 m² in both groups. 87.2% vs. 85.2% had hypertension. ~29% patients had diabetes mellitus in both groups.

Post-TAVI ejection fraction was 57.4±10.9% vs. 58.2±11.2%.

All-cause mortality at median 428 days

Major bleeding at median 428 days

Minor bleeding at median 428 days

Arterial thromboembolic events at median 428 days (stroke, myocardial infarction, pulmonary embolism and systemic embolism reported separately)

Premature study drug discontinuation due to adverse events during trial

Symptomatic valve thrombosis at median 428 days

GALILEO trial

Study funded by industry (Bayer ad Janssen Pharmaceuticals).

Transcatheter valve implantation, oral anticoagulant + single antiplatelet therapy vs. oral anticoagulant alone

Nijenhuis 2020 ⁵⁰

N=326

RCT

Conducted in Belgium, Czech Republic, Luxembourg, Netherlands

Vitamin K antagonist or direct-acting oral anticoagulant + clopidogrel

Patients continued anticoagulation were receiving prior to randomisation, which could be VKA or DOAC. 70.5% were on a VKA and 29.5% were on a DOAC.

Randomised to receive clopidogrel for 3 months in addition to their oral anticoagulation. Loading dose of 300 mg clopidogrel administered 1 day prior to or on day of TAVI, followed by 75 mg daily for 3 months.

Vitamin K antagonist or direct-acting oral anticoagulant

Patients continued anticoagulation were receiving prior to randomisation, which could be VKA or DOAC. 75.2% were on a VKA and 23.6% were on a DOAC.

Randomised not to receive clopidogrel for 3 months in addition to their oral anticoagulation.

Adults (mean age: ~81 years in the two groups) that underwent TAVI (majority for normal-flow high-gradient or low-flow low-gradient aortic stenosis) and already had an existing long-term indication for oral anticoagulation.

>90% in each group had atrial fibrillation at baseline. Mean estimated glomerular filtration rate was 55.6 vs. 53.4 ml/min/1.73 m² in the two groups. 67.3% vs. 73.2% had hypertension. 29.5 vs. 27.4% patients had diabetes mellitus.

Ejection fraction was 31-50% in 29.5% vs. 24.4% and ≤30% in 8.3% vs. 7.6%.

All-cause mortality at 12 months

Major bleeding at 12 months

Minor bleeding at 12 months

Arterial thromboembolic events at 12 months (stroke and myocardial infarction reported separately)

Mean aortic valve gradient (valve degeneration) at 6 months

POPular TAVI trial cohort B

Said to be no industry involvement in the trial.

Table 3Clinical evidence summary: DOAC versus VKA in surgical valve replacement

Outcomes	No of Participants (studies) Follow up	Quality of the evidence (GRADE)	Relative effect (95% CI)	Anticipated absolute effects
Outcomes	No of Participants (studies) Follow up	Quality of the evidence (GRADE)	Relative effect (95% CI)	Risk with VKA	Risk difference with DOAC (95% CI)
All-cause mortality at ≤12 months	27 (1 study) 3 months	⊕⊕⊝⊝ LOW^b due to imprecision	Peto OR 0.11 (0 to 5.44)	83 per 1000	8 fewer per 1000 (from 28 fewer to 11 more)^a
Health-related quality of life at ≤12 months - not measured	0		Not estimable
Major bleeding at ≤12 months	27 (1 study) 3 months	⊕⊕⊝⊝ LOW^b due to imprecision	Peto OR 0.79 (0.05 to 13.6)	83 per 1000	16 fewer per 1000 (from 78 fewer to 469 more)
Minor bleeding at ≤12 months - not measured	0		Not estimable
Arterial thromboembolic events at ≤12 Arterial thromboembolic events at ≤12 months	27 (1 study) 3 months	⊕⊕⊝⊝ LOW^b due to imprecision	Peto OR 0.79 (0.05 to 13.6)	83 per 1000	16 fewer per 1000 (from 78 fewer to 469 more)
Hospital re-admission at 12 months	27 (1 study) 3 months	⊕⊕⊝⊝ LOW^b due to imprecision	Peto OR 0.79 (0.05 to 13.6)	83 per 1000	16 fewer per 1000 (from 78 fewer to 469 more)
Thrombus on imaging at ≤12 months	27 (1 study) 3 months	⊕⊕⊝⊝ LOW^b due to imprecision	Peto OR 0.11 (0 to 5.44)	83 per 1000	8 fewer per 1000 (from 28 fewer to 11 more)^a
All-cause mortality at >12 months - not measured	0		Not estimable
Health-related quality of life at >12 months - not measured	0		Not estimable
Major bleeding at >12 months - not measured	0		Not estimable
Minor bleeding at >12 months - not measured	0		Not estimable
Arterial thromboembolic events at >12 months - not measured	0		Not estimable

a: Absolute effect calculated manually using risk difference as zero events in one arm of the study

b: Downgraded by 2 increments as the confidence interval crossed two MIDs ±

Table 4Clinical evidence summary: VKA versus SAPT in surgical valve replacement

Outcomes	No of Participants (studies) Follow up	Quality of the evidence (GRADE)	Relative effect (95% CI)	Anticipated absolute effects
Outcomes	No of Participants (studies) Follow up	Quality of the evidence (GRADE)	Relative effect (95% CI)	Risk with SAPT	Risk difference with VKA (95% CI)
All-cause mortality at ≤12 months	397 (2 studies) 3-6 months	⊕⊝⊝⊝ VERY LOW^a^,^b^,^c due to risk of bias, indirectness, imprecision	RR 1.22 (0.49 to 3.04)	47 per 1000	10 more per 1000 (from 24 fewer to 96 more)
Health-related quality of life at ≤12 months - not reported	0		Not estimable
Major bleeding at ≤12 months	397 (2 studies) 3-6 months	⊕⊝⊝⊝ VERY LOW^a^,^b^,^d due to risk of bias, indirectness, imprecision	RR 2.94 (0.97 to 8.95)	24 per 1000	47 more per 1000 (from 1 fewer to 191 more)
Minor bleeding at ≤12 months - not measured	0		Not estimable
Arterial thromboembolic events at ≤12 months	397 (2 studies) 3-6 months	⊕⊝⊝⊝ VERY LOW^a^,^b^,^c due to risk of bias, indirectness, imprecision	RR 0.82 (0.37 to 1.76)	63 per 1000	11 fewer per 1000 (from 40 fewer to 48 more)
Hospital re-admission at 12 months	328 (1 study) 6 months	⊕⊝⊝⊝ VERY LOW^b^,^c due to indirectness, imprecision	RR 1.15 (0.67 to 1.97)	130 per 1000	19 more per 1000 (from 43 fewer to 126 more)
Thrombus on imaging at ≤12 months	328 (1 study) 6 months	⊕⊝⊝⊝ VERY LOW^b^,^c due to indirectness, imprecision	Peto OR 0.13 (0 to 6.58)	6 per 1000	10 fewer per 1000 (from 20 fewer to 10 more)^e
All-cause mortality at >12 months - not measured	0		Not estimable
Health-related quality of life at >12 months - not measured	0		Not estimable
Major bleeding at >12 months - not measured	0		Not estimable
Minor bleeding at >12 months - not measured	0		Not estimable
Arterial thromboembolic events at >12 months - not measured	0		Not estimable

a: Downgraded by 1 increment as the majority of the evidence was at high risk of bias

b: Downgraded by 1 increment as one study included people who had a CABG while having the valve replacement surgery. The people in the intervention arm were subsequently given warfarin and aspirin, instead of just warfarin.

c: Downgraded by 2 increments as the confidence interval crossed both MIDs

d: Downgraded by 1 increment as the confidence interval crossed one MID

e: Absolute effect calculated manually using risk difference as zero events in one arm of the study

Table 5Clinical evidence summary: VKA and SAPT versus VKA alone in surgical valve replacement

Outcomes	No of Participants (studies) Follow up	Quality of the evidence (GRADE)	Relative effect (95% CI)	Anticipated absolute effects
Outcomes	No of Participants (studies) Follow up	Quality of the evidence (GRADE)	Relative effect (95% CI)	Risk with VKA	Risk difference with VKA and SAPT (95 % CI)
All-cause mortality at ≤12 months - not measured	0		Not estimable
Health-related quality of life at ≤12 months - not measured	0		Not estimable
Major bleeding at ≤12 months - not measured	0		Not estimable
Minor bleeding at ≤12 months - not measured	0		Not estimable
Major systemic embolism or death from vascular causes at ≤12 months	89 (1 study)	⊕⊝⊝⊝ VERY LOW^a^,^b due to indirectness, imprecision	RR 0.49 (0.09 to 2.53)	91 per 1000	46 fewer per 1000 (from 83 fewer to 139 more)
All-cause mortality at >12 months - not measured	0		Not estimable
Health-related quality of life at >12 months - not measured	0		Not estimable
Major bleeding at >12 months - not measured	0		Not estimable
Minor bleeding at >12 months - not measured	0		Not estimable
Arterial thromboembolic events at >12 months - not measured	0		Not estimable

a: Downgraded by 1 increment as the evidence reported thromboembolic events/vascular mortality and did not report the protocol outcome of thromboembolic events excluding mortality

b: Downgraded by 2 increments as the confidence interval crossed both MIDs

Table 6Clinical evidence summary: SAPT versus DAPT in biological transcatheter valve implantation

Outcomes	No of Participants (studies) Follow up	Quality of the evidence (GRADE)	Relative effect (95% CI)	Anticipated absolute effects
Outcomes	No of Participants (studies) Follow up	Quality of the evidence (GRADE)	Relative effect (95% CI)	Risk with DAPT	Risk difference with SAPT (95% CI)
All-cause mortality at ≤12 months	1086 (4 studies) 3-12 months	⊕⊝⊝⊝ VERY LOW^b^,^c due to risk of bias, imprecision	OR 0.94 (0.56 to 1.6)^a	56 per 1000	3 fewer per 1000 (from 24 fewer to 31 more)
Health-related quality of life at ≤12 months - not measured	0		Not estimable
Major bleeding at ≤12 months	1086 (4 studies) 3-12 months	⊕⊕⊕⊝ MODERATE^b due to risk of bias	OR 0.48 (0.3 to 0.77)^a	100 per 1000	49 fewer per 1000 (from 21 fewer to 68 fewer)
Minor bleeding at ≤12 months	744 (2 studies) 6-12 months	⊕⊕⊝⊝ LOW^b^,^d due to risk of bias, imprecision	RR 0.64 (0.43 to 0.94)	131 per 1000	47 fewer per 1000 (from 8 fewer to 75 fewer)
Arterial thromboembolic events at ≤12 months	222 (3 studies) 3-6 months	⊕⊝⊝⊝ VERY LOW^b^,^c due to risk of bias, imprecision	OR ranged from 0.21 to 2.24^a^,^e	Not estimable
Stroke (arterial thromboembolic events) at 12 months	665 (1 study) 12 months	⊕⊝⊝⊝ VERY LOW^b^,^c due to risk of bias, imprecision	RR 0.9 (0.48 to 1.71)	57 per 1000	6 fewer per 1000 (from 30 fewer to 40 more)
Myocardial infarction (arterial thromboembolic events) at 12 months	665 (1 study) 12 months	⊕⊝⊝⊝ VERY LOW^b^,^c due to risk of bias, imprecision	RR 0.67 (0.19 to 2.36)	18 per 1000	6 fewer per 1000 (from 15 fewer to 24 more)
All-cause mortality at >12 months - not measured	0		Not estimable
Health-related quality of life at >12 months - not measured	0		Not estimable
Major bleeding at >12 months - not measured	0		Not estimable
Minor bleeding at >12 months - not measured	0		Not estimable
Arterial thromboembolic events at >12 months - not measured	0		Not estimable
Hospital readmission at 12 months - not measured	0		Not estimable
Withdrawal due to adverse events at 12 months - not measured	0		Not estimable
Symptomatic clinical aortic valve thrombosis (thrombus on imaging) at 12 months	665 (1 study) 12 months	⊕⊝⊝⊝ VERY LOW^b^,^c due to risk of bias, imprecision	OR 2.76 (0.39 to 19.65)	3 per 1000	5 more per 1000 (from 2 fewer to 53 more)
Need for reintervention at 6-12 months - not measured	0		Not estimable
Need for reintervention at >12 months - not measured	0		Not estimable
Mean aortic valve gradient (valve degeneration) at ≤12 months	665 (1 study) 6 months	⊕⊕⊕⊝ MODERATE^b^,^f due to risk of bias		The mean aortic valve gradient (valve degeneratio n) at ≤12 months in the control groups was 10.8 mmHg	The mean aortic valve gradient (valve degeneratio n) at ≤12 months in the intervention groups was 0.20 lower (1.09 lower to 0.69 higher)

a: Odds ratio used because this summary statistic was reported for the two studies included in the IPD MA

b: Downgraded by 1 increment as the majority of the evidence was at high risk of bias

c: Downgraded by 2 increments as the confidence interval crossed both MIDs

d: Downgraded by 1 increments as the confidence interval crossed one MID

e: Outcome reported as a range of odds ratios due to heterogeneity between studies with a large difference in point estimates without sufficient study number to form valid subgroups

f: MIDs used to assess imprecision were ±2.60

Table 7Clinical evidence summary: DOAC (+ aspirin for 3 months) versus aspirin (+ clopidogrel for 3 months) in biological transcatheter valve implantation

Outcomes	No of Participants (studies) Follow up	Quality of the evidence (GRADE)	Relative effect (95% CI)	Anticipated absolute effects
Outcomes	No of Participants (studies) Follow up	Quality of the evidence (GRADE)	Relative effect (95% CI)	Risk with aspirin (+clopidogrel for 3 months) post TAVI	Risk difference with DOAC (+aspirin for 3 months) (95% CI)
All-cause mortality at ≤12 months - not measured	0		Not estimable
Health-related quality of life at ≤12 months - not measured	0		Not estimable
Major bleeding at ≤12 months - not measured	0		Not estimable
Minor bleeding at ≤12 months - not measured	0		Not estimable
Arterial thromboembolic events at ≤12 months - not measured	0		Not estimable
All-cause mortality at >12 months - median treatment duration 428 days	1644 (1 study) 428 days	⊕⊕⊝⊝ LOW^a^,^b due to risk of bias, imprecision	RR 1.67 (1.13 to 2.46)	47 per 1000	31 more per 1000 (from 6 more to 69 more)
Health-related quality of life at >12 months - not measured	0		Not estimable
Major bleeding at >12 months - VARC-2 life-threatening, disabling or major bleeding - median treatment 428 days	1644 (1 study) 428 days	⊕⊕⊝⊝ LOW^a^,^b due to risk of bias, imprecision	RR 1.47 (0.94 to 2.29)	38 per 1000	18 more per 1000 (from 2 fewer to 49 more)
Major bleeding at >12 months - BARC type 2, 3 or 5 bleeding - median treatment 428 days	1644 (1 study) 428 days	⊕⊕⊕⊝ MODERATE^a due to risk of bias	RR 1.72 (1.34 to 2.21)	104 per 1000	75 more per 1000 (from 35 more to 126 more)
Major bleeding at >12 months - ISTH major bleeding - median treatment 428 days	1644 (1 study) 428 days	⊕⊕⊝⊝ LOW^a^,^b due to risk of bias, imprecision	RR 1.62 (1.04 to 2.52)	37 per 1000	23 more per 1000 (from 1 more to 56 more)
Minor bleeding at >12 months - TIMI major or minor bleeding - median treatment 428 days	1644 (1 study) 428 days	⊕⊝⊝⊝ VERY LOW^a^,^b^,^c due to risk of bias, indirectness, imprecision	RR 1.73 (1.06 to 2.83)	29 per 1000	21 more per 1000 (from 2 more to 53 more)
Stroke (arterial thromboembolic events) at >12 months - median treatment 428 days	1644 (1 study) 428 days	⊕⊝⊝⊝ VERY LOW^a^,^d due to risk of bias, imprecision	RR 1.19 (0.71 to 2)	31 per 1000	6 more per 1000 (from 9 fewer to 31 more)
Myocardial infarction (arterial thromboembolic events) at >12 months - median treatment 428 days	1644 (1 study) 428 days	⊕⊝⊝⊝ VERY LOW^d^,^e due to risk of bias, imprecision	RR 1.34 (0.72 to 2.49)	21 per 1000	7 more per 1000 (from 6 fewer to 31 more)
Pulmonary embolism (arterial thromboembolic events) at >12 months - median treatment 428 days	1644 (1 study) 428 days	⊕⊝⊝⊝ VERY LOW^d^,^e due to risk of bias, imprecision	OR 1.48 (0.26 to 8.55)	2 per 1000	1 more per 1000 (from 1 fewer to 15 more)
Systemic embolism (arterial thromboembolic events) at >12 months- median treatment 428 days	1644 (1 study) 428 days	⊕⊝⊝⊝ VERY LOW^d^,^e due to risk of bias, imprecision	OR 0.99 (0.06 to 15.85)	1 per 1000	0 fewer per 1000 (from 1 fewer to 15 more)
Hospital readmission at 12 months - not measured	0		Not estimable
Premature study drug discontinuation (withdrawal due to adverse events - thromboembolic, bleeding or other adverse events) at 12 months - median treatment duration 428 days	1644 (1 study) 428 days	⊕⊕⊝⊝ LOW^e due to risk of bias	RR 2.01 (1.6 to 2.54)	111 per 1000	112 more per 1000 (from 67 more to 171 more)
Symptomatic valve thrombosis (thrombus on imaging) at <12 months - median treatment duration 428 days	1644 (1 study) 428 days	⊕⊝⊝⊝ VERY LOW^a^,^d due to risk of bias, imprecision	OR 0.44 (0.13 to 1.54)	9 per 1000	5 fewer per 1000 (from 8 fewer to 5 more)
Need for reintervention at 6-12 months - not measured	0		Not estimable
Need for reintervention at >12 months - not measured	0		Not estimable
Valve degeneration (mean transvalvular gradient) at ≥12 months - not measured	0		Not estimable

a: Downgraded by 1 increment as the majority of the evidence was at high risk of bias

b: Downgraded by 1 increments as the confidence interval crossed one MID

c: Combines major and minor bleeding rather than reporting minor bleeding events separately

d: Downgraded by 2 increments as the confidence interval crossed both MIDs

e: Downgraded by 2 increments as the majority of the evidence was at very high risk of bias

Table 8Clinical evidence summary: Anticoagulant (VKA or DOAC) + SAPT (clopidogrel) versus anticoagulant (VKA or DOAC) alone in biological transcatheter valve implantation

Outcomes	No of Participants (studies) Follow up	Quality of the evidence (GRADE)	Relative effect (95% CI)	Anticipated absolute effects
Outcomes	No of Participants (studies) Follow up	Quality of the evidence (GRADE)	Relative effect (95% CI)	Risk with anticoagulant alone post TAVI	Risk difference with Anticoagulant (VKA or DOAC) + clopidogrel (95% CI)
All-cause mortality at ≤12 months	313 (1 study) 12 months	⊕⊝⊝⊝ VERY LOW^a^,^b^,^c due to risk of bias, indirectness, imprecision	RR 1.15 (0.67 to 1.98)	134 per 1000	20 more per 1000 (from 44 fewer to 131 more)
Health-related quality of life at ≤12 months - not measured	0		Not estimable
Major bleeding at ≤12 months - VARC-2 life-threatening, disabling or major bleeding (major bleeding) at 12 months	313 (1 study) 12 months	⊕⊝⊝⊝ VERY LOW^a^,^b^,^d due to risk of bias, indirectness, imprecision	RR 1.87 (1.01 to 3.44)	89 per 1000	77 more per 1000 (from 1 more to 217 more)
Minor bleeding at ≤12 months - VARC-2 minor bleeding (minor bleeding) at 12 months	313 (1 study) 12 months	⊕⊝⊝⊝ VERY LOW^a^,^b^,^d due to risk of bias, indirectness, imprecision	RR 1.41 (0.83 to 2.39)	127 per 1000	52 more per 1000 (from 22 fewer to 177 more)
Stroke (arterial thromboembolic events) at ≤12 months	313 (1 study) 12 months	⊕⊝⊝⊝ VERY LOW^a^,^b^,^c due to risk of bias, indirectness, imprecision	RR 1.01 (0.41 to 2.47)	57 per 1000	1 more per 1000 (from 34 fewer to 84 more)
Myocardial infarction (arterial thromboembolic events) at ≤12 months	313 (1 study) 12 months	⊕⊝⊝⊝ VERY LOW^b^,^c^,^e due to risk of bias, indirectness, imprecision	OR 1.01 (0.06 to 16.16)	6 per 1000	0 more per 1000 (from 6 fewer to 83 more)
All-cause mortality at >12 months - not measured	0		Not estimable
Health-related quality of life at >12 months - not measured	0		Not estimable
Major bleeding at >12 months - not measured	0		Not estimable
Minor bleeding at >12 months - not measured	0		Not estimable
Arterial thromboembolic events at >12 months - not measured	0		Not estimable
Hospital readmission at 12 months - not measured	0		Not estimable
Withdrawal due to adverse events at 12 months - not measured	0		Not estimable
Thrombus on imaging at <12 months - not measured	0		Not estimable
Need for reintervention at 6-12 months - not measured	0		Not estimable
Need for reintervention at >12 months - not measured	0		Not estimable
Mean aortic valve gradient (valve degeneration - transvalvular gradient) at ≥12 months	264 (1 study) 6 months	⊕⊝⊝⊝ VERY LOW^a^,^d^,^e^,^f due to risk of bias, indirectness, imprecision		The mean aortic valve gradient (valve degeneration - transvalvular gradient) at ≥12 months in the control groups was 9 mmHg	The mean aortic valve gradient (valve degeneration - transvalvular gradient) at ≥12 months in the intervention groups was 1.5 higher (0.29 to 2.71 higher)

a: Downgraded by 1 increment as the majority of the evidence was at high risk of bias

b: Anticoagulation includes a mixture of some receiving VKAs and some receiving DOACs, whereas ideally aimed to look at these groups separately

c: Downgraded by 2 increments as the confidence interval crossed both MIDs

d: Downgraded by 1 increment as the confidence interval crossed one MID

e: Downgraded by 2 increments as the majority of the evidence was at very high risk of bias

f: MIDs used to assess imprecision ±2.55

Table 9UK costs of anticoagulant and antiplatelet drugs

Drug class	Drug	Daily dose	Cost – per day
Vitamin K antagonist	Warfarin tablet	5mg daily^(a)	£0.01
	Acenocoumarol	4mg daily^(b)	£0.18
	Phenindione	100mg daily^(c)	£76.88
Direct acting anticoagulants (DOACs)	Dabigatran capsule	110mg-150mg twice daily	£1.70
	Rivaroxaban tablet	20mg once daily	£1.80
	Apixaban tablet	2.5-5mg twice daily	£1.90
	Edoxaban tablet	60mg once daily	£1.75
Antiplatelet	Aspirin tablet	75mg once daily	£0.05
	Clopidogrel	75mg once daily	£0.05
	Ticagrelor	90mg twice daily^(d)	£1.95
	Prasugrel	5mg once daily^(e)	£1.70

: Source: BNF 2019³⁷

(a): Assumed here to be an average daily dose of 5mg. Initially 5–10 mg, to be taken on day 1; subsequent doses dependent on the prothrombin time, reported as INR (international normalised ratio), a lower induction dose can be given over 3–4 weeks in patients who do not require rapid anticoagulation, elderly patients to be given a lower induction dose; maintenance 3–9 mg daily, to be taken at the same time each day.

(b): 4mg used for calculation but BNF states daily dose is 1-8mg depending on response.

(c): 100mg daily dose used for calculation but guidance is for 50-100mg

(d): 180mg loading dose also required

(e): Based on guidance for >75 year olds. 60mg loading dose also required