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

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

.

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

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.

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 3

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

Table 4. Clinical evidence summary: VKA versus SAPT 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.

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 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 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.

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.

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.

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Appendices

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 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.

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.

Copyright © NICE 2021.
Bookshelf ID: NBK577829PMID: 35143139

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