Prosthetic Valves and Anticoagulation

Meet the patient

A 34-year-old woman with a mechanical mitral valve lands at 3am, 26 weeks pregnant, suddenly breathless and saturating 84 percent, her mitral clicks muffled, lungs full of water. Her dose-adjusted LMWH was halved last week for a nosebleed.^[1]

Two questions now decide the next hour and the next decade: is the valve clotted? (echo now) and why is she on LMWH instead of warfarin? (the pregnancy question). Hold both, and everything below slots into place.^[1][2]

The trade-off that decides everything — durability versus anticoagulation

Every prosthetic valve is one bargain, struck once, on the operating table. Degenerative aortic stenosis has overtaken rheumatic disease as the dominant indication for valve replacement in high-income practice, and the valve chosen still dictates the anticoagulation strategy.^[1]

Mechanical valves are machined from pyrolytic carbon and titanium — essentially indestructible, outliving the patient — but every non-biological surface activates clotting on every heartbeat, so the price is lifelong warfarin. Bioprosthetic (tissue) valves are built from bovine pericardium or porcine leaflets, barely thrombogenic; ACC/AHA lists VKA to INR 2.5 as reasonable for 3 to 6 months after surgical bioprosthetic replacement (Class 2b), then aspirin 75 to 100 mg (Class 2a) unless another indication such as AF requires anticoagulation — but the tissue calcifies and tears (structural valve deterioration), demanding re-operation when it fails.^[1]

The bargain is irreversible, which is why the valve consultation matters more than the operation. TAVI/TAVR added a third door — a tissue valve delivered through the groin for the elderly or inoperable, no sternotomy, no bypass.^[5]

Etymology for viva gold: prosthesis, from the Greek prosthesis, "an addition" — a part added to replace what disease took away. The word survived two and a half millennia because the concept never changed.^[1]

Three families, one decision — the classification

Enlarge

The classification runs along two axes — how it is built (mechanical, bioprosthetic, transcatheter) and where it sits (aortic, mitral, tricuspid, pulmonary). Both axes set the INR target and the thrombosis risk.^[1][2]

^{[1] [1] [5] [1]}

The position rule that earns marks: mitral and tricuspid valves thrombose far more than aortic, because the low-pressure chambers leave slow flow across the leaflets. The high-velocity aorta is protective. That single haemodynamic fact explains every INR difference on this page.^[1]

The 65-year mirage — how to choose the valve

Tissue and transcatheter options have displaced mechanical implants for many older patients who trade durability for freedom from lifelong warfarin.^[1]

^[1]

The cluster rule — "young: mechanical; old: tissue; everyone in between: a conversation." Under 50, mechanical usually wins on durability (a redo at 60 is brutal); over 70, bioprosthetic or TAVI (a redo in 15 years may never come); in between, a shared decision around anticoagulation burden, re-operation risk, comorbidity, and patient preference. Modern guidelines have dropped the rigid age cut-off in favour of individualised choice.^[1][2]

Mechanical valves — hear the click, mind the INR

The bileaflet (St. Jude, CarboMedics, On-X) is the modern mechanical standard — two semicircular pyrolytic-carbon leaflets pivoting in a housing, near-physiological laminar flow, durable for decades. Its one soft spot is the hinge, where stasis breeds thrombus the moment the INR dips.^[1]

The tilting disc (Medtronic Hall, Bjork-Shiley) and caged ball (Starr-Edwards, the first successful valve, 1960) are history you will still meet in long-term follow-up clinics. Know them by their clicks; do not implant them. The Bjork-Shiley even earned its own infamy — strut fracture with outlet-strut embolisation.^[1]

Bioprosthetic valves — buy time, not a lifetime of warfarin

The tissue valve's gift is a time-limited VKA, not a lifetime of warfarin. ACC/AHA lists VKA to INR 2.5 as reasonable for 3 to 6 months after surgical bioprosthetic AVR or mitral replacement (Class 2b), with aspirin 75 to 100 mg reasonable thereafter (Class 2a) unless another indication such as AF requires anticoagulation. Bovine pericardial (Carpentier-Edwards PERIMOUNT) leads; stented porcine (Hancock II, Mosaic) follows; stentless (Freestyle, Toronto SPV) and sutureless (Perceval, Intuity) variants serve the small annulus and the high-risk surgical patient.^[1]

Everyone forgets: structural valve deterioration is not a valve defect — it is the expected failure mode. Calcium hydroxyapatite stiffens the glutaraldehyde-fixed collagen scaffold, then the constant flexing tears the leaflet at the stent-post base, producing a mixed stenotic-and-regurgitant lesion over months.^[4]

TAVI — the valve through the groin

The balloon-expandable Edwards SAPIEN and the self-expanding Medtronic CoreValve Evolut have marched TAVI from inoperable (PARTNER 1B) to high- (CoreValve US Pivotal), intermediate- (PARTNER 2, SURTAVI), and now low-risk severe aortic stenosis — non-inferior or superior to surgery across the spectrum.^[5]

For the elderly patient with severe aortic stenosis, TAVI is an established alternative to surgical replacement.^[5] Its antithrombotic footprint is light: in GALILEO, standard care was aspirin 75 to 100 mg daily with clopidogrel 75 mg daily for the first 3 months, and rivaroxaban 10 mg daily — given without another anticoagulation indication — caused more death, thromboembolic events, and major bleeding than the antiplatelet strategy. No routine anticoagulation without a clear indication such as AF.^[7]

Why mechanical valves clot, why tissue valves fail

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A mechanical valve is a permanent intravascular foreign body, and blood does what blood does to foreign bodies — it clots on them. Factor XII meets the negatively charged carbon surface (contact activation, the intrinsic pathway); monocytes on the sewing ring express tissue factor; platelets adhere and release procoagulant microparticles; and the abnormal flow leaves stagnation in the hinges and the minor orifice — the classic address of valve thrombosis.^[1]

A tissue valve fails by calcifying. Glutaraldehyde kills the cells but leaves the collagen scaffold, and over the years calcium hydroxyapatite stiffens the leaflets until they tear — usually at the base near the stent post — producing a mixed stenotic-and-regurgitant lesion that worsens over months. That is structural valve deterioration, and it comes faster in the young, in the mitral position, in chronic kidney disease, and in pregnancy.^[4]

^[1]

Thrombus versus pannus — the face-off every stem is built on

Both obstruct the valve; only one lyses. This is the single most repeated comparison in prosthetic-valve exams, and examiners check every discriminator.^[1]

^[1]

The discriminator line: thrombus is acute, soft, subtherapeutic, and dissolves with lysis; pannus is chronic, dense, therapeutic, and needs the knife. Cardiac CT settles it — thrombus enhances with contrast, pannus stays low-attenuation.^[1]

Read the prosthetic valve like the echo does — presentation and bedside

Most replaced-valve patients are well; the click is the only sign of the metal inside them. Symptoms mean a complication has arrived, and the tempo tells you which one.^[1]

• Acute (hours): sudden severe dyspnoea, pulmonary oedema, syncope, or cardiogenic shock in a mechanical-valve patient — acute valve thrombosis until proven otherwise.
• Subacute (days to weeks): fever, sweats, malaise, new murmur, embolic phenomena — prosthetic valve endocarditis.
• Gradual (months): slowly worsening dyspnoea and fatigue with a new murmur — structural deterioration, pannus, or patient-prosthesis mismatch.
• Insidious: anaemia, jaundice, dark urine from intravascular haemolysis — paravalvular leak.
• Embolic: transient ischaemic attack, stroke, or systemic embolus — thrombus or vegetation.
• Bleeding: epistaxis, gastrointestinal bleed, bruising, intracranial haemorrhage — over-anticoagulation.^[1]

The click is the bedside anchor. A mechanical valve snaps a sharp, metallic, high-pitched click at closure — loud at the apex for mitral, at the right second intercostal space for aortic. A muffled or absent click is an alarm for thrombosis with restricted leaflet motion; a tissue valve closes with a soft, native-sounding sound you will not separate from S1.^[1]

Everyone forgets: a normal TTE does not exclude prosthetic mitral pathology — the metal casts an acoustic shadow that hides thrombus and vegetations behind it. Suspect the mitral, order the TEE. Pooled sensitivity for prosthetic vegetations is about 29 percent on TTE and 82 percent on TEE (specificity 100 percent and 95 percent respectively).^[18]

The INR ladder — name the number, name the valve

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These are the numbers a prosthetic-valve prescriber must recite from memory, in the dark, at 3am.^[1][2]

^{[1] [11] [10] [20] [3] [7] [6]}

The full ladder, in the order the examiner expects it:^[1]

• Mechanical aortic valve, bileaflet, no thromboembolic risk factors: ACC/AHA target INR of 2.5. PROACT's On-X control arm used 2.0 to 3.0 with aspirin 81 mg daily.^[1][10]
• Mechanical aortic valve with thromboembolic risk factors or an older-generation prosthesis: ACC/AHA target INR of 3.0.^[1]
• Mechanical mitral valve: ACC/AHA target INR of 3.0; PROACT Mitral restates the guideline range 2.5 to 3.5. Trial protocol added aspirin 81 mg daily.^[1][11]
• On-X mechanical aortic valve, selected patients: ACC/AHA Class 2b INR 1.5 to 2.0 from 3 months plus aspirin 75 to 100 mg. PROACT randomised that range against 2.0 to 3.0, all on aspirin 81 mg daily.^[1][10]
• Any mechanical valve, any position: vitamin K antagonists are the only approved oral anticoagulants — a DOAC is never acceptable (RE-ALIGN; PROACT-Xa stopped after 863 patients for excess thromboembolism with apixaban).^[9][20][3]
• Bioprosthetic valve: ACC/AHA lists VKA to INR 2.5 as reasonable for 3 to 6 months after surgical replacement (Class 2b). With atrial fibrillation, RIVER showed rivaroxaban 20 mg daily non-inferior to warfarin (target INR 2.0 to 3.0) after bioprosthetic mitral replacement.^[1][6]
• TAVI: aspirin 75 to 100 mg daily with clopidogrel 75 mg daily for the first 3 months was the antiplatelet arm of GALILEO; rivaroxaban given without an anticoagulation indication caused excess death, thromboembolic events, and major bleeding — no routine anticoagulation without AF.^[7]

The cluster rule — "mitral and high-risk aortic sit at INR of 3.0, low-risk bileaflet aortic at 2.5, and 1.5 to 2.0 only on On-X from 3 months": say it as one breath and you have the spine of every INR question. Add low-dose aspirin where the trial or Class 2b recommendation used it — 81 mg daily in PROACT, 75 to 100 mg in ACC/AHA On-X wording.^[1][10][11]

The one line that must never be crossed — DOACs in mechanical valves

The classic trap: a junior reaches for a DOAC because it is "easier" than INR monitoring — and converts a controlled patient into a stroke. Check the valve type before you sign any anticoagulant prescription. Dabigatran, rivaroxaban, apixaban, edoxaban — none of them belong in a mechanical valve.^[3]

Bioprosthetic plus AF, and the TAVI anticoagulation trap

The picture flips completely for tissue. For a bioprosthetic mitral valve with atrial fibrillation, RIVER (Guimarães, NEJM 2020) showed rivaroxaban 20 mg daily non-inferior to warfarin (INR 2.0 to 3.0) for death, major cardiovascular events, or major bleeding at 12 months. ACC/AHA lists VKA to INR 2.5 as reasonable for 3 to 6 months after surgical bioprosthetic replacement (Class 2b). This does not license a DOAC in a mechanical valve.^[6][1]

The TAVI trap is the mirror image. GALILEO (Dangas, NEJM 2020) tested rivaroxaban 10 mg plus aspirin versus clopidogrel plus aspirin after TAVI in patients with no other anticoagulation indication, and was stopped early for harm — rivaroxaban raised death, thromboembolic events, and major bleeding. Do not routinely anticoagulate a TAVI valve unless there is a clear indication such as AF.^[7]

^[6]

On-X — the one mechanical valve that bends the INR rule

The On-X bileaflet aortic valve is the sole mechanical valve randomised to a lower INR. From 3 months after implant, PROACT randomised patients to lower-dose warfarin (INR 1.5 to 2.0) or standard warfarin (INR 2.0 to 3.0), all on aspirin 81 mg daily.^[10]

The named trap: PROACT-Xa randomised On-X aortic valves (implanted at least 3 months earlier) to apixaban 5 mg twice daily versus warfarin INR 2.0 to 3.0 and was stopped after 863 patients because of excess thromboembolic events — 4.2 versus 1.3 percent per patient-year. Even On-X needs warfarin. The DOAC ban is absolute.^[20][9][3]

Acute valve thrombosis — the 3am emergency

This is the time-critical emergency of prosthetic-valve medicine. Estimated incidence is 2 to 4 percent per year in autopsy and surgical series.^[19] A mechanical-valve patient (especially mitral) who suddenly becomes breathless, oedematous, syncopal, or shocked has valve thrombosis until proven otherwise.^[1]

^[1]

A small non-obstructive thrombus in a stable patient can be managed with intravenous heparin and repeat imaging — in the TEE-guided series heparin succeeded in nine of 18 non-obstructive episodes and in none of four obstructive cases. Thrombolysis, surgery, and intravenous heparin were used in 43, 20, and 22 episodes respectively. The other emergencies — endocarditis with heart failure, a haemodynamically significant paravalvular leak, acute mechanical failure — all converge on urgent or emergency surgery, with antibiotics, support, and transfusion as temporising measures.^[13][1][8]

Surgery, lysis, or heparin — the thrombosis decision

The three doors are surgery, thrombolysis, and intravenous heparin — chosen by obstruction, stability, and surgical availability. That is the whole decision tree in one line, and it is exactly the comparison the TEE-guided series set out to make.^[13][1]

• Valve thrombosis, obstructive: the TEE-guided series compared thrombolysis, surgery, and intravenous heparin (43, 20, and 22 episodes). Thrombolysis was completely successful in 86 percent; heparin succeeded in none of four obstructive cases.
• Valve thrombosis, non-obstructive: heparin succeeded in nine of 18 non-obstructive episodes; thrombolysis succeeded in 10 of 11. Re-image on TEE.
• Structural valve deterioration: redo surgery for younger surgical candidates; valve-in-valve TAVI for elderly or high-risk patients with a degenerated bioprosthetic aortic valve.
• Paravalvular leak: percutaneous closure (Amplatzer vascular plug) for symptomatic or haemolysing leaks; surgical repair for large leaks or those with infection.
• Pannus: surgical excision or valve replacement — pannus does not respond to anticoagulation or fibrinolysis.
• Endocarditis: organism-targeted IV antibiotics for a completed therapeutic course; surgery for heart failure, uncontrolled infection, large mobile vegetation, periannular extension, or resistant organism.
• Patient-prosthesis mismatch: prevention at implantation; valve-in-valve or surgical replacement for severe symptomatic PPM.^[1]

The surgical threshold in prosthetic-valve endocarditis is lower than in native-valve IE. Heart failure from regurgitation, periannular extension (abscess, fistula, heart block), uncontrolled infection (persistent bacteraemia, fungal or resistant organism), and a large mobile vegetation with embolic risk are all indications to operate.^[8]

Bridging for surgery — who, when, and who to leave alone

Bridging is an examiner favourite and a daily ward decision — and the modern answer is "less than you think."^[1]

^[1]

Who needs a bridge? PERIOP2 — in patients with mechanical heart valves or atrial fibrillation requiring temporary warfarin interruption — found that postoperative dalteparin did not reduce major thromboembolism (1.0 versus 1.2 percent at 90 days). ACC/AHA 2020 still gives Class 2a bridging for mechanical AVR with thromboembolic risk factors, older-generation aortic prostheses, and mechanical mitral valves, and says bridging is not required for a bileaflet aortic valve without other risk factors. Do not routinely bridge the low-risk bileaflet aortic valve; individualise the high-risk valve with the anticoagulation team.^[12][1]

The classic trap: bridging every mechanical-valve patient "to be safe." You are not being safe — you are causing bleeds for zero thrombosis benefit in the low-risk group. Reserve the bridge for the high-risk ladder above.^[1]

Pregnancy with a mechanical valve — the highest-risk clinic

Pregnancy in a mechanical-valve patient is high-risk by definition — in the global ROPAC III registry, valve thrombosis occurred in 6 percent of mechanical-valve pregnancies and an uncomplicated pregnancy with live birth reached only 54 percent (versus 79 percent with a biological valve). ACC/AHA: first-trimester warfarin carries the highest likelihood of miscarriage, fetal death, and congenital malformation, especially when the dose exceeds 5 mg/day; if LMWH is used, target anti-Xa 0.8 to 1.2 U/ml 4 to 6 hours after the dose. The strategy is built before conception, in a joint obstetric-cardiac-haematology clinic.^[14][1]

^[14]

Emergency reversal — vitamin K and PCC

Match the reversal to the bleed — never nuke a slightly high INR. For vitamin-K-antagonist-associated major bleeding, current guidelines recommend prothrombin complex concentrate in combination with vitamin K to normalise coagulation — the PCC restores the blocked factors immediately, the vitamin K sustains the reversal.^[15]

• Avoid abrupt reversal in a mechanical-valve patient without life-threatening bleeding — the thrombotic risk sits on a metal surface.^[1]

Dental prophylaxis — restricted to the highest-risk patients

Antibiotic prophylaxis before invasive dental procedures is strictly restricted to the patients at highest risk of infective endocarditis — that is the deliberate design of the 2007 American Heart Association guideline, and national audits keep finding both over-use and under-use around it.^[16]

For a patient who qualifies, the agent, dose, and timing come from the current guideline card, applied exactly — the restriction is about who needs cover, not about improvising the what. Extractions, scaling, periodontal surgery, and implant placement are the classic high-risk dental procedures; fever plus a new murmur afterwards is endocarditis until proven otherwise.^[16][8]

Prosthetic valve endocarditis — Modified Duke and early versus late

Fever plus a new murmur in a prosthetic valve is endocarditis until proven otherwise. Three sets of blood cultures, TTE and TEE (TEE mandatory), then organism-targeted IV antibiotics for a completed therapeutic course.^[8]

Use the 2015 ESC infective endocarditis guidelines (Habib) for the modified Duke framework. The abstract of that guideline does not reprint the criterion list, so the working rule here is practical: fever plus a new murmur on a prosthetic valve is endocarditis until proven otherwise, cultures and TEE first, and a lower surgical threshold than native-valve IE.^[8]

Pooled sensitivity for prosthetic vegetations is 29 percent on TTE and 82 percent on TEE (specificity 100 percent and 95 percent); adding MDCT to TEE improves detection of periannular complications.^[18]

^[8]

The echo findings that satisfy a major imaging criterion are an oscillating intracardiac mass on the valve, an abscess, or new partial dehiscence of a prosthetic valve — and for prosthetic material, TEE is more sensitive than TTE (pooled vegetation sensitivity 82 percent versus 29 percent). ACC/AHA recommends surgery for relapsing prosthetic-valve IE after a completed antibiotic course (Class 1).^[18][1]

Investigations — echo first, always against the baseline

An echocardiography-first strategy, every time, read against the post-operative baseline.^[1][2]

^[1]

Follow-up — how often to scan

Compare every echocardiogram with the post-operative baseline. ACC/AHA 2020: after the initial post-procedure TTE, surveillance imaging is recommended at 5 and 10 years, then annually. Repeat TTE whenever the clinical status changes — new murmur, fever, dyspnoea, or an embolic event. For a bioprosthetic TAVI, annual TTE is reasonable.^[1]

• Baseline TTE before discharge after implantation — the reference for every future comparison.
• Surveillance TTE at 5 years and 10 years, then annually (ACC/AHA 2020).
• Annual TTE is reasonable after TAVI.
• TTE any time the clinical status changes — new murmur, fever, dyspnoea, embolic event; add TEE, fluoroscopy, or CT when dysfunction is suspected.
• INR monitoring for mechanical valves — dose adjustment after changes in diet, medicines, or illness; home monitoring was used in PROACT.^[1][10]

^{[5] [13] [14] [12]}

How patients come to harm — the preventable list

• A DOAC prescribed to a mechanical-valve patient — the single most preventable catastrophe. RE-ALIGN harm, reproducible in a single signature.^[3]
• An acute mitral-valve thrombosis read as "heart failure" while the muffled clicks went unexamined, delaying echo and surgery.^[1]
• A normal TTR trusted to exclude a prosthetic mitral vegetation, when TEE was mandatory.^[1][8]
• Dental prophylaxis omitted for a scaling in a prosthetic-valve patient, with endocarditis weeks later.^[1][8]
• A young woman with a mechanical valve started on warfarin in pregnancy without a pre-conception plan — ACC/AHA: first-trimester warfarin carries the highest likelihood of miscarriage, fetal death, and congenital malformation, especially when the dose exceeds 5 mg/day.^[1]
• A low-risk bileaflet aortic valve bridged "to be safe" for elective surgery, with a major bleed and no thrombosis prevented.^[1]
• High-dose vitamin K given for a trivially high INR and a nosebleed, triggering valve thrombosis from rebound hypercoagulability.^[1]
• A tissue valve chosen for a 35-year-old to avoid warfarin, failing structurally while they are still young and demanding a high-risk redo.^[4][1]
• Routine rivaroxaban after a TAVI without AF — GALILEO harm, avoidable.^[7]

The trials that changed practice

^{[3] [6] [7] [9] [10] [11] [20] [5]}

The mantra, and the mnemonic

^{[3] [9] [10] [11] [6] [16] [15] [12] [14]}

The mantra: mechanical means warfarin for life, tissue means no lifelong warfarin for the valve itself, and no DOAC ever touches a mechanical valve.^[1][3]

Ward-round test — three stems

Stem 1 — the pregnant woman from the top of the topic (answer)ShowHide

The 34-year-old with a mechanical mitral valve, 26 weeks pregnant, suddenly breathless with muffled clicks and pulmonary oedema. Her LMWH was halved for a nosebleed. What happened, and what do you do? Model: This is acute prosthetic valve thrombosis precipitated by a subtherapeutic anticoagulant dose — anticoagulation was inadequate in 82 percent of thrombosed-valve episodes in a TEE-diagnosed series, and a mechanical mitral in pregnancy is the highest-risk combination (valve thrombosis in 6 percent of mechanical-valve pregnancies, mitral position at greatest risk). Confirm with transoesophageal echocardiography — obstructive thrombosis is restricted occluder motion with an increased gradient. The three tools are thrombolysis, surgery, and intravenous heparin; thrombolysis achieved complete success in 86 percent of treated episodes. Restore adequate anticoagulation once stabilised. The deeper lesson: her anticoagulation was a pre-conception decision that should never have been halved without rechecking.^[13][14]

Stem 2 — the dabigatran prescription (answer)ShowHide

A 60-year-old with a mechanical bileaflet aortic valve is referred from the GP on dabigatran 150 mg twice daily for "stroke prevention," INR not checked. What is the error, and what do you do? Model: This is the single most preventable catastrophic error. DOACs are absolutely contraindicated in any mechanical valve — RE-ALIGN was stopped early because dabigatran caused more thromboembolic and bleeding complications than warfarin, and vitamin K antagonists remain the only approved oral anticoagulants for a mechanical valve. Stop the dabigatran and switch to warfarin with an ACC/AHA target INR of 2.5 after a bileaflet aortic valve without thromboembolic risk factors (PROACT On-X control used 2.0 to 3.0) plus aspirin 81 mg if following the PROACT protocol, and image the valve for any thrombus the DOAC may have allowed to form. The rule is absolute: no DOAC, no exception — PROACT-Xa stopped after 863 patients for excess thromboembolism with apixaban.^{[3][20][1][10]}

Stem 3 — the bioprosthetic mitral valve and new AF (answer)ShowHide

A 72-year-old, 4 months after a bioprosthetic mitral valve replacement, develops atrial fibrillation. The registrar plans to start warfarin lifelong. What is the modern alternative, and what is the trial? Model: A DOAC is acceptable here. RIVER (Guimarães, NEJM 2020) showed rivaroxaban 20 mg daily non-inferior to warfarin (target INR 2.0 to 3.0) for the composite of death, major cardiovascular events, or major bleeding at 12 months in patients with a bioprosthetic mitral valve and atrial fibrillation. Four months out from surgery, rivaroxaban is a reasonable choice. The contrast to remember: a DOAC is acceptable for a bioprosthesis with AF, but forbidden in any mechanical valve, and not routine after TAVI without AF (GALILEO harm).^[6][7]

References20ShowHide

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2. [2]Vahanian A, Beyersdorf F, Praz F, et al. 2021 ESC/EACTS Guidelines for the management of valvular heart disease Eur Heart J, 2022.PMID 34453165
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5. [5]Adams DH, Popma JJ, Reardon MJ, et al. Transcatheter aortic-valve replacement with a self-expanding prosthesis N Engl J Med, 2014.PMID 24678937
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8. [8]Habib G, Lancellotti P, Antunes MJ, et al. 2015 ESC Guidelines for the management of infective endocarditis: The Task Force for the Management of Infective Endocarditis of the European Society of Cardiology (ESC). Endorsed by: European Association for Cardio-Thoracic Surgery (EACTS), the European Association of Nuclear Medicine (EANM) Eur Heart J, 2015.PMID 26320109
9. [9]Jawitz OK, Wang TY, Lopes RD, et al. Rationale and design of PROACT Xa: A randomized, multicenter, open-label, clinical trial to evaluate the efficacy and safety of apixaban versus warfarin in patients with a mechanical On-X Aortic Heart Valve Am Heart J, 2020.PMID 32693197
10. [10]Puskas JD, Gerdisch M, Nichols D, et al. Reduced anticoagulation after mechanical aortic valve replacement: interim results from the prospective randomized on-X valve anticoagulation clinical trial randomized Food and Drug Administration investigational device exemption trial J Thorac Cardiovasc Surg, 2014.PMID 24512654
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14. [14]van der Zande JA, Ramlakhan KP, Sliwa K, et al. Pregnancy with a prosthetic heart valve, thrombosis, and bleeding: the ESC EORP Registry of Pregnancy and Cardiac disease III Eur Heart J, 2026.PMID 40237423
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19. [19]Lengyel M Management of prosthetic valve thrombosis. J Heart Valve Dis, 2004.PMID 15222276
20. [20]Wang TY, Svensson LG, Wen J, et al. Apixaban or Warfarin in Patients with an On-X Mechanical Aortic Valve NEJM Evid, 2023.PMID 38320162