What is the optimal level of anticoagulation in adult patients receiving warfarin following implantation of a mechanical prosthetic mitral valve?

July 24, 2007

July 26, 2007

Andrew Bayliss, Peter Faber, Joel Dunning, and Andrew Ronald, Specialist Registrars in Cardiothoracic Surgery and Consultant in Anaesthesia (Department of Cardiac Anaesthesia, Aberdeen Royal Infirmary, Aberdeen and Department of Cardiothoracic Surgery, James Cook University Hospital)

Joel Dunning, Department of Cardiac Anaesthesia, Aberdeen Royal Infirmary, Aberdeen and Department of Cardiothoracic Surgery, James Cook University Hospital

In patients with [mechanical prosthetic mitral valve] receiving long-term [warfarin therapy] what is the [optimal therapeutic INR target]?

You have inserted a mechanical prosthetic mitral heart valve into a 60-year-old man. He subsequently has a GI bleed while on warfarin so you decide to review the literature to confirm optimal therapeutic INR which minimises long-term thromboembolic and haemorrhagic complications.

Medline 1966 to 2006 November Week 3 using OVID interface.

EMBASE 1980 to 2006 Week 50.

[exp Cardiopulmonary Bypass/OR CABG.mp. OR exp Thoracic Surgery/OR Coronary art$ bypass.mp. OR Cardiopulmonary bypass.mp. OR exp Cardiopulmonary Bypass/OR exp Cardiovascular Surgical Procedures/OR exp Thoracic Surgical Procedures/OR exp Coronary Artery Bypass/OR cardiac transplantation.mp. OR exp Heart Transplantation/OR mitral valve.mp. OR exp Mitral Valve/OR exp Heart Valve Prosthesis/OR exp Heart Valve Prosthesis Implantation/OR mitral valve replacement.mp. OR exp Bioprosthesis/OR mitral valve prosthesis.mp.] AND [INR.mp. OR exp International Normalized Ratio/OR warfarin.mp. OR exp Warfarin/] AND [Thrombosis/OR valve thrombosis.mp. OR thromboembolism.mp. OR Thromboembolism/OR stroke. mp. OR exp Cerebrovascular Accident/OR exp Cerebral Hemorrhage/OR exp Subarachnoid Hemorrhage/OR exp Hemorrhage/OR haemorrhage.mp. OR exp Gastrointestinal Hemorrhage/OR bleeding.mp. OR postoperative complications.mp. OR exp Postoperative Complications/OR exp Prosthesis Failure/OR prosthetic valve failure.mp.] AND [limit to adults].

A total of 894 papers on Medline and 1235 on Embase were found using the above search. All major guidelines were included, and their reference lists searched. Twelve papers were considered to represent the best evidence on the topic and are summarised in the table

The thrombogenic characteristics of prosthetic mechanical heart valves are well recognised [Friedli, Cannegieter] necessitating postoperative anticoagulation therapy. However, it is important to achieve an anticoagulation balance which prevents both adverse thromboembolic events [Butchart 2004, Rosendaal] and bleeding [Levine].

There can also be variability of warfarin effects which when outwith a predetermined 'target' INR range is associated with higher risks of valve related thromboembolic or haemorrhagic mortality [Butchart 2004, Rosendaal]. Finally, prosthetic valves themselves vary in their thrombogenic properties [Vink, Kuntze, Butchart 1991].

Several major guidelines have been published which attempt to identify an 'optimal' target INR for patients with mechanical mitral valves. However, with a scarcity of large randomised trials, most guidelines are based on cohort studies and case series, a fact acknowledged by the groups themselves. The sixth and seventh ACCP guidelines recommend a target INR of 2.5–3.5 in patients with tilting disc and bi-leaflet mechanical valves in the mitral position. For older generation valves (caged ball or disc) or in patients with additional risk factors, the addition of low dose aspirin 75–100 mg/day is recommended. Previous concerns about increased bleeding events in patients receiving both aspirin and vitamin-K antagonists are somewhat allayed by studies demonstrating significant decreases in thromboembolic events with combination therapy without significant differences in bleeding events [Vaughan]. Comparable results have been reported in other studies [Turpie]. However, as emphasised in these guidelines the benefits of anti-platelet therapy combined with warfarin needs to be evaluated on the basis of total daily aspirin dose and variability of INR within and between groups of patients.

Dose-dependent bleeding risk with aspirin combined with warfarin is also reported in the 1998 AHA/ACC guidelines which were revised in 2006 [Bonow, 1998, 2006]. In parallel with the ACCP guidelines these recommend an INR target of 2.5–3.5 for newer generation mechanical mitral valves. A target of 3.0–4.5 should be considered in patients with valves of increased thrombogenicity. However, whilst the 1998 guideline suggests supplementation with aspirin in those patients with additional thromboembolic risk factors, by 2006 it has become a Class I Level B recommendation with Clopidogrel being advised for those unable to take Aspirin.

The most recent European guidelines have come from the European Society of Cardiologists (ESC) (Bonow), the British Committee for Standards in Haematology (BCSH) (Baglin) and The Scottish Intercollegiate Guidelines Network (SIGN) (Lowe). In common with the American guidelines, these support a target INR of 2.5–3.5 for second generation prosthetic mechanical mitral valves. However, the European and UK based guidelines are more restrained regarding supplementary aspirin with the BCSH making no comment and the ESC and SIGN advocating a cautious approach to addition of an antiplatelet agent, recommending use in high-risk cases only after thorough risk factor identification and warfarin optimisation. However, despite these slight differences between USA and European guidelines no studies have examined whether these produce clinically different outcomes.

As acknowledged by all guidelines there are few good RCTs or cohort studies available. This may in part reflect ethical considerations at a time when expert committees are producing contemporary evidence-based guidelines. In 1991, Butchart et al. published a cohort study comparing mean target INRs of 2.5 and 3.0 in patients who had received a Medtronic-Hall mitral prosthesis. Embolic and haemorrhagic event-free survival was greater with a higher INR and they concluded that an INR above 3 was appropriate. However, there were possible confounding factors with this study, not least that patients with lower INRs had surgery 5–10 years earlier than those with higher INRs.

n 1995 Cannegieter et al. studied adverse haemorrhagic or thromboembolic events in patients who had undergone valve replacement reporting an optimal INR range of 2.5–4.9. A literature review by Tiede et al. in 1998 recommended an INR of 3.3–3.7 for tilting disc and 2.8–3.2 for other valves . A more recent meta-analysis including nearly 10,000 patients from 30 studies concluded that an INR over 3.0 was associated with lower risks of thromboembolic complications without increased bleeding risk (Vink). However, their study patients were relatively young and excluded if on anti-platelet therapy, and they did not provide data on either the achieved INR levels or INR variability. Unfortunately these three studies included all types of valve and valve position with little if any subgroup analysis. Finally, an RCT by Pengo et al. found no significant difference in systemic thromboembolism and vascular death between patients with target INRs three and four, although 'major' and 'minor' haemorrhage were significantly greater in the higher INR group. Once again this study included all valve types with no subgroup analysis.

In patients with newer generation mechanical prosthetic mitral valves the INR should be maintained at 2.5–3.5. For older type valves the INR should be 3.5–4.5. Some patients with no contraindications to anti-platelet therapy at increased risk of thromboembolic episodes may benefit from additional low-dose aspirin therapy (75–100 mg/d). To decrease the risk of thromboembolic and haemorrhagic events associated with anticoagulation therapy it is imperative to ensure a low variability in the level of anticoagulation.

1. Stein PD, Alpert JS, Bussey HI et al.. Antithrombotic therapy in patients with mechanical and biological prosthetic heart valves.
2. Salem DN, Stein PD, Al-Ahmad A et al.. Antithrombotic therapy in valvular heart disease – native and prosthetic: The Seventh ACCP conference on Antithrombotic and Thrombolytic Therapy.
3. Bonow RO, Carabello B, de Leon AC et al.. Guidelines for the management of patients with valvular heart disease: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines
4. Bonow RO, Carabello BA, Chatterjee K et al.. ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: executive summary. (Writing Committee to Revise the 1998 Guidelines for the Management of Patients ...
5. Butchart EG, Gohlke-Barwolf C, Antunes MJ et al.. European Society of Cardiology. Recommendations for the management of patients after heart valve surgery.
6. Baglin TP, Keeling DM, Watson HG.. Guidelines on oral anticoagulation (warfarin): third edition – 2005 update.
7. Lowe G, Belch J, Burton C et al.. Antithrombotic therapy.
8. Butchart EG, Lewis PA, Bethel JA et al.. Adjusting anti-coagulation to prosthesis thrombogenicity and patient risk factors. Recommendations for the Medtronic Hall valve.
9. Cannegieter SC, Rosendaal FR, Wintzen AR et al.. Optimal oral anticoagulant therapy in patients with mechanical heart valves.
10. Tiede DJ, Nishimura RA, Gastineau DA et al.. Modern management of prosthetic valve anticoagulation.
11. Vink R, Kraaijenhagen RA, Hutten BA et al.. The optimal intensity of vitamin K antagonists in patients with mechanical heart valves. A meta-analysis.
12. Pengo V, Barbero F, Banzato A et al.. A comparison of a moderate with a moderate-high intensity oral anticoagulant treatment in patients with mechanical heart valve disease.
13. Friedli B, Aerichide N, Grondin P et al.. Thromboembolic complications of heart valve prostheses.
14. Cannegieter SC, Rosendaal FR, Briet E.. Thromboembolic and bleeding complications in patients with mechanical heart valve prostheses.
15. Butchart EG, Payne N, Li HH et al.. Better anticoagulation control improves survival after valve replacement.
16. Rosendaal FR, Cannegieter SC, van der Meer FJ et al.. A method to determine the optimal intensity of oral anticoagulant therapy.
17. Levine MN, Raskob G, Landefeld S et al.. Hemorrhagic complications of anticoagulant treatment.
18. Kuntze CEE, Ebels T, Eijgelaar A et al.. Rates of thromboembolism with three different mechanical heart valve prostheses: randomised study.
19. Butchart EG, Lewis PA, Bethel JA et al.. Adjusting anticoagulation to prosthesis thrombogenicity and patient risk factors.
20. Vaughan P, Waterworth PD.. An audit of anticoagulation practice among UK cardiothoracic consultant surgeons following valve replacement/repair.
21. Turpie AGG, Gent M, Laupacis A et al.. A comparison of aspirin with placebo in patients treated with warfarin after heart valve replacement.