Interactive Cardiovascular and Thoracic Surgery 3:450-455(2004)
© 2004 European Association of Cardio-Thoracic Surgery
Best evidence topic - Cardiac general |
Is addition of anti-platelet therapy to warfarin beneficial to patients with prosthetic heart valves?
Darbhamulla V. Nagarajana,
Philip S. Lewisa,
Phil Bothab and
Joel Dunningb,*
a Department of Cardiology, Stepping Hill Hospital, Stockport, Manchester, UK
b Department of Cardiothoracic Surgery, Freeman Hospital, Freeman Road, NE7 7DN, Newcastle upon Tyne, UK
* Corresponding author. Address: Department of Cardiothoracic Surgery, Freeman Hospital, Freeman Road, NE7 7DN, Newcastle upon Tyne, UK
joeldunning{at}doctors.org.uk
Received March 22, 2004;
accepted March 25, 2004
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Abstract
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A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was whether addition of anti-platelet therapy to warfarin reduced the incidence of thromboembolic complications in patients with prosthetic heart valves. Altogether 253 papers were found using the reported search, of which 11 papers represented the best evidence to answer the clinical question. The author, journal, date and country of publication, patient group studied, study type, relevant outcomes, results, and study weaknesses were tabulated. We conclude that low dose aspirin (80–100 mg daily) in addition to warfarin in patients with prosthetic heart valves reduces all cause long term mortality (NNT=19), with significant reductions in thromboembolism but an increase in bleeding.
Key Words: Evidence-based medicine; Prosthetic heart valves; Antiplatelet therapy; Warfarin; Review; Thoracic surgery
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1. Introduction
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A best evidence topic was constructed according to a structured protocol. This protocol is fully described in the ICVTS [1].
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2. Clinical scenario
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You are a registrar, about to discharge a 72-year-old patient who has just undergone an aortic valve replacement with a 21 mm bileaflet mechanical valve. He has a history of a possible TIA 4-years ago although he is now neurologically normal. In addition he has taken aspirin since this TIA although he tells you that he always takes ranitidine with it to ‘prevent heartburn’. You confidently tell him that in addition to his warfarin it would be far better for him to continue taking aspirin to prevent him getting another stroke, but your consultant is horrified and briskly tells you that he is certain to have a GI bleed if aspirin and warfarin are given together.
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3. Three-part question
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In [patients with prosthetic heart valves] is the use of [aspirin in addition to warfarin] of any benefit in terms of [survival or reducing embolic events]?
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4. Search strategy
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Medline 1966-March 2004 using the OVID interface
[exp heart valve diseases/OR exp heart valve prosthesis/OR exp mitral valve/OR exp aortic valve/OR valve$.mp) AND (exp warfarin/OR warfarin.mp OR exp coumarins/OR coumarin.mp OR exp anticoagulants/OR anticoagulant$.mp] AND [exp aspirin/OR aspirin.mp OR exp dipyridamole/OR dipyridamole.mp OR exp platelet aggregation inhibitors/OR anti-platelet.mp). AND (Maximally sensitive RCT search filter].
This search was repeated in Cochrane database of systematic reviews, and the American College of Cardiology, NICE, SIGN, European Society of Cardiology and the British Society for Haematology guideline databases were hand-searched.
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5. Search outcome
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A total of 253 papers were found of which 11 represented the best evidence and are included in the Table 1. Of note seven meta-analyses were found but five were out of date or had poor methodology and thus were excluded [11–15].
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6. Results
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It is interesting to note that although 11 trials exist on this topic, 12 meta-analyses or current guidelines were also found, all of which consider the evidence either from these studies or from each other!
Of the 11 trials, six used dipyridamole as an anti-platelet drug in doses of 225–400 mg once daily. Four trials used aspirin in doses of 500 mg once daily, 500 mg twice daily and in three recent trials, 100–200 mg once daily. The best meta-analyses were published by Massel et al. [3,4]. They found that aspirin reduced the risk of all cause mortality from 9% to 5.2%, which was a significant finding. Breaking this down there was a significant reduction of thromboembolic events from 9 to 3.8% but with a corresponding increase in major bleeding from 5.4 to 8.5%, which were all significant findings. Massel performed many sub-analyses and sensitivity analyses to see if the dose of aspirin, the date of the study, or the quality of study made an impact on these findings and found that the risk of bleeding appears to have diminished with the lower doses of aspirin used in the more recent trials.
Of the 11 trials only three investigate low doses of aspirin. Laffort [5] performed a single blind RCT in 229 patients comparing aspirin 200 mg with control with warfarin at an INR of 2.5–3.5. They found a significantly reduced level of thromboembolism by TOE or clinically but with an increase in major bleeding. Turpie [16] in the NEJM performed a double blind PRCT in 370 patients using aspirin 100 mg with warfarin at an INR of 3.0–4.5. All cause mortality was reduced from 12 to 4.8%, with significant reductions in thromboembolism but with a non-significant rise in major bleeding.
Meschengieser [10] performed a PRCT in 503 patients. They studied aspirin (100 mg) in combination with low dose warfarin (INR of 2.5–3.5) to high dose warfarin alone (INR of 3.5–4.5). They found that major bleeding and all major events were non-significantly higher in the warfarin only group and the rate of thromboembolism was similar.
Of the clinical guidelines, the American Heart Associaion recommends that Aspirin 80–100 mg should be strongly considered unless contraindicated with level 2a evidence. The European Society of Cardiology gives a similar recommendation, grading this at 2b, although a new guideline is imminently awaited in 2004. The British committee for standards in haematology make no recommendation for addition of aspirin but SIGN recommend aspirin for any patients who also suffers systemic embolism despite adequate anticoagulation. The ACCP recommend aspirin in addition to anticoagulation but acknowledge the increased risk of bleeding, giving this grade 1 status.
The Massel meta-analysis finds that addition of aspirin reduces the risk of all cause mortality with a number needed to treat of 19. Most guidelines recommend addition of aspirin to warfarin but Ray et al. in their survey of cardiac surgeons' opinion in North America and Canada showed that cardiac surgeons very much under-prescribe additional aspirin for fear of the increased risk of bleeding despite these guidelines.
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7. Clinical bottom line
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Low dose aspirin (80–100 mg daily) in addition to warfarin in patients with prosthetic heart valves reduces all cause mortality (NNT=19), with significant reductions in thromboembolism despite an increase in bleeding.
doi:10.1016/j.icvts.2004.03.006
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References
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- Dunning J, Prendergast B, Mackway-Jones K. Towards evidence-based medicine in cardiothoracic surgery: best BETS. Interact Cardiovasc Thorac Surg. 2003;2:405–409[Abstract/Free Full Text]
- Patrono C, Bachmann F, Baignent C, Bode C, De Caterina R, Charbonnier B, Fitzgerald D, Hirsh J, Husted S. Expert consensus document on the use of anti-platelet Agents. The task force on the use of antiplatelet agents in patients with atherosclerotic cardiovascular disease of the European Society of Cardiology. Eur Heart J. 2004;25:166–181[Free Full Text]
- Little SH, Massel D. Antiplatelet and anticoagulation for patients with prosthetic heart valves. Cochrane Libr. 2003;1:
- Massel D, Little SH. Risks and benefits of adding anti-platelet therapy to warfarin among patients with prosthetic heart valves: a meta-analysis [see comment]. J Am Coll Cardiol. 2001;37:569–578[Abstract/Free Full Text]
- Laffort P, Roudaut R, Roques X, Lafitte S, Deville C, Bonnet J, Baudet E. Early and long-term (one-year) effects of the association of aspirin and oral anticoagulant on thrombi and morbidity after replacement of the mitral valve with the St. Jude medical prosthesis: a clinical and transesophageal echocardiographic study. J Am Coll Cardiol. 2000;35:739–746[Abstract/Free Full Text]
- Scottish Intercollegiate Guidelines Network. SIGN publication No. 36. Edinburgh: SIGN secretariat, Royal College of Physicians; 1999.
- Bonow RO, Caraballo B, deLeon ACJ. 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 (Committee on Management of Patients with Valvular Heart Disease). Circulation. 1998;98:1949–1984[Free Full Text]
- Walker ID, Machin S, Baglin TP, Barrowcliffe TW, Colvin BT, Greaves M, Ludlam CA, Mackie IJ, Preston FE, Rose PE. Guidelines on oral anticoagulation: third edition. Br J Haematol. 1998;101:374–387[CrossRef][Medline]
- Ray JG, Turpie AG. Survey of cardiac surgeons' perceptions of the addition of ASA to warfarin for patients with mechanical heart valves. Can J Cardiol. 1997;13:1162–1165[Medline]
- Meschengieser SS, Fondevila CG, Frontroth J, Santarelli MT, Lazzari MA. Low-intensity oral anticoagulation plus low-dose aspirin versus high-intensity oral anticoagulation alone: a randomized trial in patients with mechanical prosthetic heart valves. J Thorac Cardiovasc Surg. 1997;113:910–916[Abstract/Free Full Text]
- Cannegieter SC, Rosendaal FR, Briet E. thromboembolic and bleeding complications in patients with mechanical heart valve prosthesis. Circulation. 1994;89:635–641[Abstract/Free Full Text]
- Loewen P, Sunderji R, Gin K. The efficacy and safety of combination warfarin and ASA therapy: a systematic review of the literature and update of guidelines [Review] [43 refs]. Can J Cardiol. 1998;14:717–726[Medline]
- Fiore L, Brophy M, Deykin K, Scherer R, Lefebvre C. The efficacy and safety of the addition of aspirin in patients with oral anticoagulants after heart valve replacement. Blood. 1993;82(Suppl):
- Cappelleri JC, Fiore LD, Brophy MT, Deykin D, Lau J. Efficacy and safety of combined anticoagulant and antiplatelet therapy versus anticoagulant monotherapy after mechanical heart-valve replacement: a metaanalysis. Am Heart J. 1995;130:547–552[CrossRef][Medline]
- Pouleur H, Buyse M. Effects of dipyridamole in combination with anticoagulant therapy on survival and thromboembolic events in patients with prosthetic heart valves. A meta-analysis of the randomized trials. J Thorac Cardiovasc Surg. 1995;110:463–472[Abstract/Free Full Text]
- Turpie AG, Gent M, Laupacis A, Latour Y, Gunstensen J, Basile F, Klimek M, Hirsh J. A comparison of aspirin with placebo in patients treated with warfarin after heart-valve replacement [see comment]. N Engl J Med. 1993;329:524–529[Abstract/Free Full Text]
- Stein PD, Alpert JS, Copeland J, Dalen JE, Goldman S, Turpie AG. Antithrombotic therapy in patients with mechanical and biological prosthetic heart valves. Chest. 1995;108:371S–378S[Medline]
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Abstract
1. Introduction