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Three Part Question

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]?

Clinical Scenario

You are a registrar, about to discharge a 72-year old patient who has just undergone an aortic valve replacement with a 21mm 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.

Search Strategy

Medline 1966-March 2004 using the OVID interface. 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.
[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]

Search Outcome

A total of 253 papers were found of which 11 represented the best evidence and are included in the table. Of note 7 meta-analyses were found but 5 were out of date or had poor methodology and thus were excluded [1-5]

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Patrono et al 2004 Italy	Taskforce on the use of antiplatelet agents, for the European Society of Cardiology	Systematic Review (level 1a)	Use of Aspirin and warfarin in patients with prosthetic heart valve	Aspirin indicated in combination with warfarin in patients with mechanical valves (grade 2B recommendation)	This systematic review only briefly considered this question and did not perform a full systematic review in this area Note that there is also an ESC working group preparing a guideline on the management of patients following heart valve surgery which is due 2004, chaired by E Butchart.
Little 2003 Canada	N=2,428 patients from 11 studies This is a repeat meta-analysis by Massel et al with one additional paper by Laffort	Meta-analysis (level 1a)	Thrombo-embolic events	Anti-platelet groups 46/1207 (3.8%). Control groups 110/1221 (9%). Odds of 0.39 (CI 0.29 to 0.56) p<0.00001	The quality of trials before 1990 scored poorly in their assessments of methodology, and 7 trials were published prior to unification of anticoagulation testing using the INR.
			Risk of Death	Anti-platelet groups 63/1207 (5.2%). Control groups 110/1221 (9%) Odds of 0.55 (CI 0.40 to 0.77) p<0.003
			Risk of major bleeding	Anti-platelet groups 92/1071 (8.5%). Control groups 59/1091 (5.4%). Odds of 1.66 (CI 1.18 to 2.34) p=0.003
Massel 2001 Canada	10 studies involving 2,199 patients comparing additional anti-platelet therapy with oral anticoagulation in patients with prosthetic valves. Six studies used dipyridamole in doses of 225-400 mg daily Four studies used aspirin in doses of 500 mg once daily, 500mg twice daily and 100 mg once daily in two recent studies.	Meta analysis (level 1a)	Arterial thrombo embolic events	Anti-platelet groups 41/1098 (3.7%). Control groups 98/1101 (8.9%). Odds ratio 0.41 p=<0.001	Analysis not adjusted for study quality. Results not subdivided by valve location Target INR varied greatly among studies from 1.8-2.3 up to 3.0-4.5.
			Mortality	Anti-platelet groups 53/1098 (4.8%). Control groups 105/1101 (9.5%). Odds rato 0.49 p=<0.001
			Major bleeding	Anti-platelet groups 571/962 (7.4%). Control groups 49/971 (5.0%). Odds ratio 1.5 p=0.033
Laffort et al 2000 France	N=229 pts with mechanical mitral valve 109pts had Aspirin 200mg and warfarin INR 2.5-3.5. 120pts had warfarin only INR 2.5-3.5 All pts had TOE at 9 days and 5 months	Single blind RCT (level 1b)	Thrombi detected by TOE day 9	Aspirin group 5/109pts (4.8%). Placebo group 15/120pts (13%) p=0.03	Mitral valves only. No placebo given to control arm 200mg of aspirin was chosen in order to comply with doses seen in other branches of vascular pathology and ACCP guidelines of 160mg of aspirin TIA and non-obstructive valve thrombi were considered as minor embolic events, in contrast to most other studies
			Incidence of total thrombo-embolism	Aspirin group 10/109pts (9.1%). (1 major event) Placebo group 30/120pts (25%) (5 major events) p=0.001
			Incidence of major bleeding	Aspirin group 21/109pts (19%). Placebo group 10/120pts (8.3%) p=ns
SIGN 1999 Scotland	Scottish Intercollegiate Guidelines Network	Systematic review (level 1a)	Addition of Aspirin	Aspirin or dipyridamole should be considered in patients who suffer systemic embolism despite adequate intensity warfarin (grade A recommendation based on Level Ib Evidence	Quoted Turpie stating that aspirin 100mg/d reduced vascular mortality but increased bleeding in this study
			INR	Range 3.0-4.5 traditionally recommended (Grade C) More recent studies support target INR to range 2.5-3.5 for second generation valves (grade B)
Bonow et al 1998 USA	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	Systematic Review (level 1a)	Guidelines on addition of Aspirin	Addition of aspirin (80 to 100 mg/d) to warfarin should be strongly considered unless there is a contraindication to the use of aspirin (level of evidence 2a)
			Recommended INR	INR 2.0-3.0 for aortic bileaflet valves or Medtronic Hall. INR 2.5-3.5 for other disk valves, mitral valves, starr-edwards valves, or all valves with other risk factors
Walker et al 1998 UK	Guidelines for British committee for standards in haematology. Papers identified from Medline from 1965 to 1996	Systematic review (level 1a)	Addition of Aspirin	Use of aspirin and low INR anticoagulation acknowledged but no recommendations given.	No specific recommendation for or against Aspirin in addition to warfarin given
			INR	Target INR of 3.5 recommended (Grade B based on level IIa evidence ). There is a sharp rise in embolism rates with an INR<2.5 and haemorrhagic rates with INR>5.0, and actual target INRs are lower than target 31% of time
Ray 1997 Canada	N= 118 north American cardiothoracic centres to assess if they routinely prescribe low dose ASA with oral anticoagulation in patients with prosthetic heart valves.	Survey (level 3b)	Additional ASA therapy	21% routinely use it, 76% would not use it 49% of these would not use it due to bleeding risk 23% would not use it due to lack of proven benefit	86% response rate
			INR range used	INR 2-3 – 28%. INR 2.5-3.5 – 54%. INR 3-4.5 – 8%
Meschengieser et al 1997 Argentina	N=503 pts with mechanical valves median follow up 23 months 258pts received Aspirin 100mg and warfarin INR 2.5-3.5 245 patients received high intensity anticoagulation, Warfarin INR 3.5-4.5	Unblinded RCT (level 1b)	Thrombo-embolic episodes	Aspirin group 7/258 (1.32% per yr). Warfarin only group 7/245 (1.48% per yr) p=0.70	Patients with valves in any position included in this study.
			Thrombo-embolism or major haemorrhage (failure-free survival)	Aspirin group 13/258 (2.45% per yr) Warfarin only group 18/245 (3.82% per yr) p=0.16
			Major bleeding	Aspirin group 6/258 (1.13% per yr). Warfarin only group 11/245 (2.33% per yr) p=0.11
			Minor bleeding	Aspirin group 35/258 (14%). Warfarin only group 41/245 (17%)
Turpie et al 1993 Canada	N=370 pts with mechanical valve or tissue valve and AF followed for mean 2.5 yrs at 3 hospitals. 186pts received 100mg Aspirin and warfarin INR 3.0-4.5 184pts received placebo and warfarin INR 3.0-4.5	Double Blind PRCT (level 1b)	Major Systemic Embolism or death from vascular causes	Aspirin group 6/186pts (3.2%). Placebo group 24/184pts (13%) p<0.001	Study was in patients with aortic, mitral, tricuspid or a combination of valve replacements.
			All cause death	Aspirin group 9/186pts (4.8%). Placebo group 22/184pts (12%) p=0.01
			Major bleeding	Aspirin group 24/186pts (13%). Placebo group 19/184pts (10%) p=0.43
			Any bleeding event (inc. haematuria, epistaxis, bruising)	Aspirin group 71/186pts (39%). Placebo group 49/184pts (27%) p=0.02
ACCP guidelines 1995 USA	4th American College of Chest Physicians consensus conference on antithrombotic therapy for prosthetic heart valves.	Systematic Review (level 1a)	Antiplatelet therapy	Aspirin in addition to oral anticoagulants offers additional protection, but with an increased risk of bleeding. Low doses (100mg/d) reduced mortality from vascular causes (level I evidence)	Search Strategies and methodology not stated The anti-platelet recommendations were mainly based on the paper by Turpie [16] who was also a co-author on this committee
			INR	INR of 2.5-3.0 recommended for bileaflet valves or tilting disk valves (grade C recommendation based on grade III – IV evidence)

Comment(s)

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 225-400mg once daily. Four trials used aspirin in doses of 500 mg once daily, 500 mg twice daily and in 3 recent trials, 100-200 mg once daily. The best meta-analyses were published by Massel et al. They found that aspirin reduced the odds 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 3 investigate low doses of aspirin. Laffort performed a single blind RCT in 229 patients comparing aspirin 200mg 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 in the NEJM performed a double blind PRCT in 370 patients using aspirin 100mg 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 performed a PRCT in 503 patients. They studied aspirin (100mg) 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 Association recommends that Aspirin 80-100mg 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

Clinical Bottom Line

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.

References

1. 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(2):166-181.
2. Little SH, Massel D. Antiplatelet and anticoagulation for patients with prosthetic heart valves. (Cochrane Review). In: The Cochrane Library, . Issue 2, 2004. Chichester, UK: John Wiley & Sons, Ltd
3. 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(2):569-578.
4. 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. J Am. Coll. Cardiol. 2000;35(3):739-746.
5. Scottish Intercollegiate Guidelines Network Antithrombotic Therapy SIGN publication No. 36. SIGN secretariat, Royal College of Physicians 1999
6. Bonow RO, Caraballo B, deLeon ACJ. Guidelines for the management of patients with valvular heart disease: executive summary. Circulation 1998;98(8):1949-1984.
7. 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. British Journal of Haematology 1998;101(2):374-387.
8. 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(12):1162-1165.
9. 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(5):910-916.
10. Cannegieter SC, Rosendaal FR, Briet E. Thromboembolic and bleeding complications in patients with mechanical heart valve prosthesis. Circulation 1994;89(2):635-641.
11. 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]. Can. J Cardiol. 1998;14(5):717-726.
12. Fiore L, Brophy M, Deykin K, Scherer R, Lefebvre C. The efficacy and safety of the addition of aspirin. The patients with oral anticoagulants after heart valve replacement. Blood 1993;82(Suppl).
13. 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(3 pt 2):547-552.
14. 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(2):463-472.
15. 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(8):524-529.
16. Stein PD, Alpert JS, Copeland J, Dalen JE, Goldman S, Turpie AG. AG Antithrombotic therapy in patients with mechanical and biological prosthetic heart valves. Chest 1995;108(4 suppl):371S-378S.