Clinical Update Thirty-Six: Anticoagulant Drugs

The Ignored Benefits of Anticoagulant Drugs

In an aging population, anticoagulant drugs provide benefits that are often ignored in favor of repeated valve operations.


Benefits of Warfarin

Current heart valve selection criteria is heavily weighted toward tissue valve implants even when an increasing number of randomized or matched clinical studies show the risks of reoperation and/or mortality are significantly worse with these devices (Table 1).1-5 The words ”rat poison” have undermined the protection that heart valve and arrhythmic patients have derived from the most widely used oral anticoagulant, warfarin, for 60 years.

Fewer Strokes and MI’s in Older Patients

Despite being the most widely prescribed anticoagulant drug and the eleventh most prescribed drug in general in the US, warfarin is reported as being underutilized for stroke prevention.6 The benefits of warfarin therapy after myocardial infarction (MI) have been demonstrated in the WARIS trials.7,8 Patients taking warfarin after an MI experienced a 24% reduction in mortality, a 34% reduction in reinfarction and a 55% reduction in total cerebral vascular accidents in the “intention to treat” group (Table 2). Warfarin caused less complications than aspirin alone in these trials but the two drugs combined produced the best result.

With an ever increasing number of people over 60 and an increasing number of those with atrial fibrillation, oral anticoagulation therapy has become a focus of clinicians. Warfarin trials with these aging arrhythmic patients show clinical benefit overall but the greatest benefit appeared in patients older than 85 and in those who had previous stroke.9 Home monitoring trials have proven effective for keeping patients in therapeutic range and cutting complication rates.10,11 Based on these results, belief that warfarin is especially dangerous in elderly valve patients may perhaps be exaggerated.

Table 1. Does protection with warfarin prevent higher mortality rates in mechanical valve patients?

Study (valve position) (age group) Biological
Patient Survival
Patient Survival
P Value Length of Follow-up
Brown1sup> (aortic) (50-70) 50% 68% p<.01 10 years
Vicchio2 (aortic) (80) adjusted 46.5% 70% p=0.025 8 years
Daneschmand3 (mitral, estimated) (62-72) unadjusted ~25% ~58% p<0.0001 10 years
Daneschmand3 (mitral, estimated) adjusted ~43% ~56% p=0.0017 10 years
Weber4 (aortic) (<60) 89.1% 96.7% p<0.05 10 years

Table 2. Reproduction of table from WARIS trial (Distribution of Events, According to Treatment Group*, *CI denotes confidence interval)

Type of Analysis and Event Warfarin (N=607) Placebo
Risk Reduction
% (95% CI)
P Value
Intention to treat
Death 94 123 24 (4-44) 0.0267
Reinfarction 82 124 34 (19-54) 0.0007
Cerebrovascular accident 20 44 55 (30-77) 0.0015
“On treatment”
Death 60 92 35 (17-57) 0.0050
Reinfarction 70 122 43 (29-61) 0.0001
Cerebrovascular accident 16 41 61 (38-81) 0.0003

Future of Anticoagulation

The future holds hope for new oral anticoagulants for heart valve patients that may be easier to control and have less side effects than warfarin. Dabigatran etexilate (Pradaxa) is an anticoagulant from the class of the direct thrombin inhibitors. The initial trials for its performance in atrial fibrillation that resulted in FDA approval and its performance in deep vein trombosis (DVT) are promising.12,13 Other thrombin inhibitors are bivalirudin, argatroban and orally available heparins. Factor Xa inhibitors such as rivaroxaban (Xarelto), recently approved prevention for DVT in orthopedic surgery, and apixaban have been tested successsfully for atrial fibrillation and venous thromboembolism prevention as well.14-19 With the innovative new drugs on the horizon, it now appears unlikely that mechanical heart valve patients will be maintained with warfarin for more than a few years.

The number of heart valve patients will increase dramatically in the next 30 or 40 years along with the aging population, but the ideal valve has not emerged—one that will last a lifetime and not require anticoagulation therapy. While warfarin has benefited millions of patients during its existence, the presence of new drugs that are easier to control and improved valve designs in mechanical valves may provide the solution to high mortality and reoperative rates seen with tissue valves.

The On-X Prosthetic Heart Valve has been shown to be clinically superior to current mechanical and tissue products in clinical trials.20-27 It is the only mechanical valve currently being studied under an FDA approved protocol to determine if it is safe with a lower warfarin level or with nonwarfarin treatment.

With the advent of new drugs and the clinical advantage offered by the On-X Heart Valve, the future for valve recipients is definitely improving.



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  8. Hurlen M, Smith P, Arnesen H. Effects of warfarin, aspirin and the two combined, on mortality and thromboembolic morbidity after myocardial infarction. Scand Cardiovasc J 2000;34:969-74
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  10. Kortke H, Korfer R. International normalized ration self-management after mechanical heart valve replacement: is an early start advantageous? Ann Thorac Surg 2001;72:44-48
  11. Heneghan C et al. Self-monitoring of oral anticoagulation: A systematic review and meta-analysis. Lancet 2006 Feb 4; 367:404-11
  12. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009:361(12):1139–51
  13. Schulman S, Kearon C, Kakkar AK, et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med 2009;361(24):2342–52
  14. Bauersachs Rupert, The EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Eng J Med 2010;363:2499–2510
  15. Randomized, double-blind study comparing once daily oral rivaroxaban with adjusted-dose oral warfarin for the prevention of stroke in subjects with non-valvular atrial fibrillation. Retrieved 2009-02-11
  16. Lassen MR, Davidson BL, Gallus A, et al. The efficacy and safety of apixaban, an oral, direct factor Xa inhibitor, as thromboprophylaxis in patients following total knee replacement. J Thromb Haemost 2007;5(12):2368–75
  17. Lassen MR, Gallus A, Raskob GE, et al, ADVANCE-3 Investigators. Apixaban versus enoxaparin for thromboprophylaxis after hip replace-ment. N Eng J Med 2010;363(26):2487–98
  18. Connolly, SJ, Eikelboom J, Joyner C, et al. Apixaban in Patients with Atrial Fibrillation. N Eng J Med 2011;364(9):
  19. Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation (ARISTOTLE). NCT00412984. Retrieved 2011-06-23
  20. Clinical Comparison of FDA Approval Studies for Heart Valves with Implications for Cost of Complications. On-X Life Technologies, Inc., © 2010, Austin, Texas USA
  21. On-X® Prosthetic Heart Valve. Summary of Safety and Effectiveness Data submitted to the United States Food and Drug Administration. PMA P000037. Approval date May 30, 2001 and October 11,2002
  22. SJM Regent® Valve. Clinical Study Summary (package insert)
  23. CarboMedics® Prosthetic Heart Valve. Summary of Safety and Effectiveness Data submitted to the United States Food and Drug Administration. PMA P900060. Approval date April 13, 1993
  24. ATS Open Pivot® Bileaflet Heart Valve. Summary of Safety and Effectiveness Data submitted to the United States Food and Drug Administration. PMA P990046. Approval date October 13, 2000
  25. Edwards Life Sciences Carpentier-Edwards Perimount Magna Pericardial Bioprosthesis. Instructions for Use. Copyright 2003
  26. Mitroflow Aortic Pericardial Heart Valve. Summary of Safety and Effectiveness Data submitted to the United States Food and Drug Administration. PMA P060038. Approval date October 23, 2007
  27. ATS 3f® Aortic Bioprosthesis, Model 1000. Instructions for Use

On-X aortic and mitral valves are FDA approved.
CAUTION: Federal law restricts this device to sale by or on the order of a physician. Refer to the Instructions for Use that accompany each valve for indications, contraindications, warnings, precautions and possible complications. For further information, visit


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