European Heart Journal Advance Access originally published online on September 22, 2007
European Heart Journal 2007 28(20):2424-2426; doi:10.1093/eurheartj/ehm405
Improving the quality of anticoagulant therapy in patients with mechanical heart valves: what are we waiting for?
1 Department of Cardiac Surgery, K.U. Leuven, B-3000 Leuven, Belgium
2 Center for Molecular and Vascular Biology, K.U. Leuven, B-3000 Leuven, Belgium
* Corresponding author. Tel: +32 16 344260; fax: +32 16 344616. E-mail address: paul.herijgers{at}med.kuleuven.be
This editorial refers to ‘Low-dose oral anticoagulation in patients with mechanical heart valve prostheses: final report from the early self-management anticoagulation trial II’ by H. Koertke et al., on page 2479
Footnotes
The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.
The replacement of destroyed heart valves by mechanical, thrombogenic prostheses would be hard to imagine without the availability of anticoagulant treatment. Coumarins were introduced in clinical practice during and shortly after the Second World War, in the same era that heart valve replacement surgery was pioneered. Still today, vitamin K antagonists are the only available oral anticoagulants for chronic use in patients with mechanical heart valves. Has no progress been made in this field over the past 50 years?
Mechanical heart valves and anticoagulation
Thromboembolic complications and bleedings comprise up to 75% of all complications after mechanical heart valve surgery and predominantly occur in the first year after surgery. For obvious reasons, well-controlled data on the incidence of thromboembolism in the absence of anticoagulation are scarce. The incidence of major thromboembolism in patients with aortic heart valves is roughly estimated as between 4 and 12% per year, and is even higher in patients with a mechanical valve in the mitral position. Vitamin K antagonists reduce this incidence to around 1%.1
Based on the lower reported valve thrombosis rates,1,2 both the European Society of Cardiology (ESC)3 and American College of Cardiology/American Heart Association (ACC/AHA)4 guidelines recommend a lower target international normalized ratio (INR) for current bileaflet and the Medtronic Hall monoleaflet prostheses in the aortic position than for other monoleaflet and caged-ball valves. Not only valve design but also valve position and other patient risk factors influence the rate of valve thrombosis and thromboembolic events, and, thus, the required level of anticoagulation.
Less thrombogenic materials and an improved valve and hinge design may further reduce the propensity for thrombus formation and the need for aggressive anticoagulation.5 This might reverse the present trend to increased use of bioprosthetic valves. The step from flow analysis and preclinical in vitro and in vivo testing to widespread clinical use is hampered by the lack of good predictive animal models and always entails a certain risk.
Reduced thrombogenicity of modern bileaflet valves is demonstrated by the low thromboembolic event rate in a recent trial with low-range anticoagulation6 (INR 1.5–2.5) and in a poorly anticoagulated population.7 The event rate fell in the range of the objective performance criteria required by the Food and Drug Administration.2 This has prompted a randomized, controlled, ongoing trial comparing coumadin/aspirin therapy with aspirin/clopidogrel after low-risk aortic valve replacement with the On-X mechanical prosthesis (ClinicalTrials.gov Identifier NCT00291525 [ClinicalTrials.gov] ).
At present, the only orally available anticoagulant drugs are coumarin derivatives. Cattle bleeding to death after ingestion of spoiled sweet clover led to their discovery. The anticoagulant properties of coumarin derivatives were exploited in two different directions: as rodenticides and as therapeutic agents in human medicine. The well-known disadvantages limit their clinical use: a narrow therapeutic window, an unpredictable biological response, and numerous interactions with medications and food impose strict monitoring of the INR. Insufficient anticoagulant effect may result in thrombosis, whereas overdosing is associated with an increased risk of bleeding complications. At best, the incidence of major bleeds with coumarins is between 2 and 4% and should be balanced against the risk of thrombosis. Recent understanding of the importance of cytochrome P450 2C9 (CYP2C9) and vitamin K oxidoreductase complex 1 (VKORC1) polymorphisms in the individual response to coumarins opens a perspective for a dosing algorithm incorporating CYP2C9 and VKORC1 genotyping that could improve initial warfarin dose selection and reduce related complications.8
Self-monitoring and self-management to improve the quality of anticoagulation
The time in therapeutic range (TITR) is an important parameter for the quality of anticoagulation and is inversely correlated with thromboembolic and bleeding complications. A large variability in INR predicted major complications and increased valve-related mortality after mechanical valve replacement. TITR is 
55–60% if anticoagulation is managed by general practitioners, 60–65% in anticoagulation clinics, 70–75% in clinical trials, and up to 80% in (a selected group of) patients that were well trained and well motivated for self-management and self-monitoring with a point-of-care device.9
In the Early Self Controlled Anticoagulation Trial I (ESCAT I) trial, INR self-management resulted in a TITR of 78% compared with 62% when managed by anticoagulation clinics, reduced thromboembolic events, and improved long-term survival.10,11
The ESCAT II trial12 investigated whether INR self-management with an INR target range of 1.8–2.8 in aortic valves and 2.5–3.5 in mitral valves would reduce bleeding without increasing thromboembolic complications when compared with INR self-management with an INR target range of 2.5–4.0. Although an interim analysis13 of the data suggested a reduction of major bleeds, this was not confirmed in this final report (incidence of 1.52 and 1.42%, respectively). The difference in mean INR in both groups was only modest, which may explain the absence of a difference in both bleeding and thromboembolic complications. A learning effect after the publication of the preliminary results may have occurred. In the group with the lower target INR, the INR results out of the target range were more frequently above than below the target range (16 vs. 7%), whereas in the higher target range this was the opposite (2 vs. 23%).
Modest reduction of the INR target range did not significantly affect bleeding complications or thromboembolic complications, suggesting that the overall quality of anticoagulation (TITR) is probably more important than the target range.
ESCAT I and II established the safety and efficacy of self-monitoring and demonstrated that self-monitoring is feasible in a broader population. Trials with INR self-monitoring are criticized because of an inclusion bias by selecting a patient population at lower risk for complications. The ESCAT study population is a group of relatively younger and motivated patients that are instructed to perform INR testing every week in the first year and every two weeks in the second year. In this selected group of patients (it is not known what percentage of patients was eligible for the study but refused to participate), the drop-out rate after the beginning of the study was 20%. Patients unable or unwilling to perform self-management are probably at higher risk for poor quality of anticoagulation and at higher risk for complications. The question is still open as to whether for these patients improved quality of anticoagulation as quantified by TITR can be reached by physician-led anticoagulation management, and whether this translates into the same reduction of thrombo-embolic events and comparably improved survival.
Do we need to study the safety and efficacy of an even lower INR target range? A clinical trial comparing different INR target ranges in the secondary prevention of venous thromboembolism calls for prudence.14 The (low) incidence of major bleeding was not different in patients with an INR target range of 1.5–2 vs. a conventional INR target range of 2–3, whereas the risk of recurrent thrombosis was significantly higher in patients with the low INR target range.
Unresolved issues and call for action
Many other unresolved questions require carefully designed studies. Optimal bridging of anticoagulant therapy in the case of a planned or emergency intervention after valve implantation is still a matter of debate. The addition of antiplatelet therapy is recommended by the ACC/AHA guidelines for all patients with mechanical valves, in contrast to the ESC guidelines that only advocate it in selected patients. The risk/benefit ratio in many patient subpopulations for this is unclear. In the ESCAT II trial, the low thromboembolic event rate with low use of concomitant aspirin does not support the routine use of low-dose aspirin in addition to coumarins in the absence of additional risk factors.
The expanding demand for long-term antithrombotic therapy and the major limitations of the vitamin K antagonists have stimulated the development of new oral antithrombotic agents. The development of direct thrombin inhibitors and factor Xa inhibitors is most advanced.15 Studies in patients with a strong indication for anticoagulant therapy because of high thromboembolic risk without adequate protection, such as patients with a mechanical heart valve, are not scheduled in the early phase of development of new antithrombotics. Inappropriate dosing would lead to unacceptable disasters in this high-risk population. New agents are, however, most welcome to improve the care in these patients.
While awaiting these new antithrombotic drugs and more detailed protocols for specific patient groups and situations, improving the quality of anticoagulation with vitamin K antagonists after mechanical valve replacement is of prime importance for all patients. Increased awareness by physicians, improved training and education, and individualized and adaptive dosing algorithms can contribute to improved anticoagulation quality. The implementation of self-monitoring and self-management can be another important tool for this, as is shown by the ESCAT trials.
Conflict of interest: none declared.
Footnotes
The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.
doi:10.1093/eurheartj/ehm391 
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