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Birmingham, UK
Dr. Lane is Lecturer in Medicine, Dr. Boos is Research Fellow. Dr. Lip is Professor of Cardiovascular Medicine, University Department of Medicine, City Hospital.
Correspondence to: Gregory Y. H. Lip, Haemostasis, Thrombosis, and Vascular Biology Unit, University Department of Medicine, City Hospital, Birmingham B18 7QH, UK; e-mail: g.y.h.lip{at}bham.ac.uk
Over half a century since their initial inception, vitamin K antagonists (VKAs), in particular warfarin, still represent the cornerstone of oral anticoagulation (OAC) therapy worldwide. Despite their proven antithrombotic efficacy across a broad spectrum of patient groups, VKAs are beset by numerous inherent problems. The complex pharmacokinetic profile of VKAs means that they have a narrow therapeutic range requiring regular monitoring, a slow onset/offset of action, and are subject to multiple interactions with food, alcohol, and medications.1 Further, they also exhibit potential ethnic, genetic, and age-related variations in their dose response.
It is well established that anticoagulant control with the careful maintenance of the international normalized ratio (INR) within the therapeutic range results in reductions in all-cause mortality, stroke, and thromboembolic events.2 While numerous analyses of the efficacy of VKAs in relation to outcomes have been reported, a clear overview of the various studies investigating the proportion of time spent in the therapeutic INR range and the factors that may influence INR control is needed.
In this issue of CHEST (see page 1155), van Walraven et al3 provide a systematic review and metaregression analysis of INR control in > 50,000 patients from 67 studies who were receiving OAC for various indications (mainly atrial fibrillation [AF], venous thromboembolism, and valvular heart disease) during the last 20 years, and demonstrates that the study setting, type of OAC, and method of INR monitoring significantly affected the mean percentage of time patients spent in the therapeutic INR range. Significantly better INR control was achieved in randomized controlled trials and anticoagulation clinics (absolute percentage of time in therapeutic range, 12.2% and 8.3% higher, respectively) when compared to community practices and among patients who self-monitored their INR (7.0%; 95% confidence interval [CI], 0.7 to 13.3%).3 Although patients receiving warfarin achieved significantly poorer INR control (60.6%) than patients receiving acenocoumarol (68.1%), this difference was not significant in the metaregression model. This analysis also revealed that INR control was worst in patients who received warfarin and were managed in the community, without self-monitoring: these patients achieved only one half of their time within the therapeutic INR range.3
Unfortunately, the majority of patients receiving long-term OAC therapy are characterized by those factors associated with the poorest INR control. Equally concerning is the finding that among all patients receiving OAC, more than one third of the time is spent outside the therapeutic range,3 especially since a 10% increase in the time out of the therapeutic range has been associated with an increased risk of death, ischemic stroke, or other thromboembolic events.4 It is also particularly disappointing to discover that anticoagulation control has only improved marginally over the last 20 years (from 1987 to 1997, 62.2%; vs from 1998 to 2005, 65.0%; p = 0.08).3
What can we do to improve compliance with VKAs? The inconvenience of regular INR checks for VKA treatment at a hospital outpatient clinic or general practice is an inherent problem that significantly effects compliance. The benefits of anticoagulation clinics and self-management of INR15 over traditional community- or clinic-based testing, as illustrated by van Walraven et al,3 are further supported by a recent systematic review and meta-analysis6 of self-monitoring of OAC. Significant reductions in thromboembolic events (odds ratio, 0.45; 95% CI, 0.30 to 0.68), all-cause mortality (odds ratio, 0.61; 95% CI, 0.38 to 0.98), and major hemorrhage (odds ratio, 0.65; 95% CI, 0.42 to 0.99) were demonstrated. Further, trials combining self-monitoring and self-adjusted therapy also demonstrated significant reductions in thromboembolic events (odds ratio, 0.27; 95% CI, 0.12 to 0.59) and death (odds ratio, 0.37; 95% CI, 0.16 to 0.85), but not major hemorrhage (odds ratio, 0.93; 95% CI, 0.42 to 2.05). Improvements in the mean proportion of INRs in range were reported in 11 of the 14 trials, which were significant in 6 trials.6 Thus, the option of self-monitoring of the INR and dose adjustment for selected patients may be a viable alternative to outpatient or general practice checks. Improving education and knowledge about the risks and benefits of OAC therapy have also been shown to improve the safety and efficacy of such treatment.78
Maintaining therapeutic anticoagulation is not the only hurdle to achieving effective anticoagulation. Given that less than one half the patients with nonvalvular AF requiring long-term OAC for stroke thromboprophylaxis are actually prescribed it, due to a combination of institutional-, patient-, and physician-related factors,9 one obvious potential solution lies in the increased the availability of newer, safer, and more effective anticoagulants.
Unfortunately, while an appetizing concept, the potential "front runners" in the race to replace warfarin, such as the as oral direct thrombin inhibitors (DTIs), still have some way to go in their clinical development before they can be fully advocated.1 Indeed, the DTI ximelagatran has so far failed in its bid for approval by the US Federal Cardiovascular and Renal Drugs Advisory Committee for use in any of its intended anticoagulation indications,10 and has just been fully withdrawn from further development owing to liver safety concerns. The recent results of the Atrial Fibrillation Clopidogrel Trial With Irbesartan for the Prevention of Vascular Events (warfarin arm) study11 suggest the superiority of warfarin over aspirin-clopidogrel antiplatelet combination, for the prevention of stroke among patients with nonvalvular AF. Other new oral agents—such as new DTIs and oral Factor Xa inhibitors—are in development, but we still have to wait patiently, pending clinical trial data.
Thus, the VKAs will continue to have an extensive role to play in OAC therapy for the foreseeable future. Any efforts at maximizing their potential use, both safely and efficaciously, remains a great priority.
Footnotes
The authors have no financial disclosure on this subject matter.
References
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