Monitoring new oral anticoagulants, managing thrombosis, or both?

Editorial on Douxfils et al. Thromb Haemost 2012; 107: 985-997. Administration of oral anticoagulants is the cornerstone in the prevention of (chronic) morbidity and mortality due to arterial thromboembolic stroke (1) and, on the venous side, of pulmonary embolism and recurrent thrombosis (2). The largest population at risk of arterial thromboembolism is the elderly suffering from atrial fibrillation (AF). Advanced age contributes to a rise in the prevalence of AF, while more accurate diagnostic classification prompts earlier anticoagulant treatment in the vast majority of elderly subjects with AF (3). Long term anticoagulation in AF (and venous thromboembolism [VTE] as well) aims at reducing a life time risk of stroke (or recurrent VTE), and monitoring its effect would theoretically make sense in comparison with other chronic diseases or risk conditions like diabetes, hypertension and hypercholesterolaemia, where blood glucose, gycosylated haemoglobin (HbA1c), blood pressure and lipids are monitored and therapy is adjusted accordingly. While current oral anticoagulation with vitamin K antagonists (VKA) is being monitored by laboratory testing and dose adjustment, with the introduction of new oral anticoagulant agents (4) (NOACs) it appears that most physicians are willing or even eager to proceed with unmonitored therapy. Since the introduction of the VKAs in the 1950s, monitoring the anticoagulant effect by prothrombin time, later expressed as international normalised ratio (INR), in order to adjust the VKA dose, has been routine practice. Through clinical trials, the therapeutic range for VKA was set at 2–3 for most indications, including AF (1, 2). Since fixed, low-dose therapy with warfarin does not offer sufficient protection, dose adjustment of VKA to the desired INR level is required. This is important, since many factors interfere with VKA uptake and metabolism by the liver, including food, medication, and comorbidity (5). Particularly in elderly subjects, many of these factors can be present concurrently. The time within the therapeutic range (TTR) is a good overall measure of the quality of antithrombotic treatment with VKA (6). However, it shows a wide variation by country. In an analysis by country of the RELY study data, excluding the first week of treatment, the average TTR varies from a very low level of 44% in Taiwan to a highest level of 77% in Sweden (7). Even at a good level of anticoagulant control of ∼75% (as in the Netherlands) this means that in around 25% of the time INR values are either too low (at risk of thrombosis), or too high (at risk of bleeding). In order to achieve proper laboratory control patients need blood drawing ∼20 times/year and, obviously, this poses a burden on their daily life. The quality of life, as well as the TTR, can be positively influenced with methods that provide (supported) self-management of VKA treatment, being increasingly popular among patients on long-term anticoagulant treatment (8, 9). However, even selfmanagement requires a reliable support system, which may not be feasible throughout the world. In spite of all these practical limitations of VKA treatment, one of the main advantages is that at least the occurrence of potentially harmful situations (outside the “TTR”) are detected at some point in time, allowing dose adjustment, as well as actions taken to prevent recurrence of this situation. In the patient on VKA a number of measures can be taken to improve the TTR, including reminding the general practitioner to see the patient in order to deal with problems that may hamper adequate medication intake (poor cognitive function, lack of social network, treatment of comorbid conditions etc) so that appropriate action can be taken when needed. This may also include nurse-supervised medication intake (usually more than just the anticoagulants), involving family or neighbours in helping out etc. Such scenarios are frequently encountered in the daily practice of anticoagulation clinics, mainly because the majority patients on anticoagulants are elder and often frail, requiring blood drawing at home in 40% of cases, due to comorbidity (10). The marked innovation in oral anticoagulant agents heralds a striking paradox in the management of patients with (risk of) thrombosis. While NOACs have been developed under the assumption that monitoring and dose adjustment would be abolished (illustrated by provocative paper headlines like “Funeral of the Anticoagulation Clinic”), the implication may be that patients are left with a prescription and a single advice, but without any kind of formalised support (including laboratory control). I consider this development potentially harmful to the patient, requiring critical consideration of causes and consequences. Pharmaceutical companies have invested heavily in the development of novel, targeted synthetic drugs that directly interfere with a specific coagulation protease, blocking its clotting activity. After many years of struggle (including the failure of ximelagatran to reach the market due to liver function problems), several NOACs have now successfully reached the clinical arena. Competition among several large companies is strong and rapid penetration of the most important segments of the market (including the AF population) is economically important.