Oral anticoagulants: the dawning of a brighter era

Professor Sabine Eichinger of the Medical University of Vienna, led the presentations with a discussion on the clinical considerations that determined which anticoagulant a particular patient received. She reviewed the coagulation cascade and the mechanisms of action of the indirect parenteral anticoagulants fondaparinux (which acts on Factor X), heparin and danaparoid (which act on Factor II), the direct parenteral anticoagulants bivalirudin and argatroban (which act on Factor II), the indirect oral anticoagulants, also known as vitamin K antagonists (VKAs) such as warfarin, which act at Factors II, VII, IX and X and the new class of direct oral anticoagulants (DOACs). Whereas the DOACs rivaroxaban, apixaban and edoxaban directly inhibited activated Factor X, dabigatran exerted its inhibitory effect on activated Factor II (thrombin).

Professor Eichinger reminded the audience that the requirement for the direct oral anticoagulants arose largely from the disadvantages associated with the vitamin K antagonists, such as slow onset and offset of action requiring heparin bridging, coumarin necrosis and the need for monitoring due to unpredictable dose response, narrow therapeutic window and food and drug interactions. Unlike with vitamin K antagonists, no monitoring of anticoagulant effect is required with the DOACs. Like vitamin K antagonists, however, direct oral anticoagulants were also subject to interactions with foods and drugs that inhibit or induce the enzymes CYP3A4 and p-glycoprotein.

Professor Eichinger outlined the pharmacokinetics of the direct oral anticoagulants, intimating that their administration could be once-daily (rivaroxaban, edoxaban) or twice-daily (apixaban, dabigatran), due to their relatively short half-life (5 to 17 hours). The attainment of maximum concentration (Cmax) within one to four hours meant that there was a rapid onset of anticoagulant effect, so there was no need for heparin bridging, as is the practice with vitamin K antagonists. Bioavailability ranged from 3% (with dabigatran) to more than 80% with food, in the case of rivaroxaban. Although monitoring of anticoagulant effect was not necessary with DOACs, the monitoring of renal function is crucial, as excretion via this route accounts for a range of 27% (with apixaban) to 80% (with dabigatran). Patient doses should therefore be modified to take account of creatinine clearance.

All four direct oral anticoagulants are licensed for anticoagulation in hip/knee replacement surgery. Apixaban, dabigatran and rivaroxaban, are licensed for atrial fibrillation, and rivaroxaban is licensed for venous thromboembolism and acute coronary syndrome. Professor Eichinger outlined the main advantages of DOACs as their target specificity, rapid onset and offset of action (no need for injections), predictable (fixed) dose response and equivalent efficacy to vitamin K antagonists. She allayed fears about the bleeding risks associated with direct oral anticoagulants by quoting phase III studies that demonstrated that direct oral anticoagulants are as effective and as safe as warfarin. These studies also showed the median time in therapeutic range (TTR) for direct oral anticoagulants to be between 58% and 68% compared with the vitamin K antagonist warfarin with a TTR >80% in international normalised ratio (INR) target range.

Professor Eichinger stated that the potential disadvantages of direct oral anticoagulants include the need for renal function considerations, the lack of an antidote, higher costs than warfarin and the lack of data on correlation between coagulation test results and clinical outcomes. Perhaps the greatest potential disadvantage, she indicated, is the lack of therapeutic monitoring with direct oral anticoagulants, as it meant that there was no method of assessing adherence, unlike for vitamin K antagonists where regular blood tests monitor the INR, and provide a contact opportunity for counselling and discussions with healthcare professionals, to support ongoing patient compliance.

The matter of adherence was the focus of the second presentation, by Duncan McRobbie (Guy’s and St Thomas’ NHS Foundation Trust, London). He stated that medicines would not be effective if the patients did not take them, and that poor adherence led to significant negative clinical outcomes for patients, and created significant economic burdens for the health service. He explained that, generally, it was difficult to measure or ensure adherence. Mr McRobbie gave an overview of the problem of non-adherence, stating that non-adherence to new medication for chronic conditions were apparent as early as ten days post-initiation, even in life-threatening conditions such as prophylaxis following a non-fatal myocardial infarction.

To tackle non-adherence, he encouraged delegates at the conference to explore the various causes of non-adherence, which he broadly classified as intentional and unintentional non-adherence. Intentional non-adherence is the patient’s deliberate refusal to take the medicines for whatever reason, while unintentional non-adherence could be the result of a host of factors such as cost, forgetfulness, inability to open the medicine container or read the label. He suggested that pharmacists could play a pivotal role in ensuring adherence by employing tools, such as compliance aids, targeted labelling and reminder charts, to resolve unintentional non-adherence and by providing adequate information to address belief systems to help resolve intentional non-adherence.

He stated that belief systems were largely influenced by culture, the media, social support, significant others, social norms, health policy and available information. He explained that there was a positive correlation between patients’ satisfaction with information about medicines (Satisfaction with Information about Medicines [SIM] scale) and adherence; meaning that the more patients were satisfied with the information about their medicines, the more they were likely to be adherent.

To improve satisfaction with information about medicines, he suggested empowering patients to ask questions, targeting information provision and signposting to main sources of information. He reported on the results of a ‘Questions about medicines’ study at Guy’s and St Thomas’ hospital where, of the three main healthcare professional groups, patients reported the greatest satisfaction with information about medicines from the pharmacists (78%), with nurses second (69%) and doctors third (62%). He also reported on a multi-centre study on satisfaction with information on anticoagulants, which showed a better SIM for the widely used vitamin K antagonist warfarin, than for the direct oral anticoagulants. However, if clinicians followed the recommendations of clinical guideline 76 from the United Kingdom’s National Institute for Health and Care Excellence on “Best practice advice on how to involve patients in decisions about prescribed medicines and how to support adherence,” and took additional steps such as improving communication, involving the patient in decision-making, providing appropriate information, taking the time to understand patients’ knowledge concerns and beliefs about the new direct oral anticoagulants, then the significant benefits of direct oral anticoagulants would be realised. He suggested that the initiation of direct oral anticoagulants should follow a structured approach, with follow-up appointments at regular intervals, as outlined in the European Heart Rhythm Association’s “Practical guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation.”

Mr McRobbie concluded that

The introduction of novel oral anticoagulants into clinical practice challenge well established concepts of anticoagulation, such as the low molecular weight heparins and vitamin K antagonists. The results of landmark clinical trials and ongoing research will undoubtedly lead to changes in the use of vitamin K antagonists and likely influence the pharmacotherapy of relevant cardiovascular diseases.

Hospital pharmacists play a key role in assessing and selecting drugs for in-hospital use and patient education, and therefore need to acquire an in-depth knowledge of these novel anticoagulants, and be competent to comment on their safety.