Authors' response: From monitoring to vigilance about patient adherence to new oral anticoagulants

We would like to thank Mr Vrijens and Dr Urquhart for their interest in the new oral anticoagulant (NOAC) Practical Guide, although they may have judged it by a false pars pro toto stating that ‘ambivalence envelops the Practical Guide’.¹ We are confident that our document has created more concrete help than confusion for physicians working with NOAC patients. However, we are happy with the authors' focus on the issue of medication adherence, which is of primordial importance in the NOAC arena. We have already devoted a whole section in the Guide to the issue of adherence (or compliance), and fully agree with the authors that non-adherence is a major threat to the effectiveness of these drugs in daily practice.² Moreover, we have stressed repeatedly the importance of patient education, and re-education during follow-up (see e.g. the NOAC anticoagulation cards). Some specific suggestions by the authors (like calendered blisters, pharmacy involvement, and the use of electronic adherence recording devices) were already mentioned in our text. We have to remind the readership that the authors of the letter have a conflict of interest here, both being employees of a company that is active in the market of drug packaging and electronic adherence recording. Moreover, we have to wait for validation of whatever approach. In the absence of any available validated data, we had to restrict ourselves to a summary of the potential approaches to optimize adherence. Definitely, we ask for ‘vigilance’ among prescribers to tailor adherence approaches to their individual patients. Moreover, this required vigilance goes far beyond monitoring adherence, as we have highlighted important issues related to plasma levels and pharmacodynamic interactions in the Guide too. Inappropriate use of the correct drug, or with an inappropriate dose, carries a potential for harm. We agree that reliance on patient information like (last) drug intake is weak: in the section on cardioversion, for instance, we stated that if any incorrect information is suspected, it may be safer to proceed with a transoesophageal echocardiography, rather than rely naively only on patient information. Physicians, be vigilant, indeed!

Only on-going randomized trials on adherence measures and large registries will be able to tell how well the results of controlled clinical trials are translated to the real world. In modern clinical NOAC trials, adherence was still measured in the old-fashioned way of pill counting, but we agree that the uncertainty of when a new drug package was delivered to the patient and opened for the first time, severely limits its usefulness in daily practice. We take that suggestion at heart and will ponder on how far the proposed NOAC card could be modified to also keep track of this information, to be filled out by pharmacists and patients.

We do object to the assertion of the authors that we stated in the Guide that once-daily NOAC dosing is preferable to twice-daily dosing. Exactly for the reasons spelled out by Vrijens and Urquhart, we suggested that ‘it is unknown whether any regimen is superior in guaranteeing the clinical thromboembolic preventive effects and the safety profile as seen in the clinical trials’. Also, in this respect, more data are required. Again, registries will have to tell us to what extent the Phase 3 study results can be replicated in the overall population for different drugs and dosing schemes.

The NOACs marketed come in calendered blister packages or calendered boxes (containing the blisters), although the former do not all spell out the days of the week and the latter are not rated to be very practical by patients. Calendered pill boxes (also containing other medication) unfortunately cannot be used for dabigatran, which needs to be preserved in its original packaging. Electronic means certainly have high potential value concerning traceability and information sharing, and we look forward to studies on their use in the NOAC field. However, patients may also develop some wariness concerning such electronic surveillance. Again, we will need proof that the benefits outweigh the disadvantages in the field, and that such measures really translate into a clinically meaningful effect. Therefore, we all have to work on making patients adherent to their treatment to guarantee the intended safety and effectiveness. We certainly feel as partners of Vrijens and Urquhart on this issue.

Conflict of interest: none declared.

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