Cardiac Safety Research ConsortiumNOAC monitoring, reversal agents, and post-approval safety and effectiveness evaluation: A cardiac safety research consortium think tank
Section snippets
PK/PD-Guided Dosing of NOACs
The NOACs have reasonably predictable pharmacologic profiles, with well defined relationships between plasma concentrations and anticoagulant effects and generally predictable blood levels based upon administered dose.35, 36, 37, 38, 39, 40, 41, 42, 43, 44 As such, routine monitoring of coagulation tests has not been a requirement for therapy. Moreover, even without such monitoring, the NOACs performed well versus monitored warfarin in their pivotal trials, including reduced fatal and
Current monitoring possibilities and their limitations
For dabigatran, a normal thrombin time (TT) or ecarin clotting time (ECT) essentially exclude clinically relevant drug concentrations and the dilute thrombin time as well as the ECT exhibit strong linearity across dabigatran drug concentrations and could be used for drug quantification.45, 46 However, these tests are not widely available and were not used for dosing or monitoring in the NOAC versus warfarin pivotal trials. The aPTT is somewhat useful for dabigatran as an aPTT <1.3 is associated
Do we need to monitor NOACs to improve benefit-risk, when might we use monitoring, and what monitoring tests might we consider?
An examination of the dabigatran story and its RE-LY trial can help frame these issues. Recall; however, that in RE-LY, patients were randomized to 150 or 110 mg doses; in practice, dose selection is based on clinical characteristics—mainly creatinine clearance, age and bleeding risk—to better tailor the dose to the patient. The post-hoc analysis by Greg Lip and colleagues57 suggests that if dabigatran concentrations were used to modify dosing, outcomes might be even better. In RE-LY, there was
Adjusted-dose NOACs
Importantly, there are several challenges in trying to implement adjusted-dose NOACs.59 One in particular relates to the United States where the 110 mg bid dose of dabigatran1, 60 is not available although it was studied in RE-LY and is available in most of the world. Additional doses, however, could be created. Others include: The target levels (therapeutic range) for each NOAC and each risk profile would need to be defined. Should the target be optimized for bleeds or for strokes? It does not
NOAC antidotes (also termed reversal agents)
Physicians have decades of experience and comfort using vitamin K to reverse the effect of vitamin K antagonists. No matter that the time course of vitamin K reversal of warfarin61, 62 effect is similar to the elimination half-life of the four available NOACs and, despite the excellent performance of the NOACs in their pivotal clinical trials versus warfarin without the availability of a NOAC antidote, there have been appeals for their development. In circumstances such as major hemorrhage or
Development issues for consideration: indications, dosing, outcomes, rebound, antigenicity, off-target effects, logistics
The predominate focus of our meeting addressed the use of NOAC antidotes—to define the data elements deemed essential to a new reversal paradigm; to delineate data sources to inform the safety and effectiveness of these new agents once they become generally available; and to address the logistical issues regarding their distribution and reimbursement. The presentations during this portion of the meeting therefore included: (1) Assessing the efficacy and safety of NOAC antidotes following their
Clinical considerations
There was a broad consensus that following the approval of NOAC antidotes, post- marketing requirements should be put in place. Pre-release studies have been small and may not reflect the potential spectrum of adverse effects that could occur upon large-scale use. One of particular concern could be antibody formation to the antidote in even a very small percentage of patients such that repeat administration could be met with the same contraindication to repeat use as can occur with
Additional logistical considerations
Overwhelmingly, NOACs are prescribed in the out-patient setting while most if not all NOAC reversal agents will be administered in a hospital setting. And, bleeding events are likely to occur closely in time to administration of a reversal agent, while long-term follow-up, if required, will likely occur in the out-patient setting. Therefore, data collection in post-marketing assessment will not be feasible using only hospital or only out-patient records. Rather, use of health insurance claims
Regulatory considerations for NOAC reversal agents; the post-marketing evaluation possibilities; and the FDA sentinel initiative: active surveillance of post-market drug safety
Determination as to what constitutes substantial evidence for effectiveness from the FDA viewpoint as well as regulatory approval pathways was reviewed. Regarding evidence for effectiveness, the Federal Food, Drug, and Cosmetic Act (FD&C) Drug Efficacy Amendment of 1962 requires effectiveness of products be demonstrated through adequate and well-controlled clinical investigations. As to what qualifies as substantial evidence of effectiveness, presenters noted that the FDA's standard for regular
Active post-marketing surveillance and considerations for an active comparator for the NOAC reversal agents
Beyond the above, additional considerations for post-marketing surveillance and considerations of an appropriate comparator in such surveillance were discussed. An “active surveillance” approach could be used in post-marketing evaluation of NOAC antidotes -- defined as a systematic process for capturing and analyzing health care data sources to better understand the effects of medical products (in combination with data from randomized clinical trials, pharmacovigilance studies, etc.) and for
Concluding comments
While the purpose of the meeting was not to agree upon the details of specific monitoring assessments for our available NOACs or specific phase-4 post-marketing studies to be developed and used, several conclusions and general consensus positions were reached. First, with respect to monitoring, having a means to determine the presence of a NOAC and/or the extent anticoagulation magnitude when clinical circumstances and patient care would benefit from it is desirable and should be pursued. We
Disclosures
James A. Reiffel, MD: consultant for and/or speakers’ bureau member for Boehringer Ingelheim, BMS, Daiichi Sankyo, Pfizer, Portola. Jeffrey I Weitz, MD: consultant for Boehringer Ingelheim, BMS, Pfizer, Bayer, Janssen, Daiichi Sankyo, and Portola. Paul Reilly, PhD.: Employee of Boehringer Ingelheim. Edvardas Kaminskas, MD: no conflicts to report. Troy Sarich, PhD.: Employee of Janssen Scientific Affairs, LLC. Philip Sager, MD: Sager Consulting Experts. Jonathan Seltzer, MD: Consultant
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