NOAC monitoring, reversal agents, and post-approval safety and effectiveness evaluation: A cardiac safety research consortium think tank

Cardiac Safety Research Consortium

NOAC monitoring, reversal agents, and post-approval safety and effectiveness evaluation: A cardiac safety research consortium think tank James A. Reiffel, M.D., a Jeffrey I. Weitz, M.D., b Paul Reilly, Ph.D., c Edvardas Kaminskas, M.D., d Troy Sarich, Ph.D., e Philip Sager, M.D., f and Jonathan Seltzer, M.D. g, on behalf of the other Cardiac Safety Research Consortium presenters and participants New York, NY; Ontario, Canada; Ridgefield, CT; Silver Springs, MD; Titusville, NJ; San Francisco, CA; and Wynnewood, PA

Four non-vitamin K antagonist oral anticoagulants (dabigatran, rivaroxaban, apixaban, and edoxaban) have been approved in the United States for treatment of atrial fibrillation (AF) and venous thromboembolic disease. They have been as or more effective than the prior standards of care, with less fatal or intracranial bleeding, fewer drug and dietary interactions, and greater patient convenience. Nonetheless, the absence of the ability for clinicians to assess compliance or washout with a simple laboratory test (or to adjust dosing with a similar assessment) and the absence of an antidote to rapidly stop major hemorrhage or to enhance safety in the setting of emergent or urgent surgery/procedures have been limitations to greater nonvitamin K antagonist oral anticoagulant usage and better thromboembolic prevention. Accordingly, a Cardiac Research Safety Consortium “think tank” meeting was held in February 2015 to address these concerns. This manuscript reports on the discussions held and the conclusions reached at that meeting. (Am Heart J 2016;177:74-86.)

The non-vitamin K antagonist oral anticoagulants (NOACs), which include dabigatran, rivaroxaban, apixaban, and edoxaban, have been approved in the U.S. for treatment of atrial fibrillation (AF) and venous thromboembolic disease (VTE), starting with dabigatran in 2010. They have been as or more effective than the previous standard of care for reducing the risk of thromboembolic stroke in AF with a lower risk of causing hemorrhagic stroke, and for venous thromboembolic disease (VTE). 1–13 Their dosing regimens are simpler, though they are consequent to the status of renal function; they work within hours obviating the need for bridging with a parenteral anticoagulant under most circumstances; they have limited (rivaroxaban) or no dietary interactions; they have not required routine coagulation test monitoring; From the aColumbia University, New York, NY, bMcMaster University and Thrombosis and Atherosclerosis Research Institute, Ontario, Canada, cEmployee of Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT, dDivision of Hematology Products, CDER, FDA, Silver Springs, MD, eEmployee of Janssen Scientific Affairs, LLC, Titusville, NJ, fStanford University and Sager Consulting Experts, San Francisco, CA, and gEmployee of ACI Clinical and Lankenau Heart Institute, Wynnewood, PA. Submitted April 20, 2016; accepted April 20, 2016. Reprint requests: James A. Reiffel, M.D., Columbia University, c/o 202 Birkdale Lane, Jupiter, FL, 33458. E-mail: [email protected] 0002-8703 © 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ahj.2016.04.010

and they have fewer drug-drug interactions than warfarin. 14–16 As such, they have steadily begun to replace warfarin for anticoagulation for AF and VTE in a growing fraction of patients. 17–19 Nonetheless, clinicians and patients have expressed concerns about some aspects of NOAC therapy, including the absence of an antidote to reverse their effects when desired (such as in the presence of severe bleeding, trauma, or emergent surgery or other interventional procedure), and the inability to determine the extent of anticoagulation as one can with the INR for warfarin when documentation of washout or adherence is desired or to optimize the balance between stroke prevention and bleeding. The former is being addressed by the development of antidotes specific for these agents 20–26 while the latter would require laboratory tests that are sensitive, specific, standardized, and reproducible in their ability to measure the plasma concentrations of the NOACs and/or their anticoagulant activity. As antidotes for both dabigatran and the factor Xa inhibitors have been developed and are nearing completion of the clinical trials required for FDA approval, 22,23,26–34 and, as laboratory assessment specific for each drug or its effect would be useful provided that standardized test were available, a “think tank” meeting utilizing the Cardiac Safety Research Consortium (CSRC)24 was held at the FDA's (Federal Food and Drug Administration) campus in

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Table I. Possible roles for NOAC monitoring

• To assess/verify washout pre-procedure or to assess risk of bleeding if emergency procedure is needed, and to perhaps assess if an antidote should be available. • To assess dosing compliance. • Possibly to assess/modify dosing if dose-confounders are present (especially if multiple), e.g., renal dysfunction, P-gp and/or CYP3A4 inducers or inhibitors. • To assess any possible role in an actively bleeding patient or to assess the feasibility of giving a thrombolytic to a patient with an acute ischemic stroke who has previously been prescribed a NOAC.

Maryland, on February 3, 2015, to address these issues. This meeting followed a prior meeting regarding considerations for clinical development of reversal agents held in April 2014. 24 The current manuscript presents a summary of the content of, suggestions made at, and consensus opinions generated at the February 2015 meeting and its appendix presents the meeting's agenda and the list of participants. About a third of the meeting addressed monitoring the anticoagulant effect of the NOACs; about two thirds addressed NOAC antidotes. Most importantly, the discussion about the latter also addressed considerations for post-marketing assessments regarding efficacy, safety, appropriate utilization, and cost. The CSRC is a public-private partnership aimed to support research into the evaluation of cardiac safety of medical products. It was created on the basis of the principles of US Food and Drug Administration's (FDA) Critical Path Initiative to facilitate collaborations among academicians, industry professionals, and regulators to develop consensus approaches addressing cardiac and vascular safety issues that can arise in the development of new medical products. The views expressed in this manuscript do not represent new regulatory policy but do represent the presentations and discussions among the FDA, NIH, academic, and industry participants who were present.

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. 35–44 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 intracranial bleeding and, at least in AF trials, a 10% reduction in all-cause mortality. 1,5,8,12 Nonetheless, it is possible that they might have performed even better regarding thrombotic or bleeding events and stroke reduction if PK or PD monitoring were available. This is a major clinical issue given the continued stroke risk in patients receiving NOAC's who have atrial fibrillation. Additionally, it would be clinically helpful to be able to assess the presence and amount of circulating drug or the magnitude of anticoagulant effect present: (a) if patient compliance or

overdose is questioned; (b) if emergent or urgent surgery or other intervention (including spinal procedures) is required or major trauma has occurred, and/or if drug washout needs to be confirmed; or, (c) to guide dosing adjustments. With respect to the last, assessment may be particularly helpful in patients with varying or progressive renal dysfunction; at extremes of body weight; when one or more drugs having pharmacokinetic interactions with a NOAC are co-administered; or in patients presenting with an acute ischemic stroke where thrombolytic therapy is being considered. Possible uses of NOAC monitoring are further summarized in Table I.

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 b1.3 is associated with minimal drug effect/ a plasma dabigatran concentration below the target range whereas a markedly elevated result could indicate an increased risk for bleeding. 45,47–50 But the aPTT methodology varies across sites and we do not have clinical data to suggest specific dosing changes based upon the aPTT value. The PT is not sensitive to dabigatran and is not useful in its management. 45–51 For the factor Xa inhibitors, anti-XA activity is linear over a wide range of drug levels 52–55 and may be used for drug quantification; however, there is not a uniform standardized anti-Xa test that is useful for all of the oral factor Xa inhibitor drugs. While the same assay might be used for all of the oral fXa inhibitors, it would need to be calibrated with each agent thereby impairing clinical utilization. 54,55 Also, anti-Xa assays are not available in all hospitals and even when available, the turnaround time may be too long to be useful. Unmeasurable anti-Xa levels with an appropriate assay should indicate absence of a factor Xa inhibitor effect. The PT is less sensitive (especially for apixaban) and is reagent-dependent, and a normal PT may not exclude clinically relevant drug levels. 50,55,56 The aPTT demonstrates insufficient sensitivity and linearity for

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quantification with the Xa inhibitors.45,47–50,56 Additionally, in contrast to dabigatran, factor Xa inhibitors have no effect on the thrombin time. Therefore, currently available global tests of coagulation may be useful to measure the anticoagulant effect of some agents in some circumstances but not in all that are needed. However, they cannot adequately quantify anticoagulant intensity; they are not useful for dose selection or adjustment; and, at least for some of the NOACs, they are not sensitive enough to assess compliance or wash-out. New, widely available, reproducible, and cost-effective tests, possibly drug-specific, are needed.

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 colleagues 57 suggests that if dabigatran concentrations were used to modify dosing, outcomes might be even better. In RE-LY, there was a dose response in the overall study for both ischemic stroke and major bleeding, 1 confirming that more drug resulted in the more pharmacologic effect, which in turn was manifested in different clinical outcome rates, specifically, higher blood levels led to fewer strokes but more bleeding. On closer examination of the individual drug concentrations from these patients in a large pre-specified substudy, 36 the concentration response relationships had quite different shapes, as was known to be the case for warfarin. Below a critical level, about 50 ng/mL stroke rates rose shortly (as they do for warfarin if INR is b2), whereas the rate of bleeding rises slowly and continuously with dabigatran concentration. There appears to be a “sweet spot” between 50 and 150 ng/mL (with little further benefit above that) where stroke prevention is optimal, with little benefit from higher levels. Bleeding, at the 50–150 ng/mL level is fairly low, but then rises continuously at higher levels. Thus, there is a clear possibility that dose adjustments to attain a level of 50–150 ng/mL could give optimal rates for bleeding or ischemic stroke. Unfortunately, an assay for plasma dabigatran levels is not widely available. Without such an assay, getting to the right concentration may be difficult, as concentrations are dependent on individual patient characteristics In addition, these relationships were strongly dependent on individual patient characteristics (notably renal dysfunction), as well as interactions between these demographics and plasma concentrations (see example in Figure). Stroke rates are also dependent on patient characteristics (such as renal function, CHADS

score) but the concentration-response relationship is similar for all. Interestingly, the relationship between drug level and ICH was pretty flat, and the rate was actually numerically lower for the 150 mg dose than the 110 mg dose. A critical question is whether we already know that blood level or do we need clinical outcomes data for each agent with such monitoring? Is there a target range for all patients or is it specific to the type of patient (such as the very elderly, those with renal dysfunction where the half-life and time of monitoring would be different, or those on concomitant medications that could also alter drug clearance and the appropriate time for monitoring)? These are critical questions. The data on dabigatran from RE-LY (1) and on edoxaban from ENGAGE 43,58 strongly support the variation of risk dependent on patient characteristics. Figure demonstrates that the risk of both a major bleed and a thromboembolic event varies by patient demographics over the same range of plasma dabigatran concentrations. With respect to anticoagulation monitoring, rather than plasma concentration measurement, there is not yet a reliable and approved assay for each NOAC as was noted above. Moreover, if monitoring protocols were developed with reproducible and clinically meaningful assays: (1) don't we still have to determine for each NOAC whether the relationship between blood level and stroke and bleeding is the same (within patients and across patients); and (2) shouldn't we then develop dosing algorithms based upon the results; and (3), wouldn't we then have to determine at what frequency re-testing should be performed, both with and without changes in the dose being given? Moreover, while we would want evidence of improved outcomes based upon adjusted dose NOACs, is it really necessary given the above data? The need for a prospective study and other key issues with this approach will be further discussed and examined in a follow-up CSRC think tank meeting in Dec 2015.

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 dabigatran 1,60 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 seem possible to do both unless settling for a range as is the case with INRs for warfarin. What would be the best way to deal with fluctuations within patients and across patients? Should the frequency of assessment be patient­ specific or should there be a standardized pattern of assessment? Finally, there are important methodological limitations at present. Although no supportive data from a randomized controlled trial of fixed versus adjusted dose NOAC

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Figure

Patient Demographics Affect NOAC Efficacy and Risk (adapted from reference 36).

treatment are available (though they would be desirable), there was no consensus at the meeting to do such a trial at this time. In contrast, there was a strong sense that reliable monitoring tests applicable to assess compliance, anticoagulation status, and possibly dose-adjustment should be pursued with FDA guidance. In association with the latter, and the potential for test-guided NOAC dose adjustments under particular clinical circumstances, several participants present strongly suggested that: (1) The 110 mg bid dose of dabigatran should be reconsidered for approval in the U.S. (2) That the 150 mg bid dose should be the recommended dose unless excessive plasma concentrations were present at baseline or were to develop during treatment consequent to such things as old age, moderate renal insufficiency, and/or administration of P-gp inhibitors. In such circumstances, down titration to the 110 mg bid dose would be advised if it was confirmed that dabigatran plasma concentrations exceeded a pre­ specified level. (3) That without such dabigatran plasma concentration monitoring, it was unlikely that the 110 mg bid dose for AF would become available in the U.S. since we know that despite its lower bleeding rate, it was associated with significantly higher stroke rates than the 150 mg bid dose.

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 warfarin 61,62 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 an urgent interventional procedure, the availability of an antidote could potentially enhance patient safety and improve outcomes. Moreover, the availability of an antidote would improve the “perception” of safety and thus NOAC utilization. In other words, there is also a case to be made that the psychological comfort in knowing that there is a reversal agent may make more physicians comfortable in prescribing NOACs and patients more comfortable in accepting them. Accordingly, over the past few years, antidotes to the NOACs have been under development. 22,23,26–34 Importantly, the FDA has granted “breakthrough status” (rapid assessment/ approval) to two of these reversal agents: idarucizumab (developed by Boehringer-Ingelheim)—a fully humanized antibody fragment (Fab) specific for dabigatran; and andexanet alfa (developed by Portola)—a truncated form of enzymatically inactive factor Xa which binds factor Xa inhibitors and reverses their anticoagulant effects, to be used for the oral factor Xa inhibitory NOACs and enoxaparin. Also under development is ciraparantag (PER977, aripazine), a synthetic small molecule manufactured by Perosphere, which is being developed as a reversal agent for all of the NOACs as well as for fondaparinux and low molecular weight heparins (Table II).

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Table II. NOAC antidote properties reported to date efficacy ldarucizumab: Onset of action was detected immediately following a 5 minute infusion with a half-life of approximately 45 minutes. A 5 minute infusion resulted in a reduction of plasma dabigatran concentration to undetectable levels within 4 hours. A phase 1 trial achieved immediate, complete, and sustained reversal of dabigatran-induced induced anticoagulation in healthy subjects. Reversal of the anticoagulation effect was complete and sustained in 8 of 8 subjects given a 4 gram dose. Additional data from an interim analysis of its phase 3 study was recently published in the New England Journal of Medicine.34 Andexanet Alfa: Reversal of over 90% of anti-factor Xa activity for all factor Xa inhibitors studied in healthy volunteers (rivaroxaban, apixaban, edoxaban) within 2 to 5 minutes of bolus infusion, maintained during a 2 hour infusion, with a half-life of approximately 45 minutes. Ciraparantag: Has demonstrated reversal of whole-blood clotting time without effect on typical markers of anticoagulation—within 10 minutes of completion of infusion. No change in PK of inhibitors in animal models. Safety: Idarucizumab: No rebound thrombosis detected so far. No reactive antibody formation detected so far. No serious infusion reactions requiring treatment have occurred. Andexanet Alfa: No rebound thrombosis detected so far. No antibodies developed or detected to endogenous factor Xa but anti-andexanet antibodies noted in b2%. Non-serious infusion reactions, rarely requiring treatment have occurred. Ciraparantag: No rebound thrombosis detected so far. Potentially related transient mild perioral and facial flushing and dysgeusia. One person has reported a moderate headache.

Studies with NOAC antidotes have confirmed in phase 1, phase 2, and ongoing phase 3 trials that these agents can rapidly and virtually completely reverse the anticoagulant actions of the NOAC for which they have been tested, using a bolus injection +/− an ongoing infusion. 28–34 To date, tolerance has been good in the small number of subjects tested. However, larger scale safety data, including with repeat dosing, will be needed. Studies are also needed in actively bleeding patients. To this end, a global phase 3 study, RE-VERSE AD, 34 is underway in patients on dabigatran who have uncontrolled bleeding or require emergency surgery or procedures. Interim results in the first 90 patients enrolled in RE-VERSE AD have been reported 34 and appear positive re: both reversal of anticoagulant effects and safety. Phase 3 studies are also currently ongoing with andexanet alfa.

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 approval; (2) Clinical considerations specific to the Emergency Department; (3) Regulatory considerations for NOAC reversal agents; (4) Defining desired data elements for safety and effectiveness post-approval; (5) Other post-marketing considerations, including the FDA Sentinel Initiative of active surveillance of post-marketing drug safety. These will be summarized sequentially.

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 streptokinase. Notably, this has not been seen in the small numbers of patients given the antidotes so far. Moreover, pre­release studies have shown reversal of anticoagulation effects though this may or may not translate into measurably improved major clinical outcomes in actively bleeding patients or other important clinical scenarios as compared with infusions of procoagulant factors (as suggested so far by only small case reports). Thus, phase-4 studies would be highly desirable (see more below regarding possible formats). Additionally, indications will need to be clearly defined and limited—especially before large-scale efficacy and safety data are known and given the anticipated significant medication costs. A system to verify appropriate use would also be desirable. The clinical circumstances most likely to require a NOAC antidote would form the settings for possible phase 4 trials. They may be considered in terms of urgency. Emergency would include life-threatening bleeding, such as intracerebral, perforation of a major vessel, aneurysm rupture. Urgent would include severe but not immediately life-threatening bleeding, such as ongoing gastro-intestinal bleeding with a high transfusion requirement. Other possible settings include before, during, or following non-elective surgery/intervention, such as if the patient has ongoing bleeding pre-procedure that would prohibit the procedure unless stopped; or a stable patient who requires an urgent procedure associated with a moderate or high risk of bleeding; or the patient who develops bleeding during re-anticoagulation following a procedure.

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What information would a clinician desire from a phase-4 trial or a post-marketing registry? Clearly this would include dosing regimens and meaningful endpoints. Regarding the latter, such might include: (1) does bleeding stop sooner than it would simply by withholding the NOAC and providing supportive care plus active procoagulants? (2) Is non-elective surgery safe earlier than it would be in the absence of the antidote? (3) Are there objective and measurable major outcome benefits, such as mortality, transfusion requirements, length of stay, major morbidity endpoints (stroke score, etc.), cost that can be clearly determined with the trial design to be tested? (4) Are there rare but serious adverse effects that only become apparent when large numbers of patients receive the agent being tested? All but the fourth circumstance would require comparison with a control group, a difficult design criterion in potentially life-threatening conditions where it may be ethically unacceptable to deny the antidote to some patients. Thus a registry may be more realistically and logistically feasible than a prospective, randomized trial. In considering possible Phase 4 trials, it is worthwhile noting that even after more than 50 years of Vitamin K antagonists, controlled data on the effect of Vitamin K or Vitamin K plus fresh frozen plasma in reducing clinical outcomes such as bleeding or mortality are still lacking. What might clinicians view as favorable phase 4 studies designed to assess efficacy and safety? One could be a prospective, randomized, double-blind trial against PCC +/− other replacement factors [a placebo control would not be ethical if we know that the antidote reverses the anticoagulant activity of a NOAC and we know that PCC does not]. Another possibility could be a trial with surrogate outcomes, such as more rapid normalization of laboratory measurements of coagulation. However, the latter might not necessarily be clinically meaningful regarding more rapid termination of bleeding or other beneficial clinical outcomes. An alternative study would be a registry, either of (1) all patients given the NOAC antidote—which would be severely limited as determination of benefit would not be more than anecdotal; or (2) of all bleeding patients, which would optimally require a case-controlled comparison of antidote-treated patients to those not so treated; or (3) of all patients on NOACs who require non-elective surgery, with a comparison of clinically determined outcomes, such as bleeding, transfusion, ICU stay, hospital length of stay, mortality, etc. in a case-controlled comparison. Yet additional data could come from database interrogations, such as an electronic medical record with in-hospital pop-up screens whenever a bleed occurs on a NOAC and whenever an antidote is given; or correlation with hospital discharge summaries or with insurance or other data sets that incorporate such outcome events and treatments used. Since major bleeds on NOACs severe enough to require an antidote are infrequent, use

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of large data bases will most likely be necessary to answer at least some of the questions we need to resolve although using matched case-controls may provide some useful information. Finally, additional clinical issues will need to be addressed: Where should the NOAC antidotes be available? Should any tests be followed before and after administration—which ones and when? Will cost be prohibitive and under what circumstances will it be covered by insurance? Lastly, how much use will there be for less-than-indicated circumstances, and how might we best track it and limit it? Beyond the above clinical considerations, there are some that may be site-specific. In the emergency department (ED), for example, 19 at present, there is a great deal of insecurity, due to lack of familiarity with the growing list of NOACs and inconsistency in bleeding management protocols. ED physicians see complications from both under- and over­ anticoagulation and also manage anticoagulated patients who need emergent interventional procedures/surgery. Most have standardized protocols to address this for warfarin, but not for the NOACs. They should have as NOAC antidotes would be strongly welcomed there. Post-marketing studies targeting the ED setting following any NOAC antidote release might best include: (1) a means to compare outcomes for similar patients who are managed with and without an antidote; (2) a comparison of outcomes in patients managed by different physician specialties; and, (3) determination of a consistency of effect, without signs of thrombin generation or frequent hypersensitivity. Importantly, “formulary roadblocks” must not be put in place, as we will need to be able to reverse the effect of each NOAC that a patient coming to the ED might be taking.

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 data, pharmacy claims data (both in­ patient and out-patient), and electronic medical records will need to be utilized. Moreover: Understanding drug safety from “big data” is not always simple, due to variability such as treatment heterogeneity, natural variability in outcomes of interest, and more. There is lack of clarity around definition(s) of “major” or “lifethreatening” bleeding, variation in clinical presentation, variation in possible treatment approaches, and variation in time elapsed from last dose as well as in and biomarkers utilized in assessment in the clinical setting. These would all have to be considered when designing

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phase 4 studies. The impact of approval of reversal agents could be mixed. Approval could increase appropriate use of NOACs and improve the net clinical benefit. “Low evidentiary thresholds for approval, while perhaps reasonable, raise the stakes further in the post­approval period” and thus support the need for phase 4 studies in the NOAC antidote arena. (4) Data collected in phase 4 studies should include presenting signs and symptoms; formal assessment of clinical co-morbidities and covariates; treatments used; pharmacokinetic, pharmacodynamics, clinical, and resource-utilization and cost data; any evidence for “off-label” use, and restarts of anticoagulant treatment. As at the prior CSRC think tank in April 2014, the participants at this meeting agreed that after approval of each NOAC antidote, efforts should be made to augment the available clinical information until such time as there is a body of evidence to demonstrate real­world clinical outcomes with the reversal agents.

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 approval is demonstration of clinical benefit in at least two adequate and well-controlled studies, (i.e., phase 3), but there can be a single such study and confirmatory data from other studies. The latter might include other doses and regimens, other dosage forms, other stages of disease, other populations, etc. Another available approval pathway is accelerated approval. It was authorized in 1992, for drug products under Subpart H of the New Drug Regulations (21 CFR, Part 314.510) and for biological products under Subpart E of the Biological Licensing Regulations (21 CFR, Part 601.41). The requirements for accelerated approval is that the condition to be treated is serious or life-threatening, that the drug or biologic product has meaningful advantage over available therapy, and that evidence of efficacy may be determined by a surrogate endpoint that is reasonably likely to predict clinical benefit. Additional post-approval studies or trials that confirm the relationship of the effect on the surrogate endpoint to clinical benefit must be ongoing or agreed to at the time of accelerated approval. In addition, Fast Track and Breakthrough Therapy designations may expedite the

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review and potential approval (Guidance for Industry Expedited Programs for Serious Conditions—Drugs and Biologics, May 2014). Fast-track designation requires nonclinical or clinical data that demonstrate the potential to address unmet medical need and stipulates actions that expedite development and review. The more recent breakthrough therapy designation requires preliminary clinical evidence of substantial improvement on a clinically significant endpoint over available therapies. FDA provides intensive guidance, frequent communications, as well as organizational commitment to expedite drug development.) There are several important problems with the regular approval pathway as it relates to the NOAC reversal agents. The population that will require NOAC antidotes is small (must be taking a NOAC and have significant bleeding [only about 2%-3%]) and/or be in need of emergency surgery/procedure). Feasibility and an adequate control group would be difficult issues. Important data in the development of NOAC antidotes are reliable mechanism of action studies, nonclinical results in bleeding models that support an effect on NOAC anticoagulation reversal and provide some safety information, detailed pharmacokinetic/pharmacodynamics studies in normal human volunteers, and clinical data (single-arm trials or registries) that indicate anticoagulant reversal and absence of safety issues that would result in a negative benefit to risk assessment. Such data may suffice for filing a NDA/BLA application via the accelerated approval pathway. After approval based upon biomarker and pharmcodynamic data occurs, additional post­ marketing data from confirmatory studies in patients will be necessary to collect and evaluate for the reversal agents as part of the development plan since important components of safety and efficacy will be incompletely defined at their approval. The design and findings of the clinical studies leading to approval will influence the post­ marketing data that would be desirable. For example, a single-arm trial has inherent problems in isolating adverse drug effects, and, by definition, observation of rare events is proportional to the size of any trial's population. Variables that can affect efficacy outcomes include: the indication for reversal; the indication for anticoagulation; the NOAC dose, time from dose, creatinine clearance, and co-morbidities—including age, organ function, concomitant diseases; concomitant medications; and laboratory criteria used. Small size studies, as have been performed with the NOAC antidotes so far, are significantly limited with respect to these important data items. Hence, important components of safety and efficacy will be under-defined at approval, including: thrombosis, immunogenicity, hypersensitivity, other unpredicted serious adverse effects, and the true efficacy in bleeding patients (or lack thereof). Consequently, post-marketing assessments will be essential. The tools available to better define efficacy in a post-marketing environment include: post­ marketing

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commitments (voluntary); post-marketing requirements for products under Accelerated Approval (required); and clinical trials with either confirmation of surrogate endpoints (analogous to VKA reversal trials) or defining efficacy in specific subpopulations. Our meeting consensus was that registries provide additional useful data and should be pursued. Possible post-marketing requirements under the FDA Amendments Act of 2007 (FDAAA) regarding safety include: (1) clinical trials with controls in specific populations; (2) observational epidemiologic studies; (3) standard pharmacovigilance studies; (4) enhanced pharmacovigilance (PV) studies (targeted, dependent on voluntary reporting, registries); (5) electronic health records reviews; and/or (6) a program using a risk evaluation and mitigation strategy with elements to assure safe use (REMS) though these are not all of equal utility regarding each efficacy and safety issue being addressed. Additionally, with respect to the NOAC antidotes, the reversal agents are proteins, thus increasing the potential for allergic and hypersensitivity reactions—for which spontaneous reporting may define severity but not incidence. The best assessment of immunogenicity would require specific monitoring in a defined protocol or in a registry to detect new antibody formation. Ideally, such a protocol or registry would also include: specific criteria for use of the reversal agent (indication}, time from last NOAC dose and dose size, serum creatinine and calculated GFR, evaluations of hemostatic function, standard elements (concomitant medications, pertinent medical history), consequences, and a logical narrative. Finally, with respect to the FDA and post-marketing evaluation of the NOAC antidotes, utilization of the FDA Sentinel Initiative program (active surveillance of post-marketing drug safety) as well as its preceding Mini-Sentinel pilot program was addressed. The FDA Sentinel Initiative has several goals: (1) to develop a national electronic safety monitoring system by leveraging multiple sources of currently available electronic data and by partnering with data holders; (2) to enhance active post-market monitoring of medical product safety, including to more effectively look at common outcomes; to have denominators to easily calculate rates; and to increase sample size with improved access to population subgroups; (3) to use valid design and statistical methods; (4) to have “near real-time” monitoring by using a common data model and a “library” of tools/resources, and, (5) to integrate active surveillance with current post-market safety monitoring systems—for which there are several partner organizations. The Harvard Pilgrim Healthcare Institute has taken the lead role but there are multiple university and insurance company data and scientific partners. The program has been successful in post­ marketing assessment of several NOACs re: increasing safety data in a rigidly assessed format and

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has possible use for post-market surveillance of the NOAC reversal agents. For the latter it could: (1) use historic data to set some risk thresholds for adverse outcomes and compare these to actual rates in the Mini-Sentinel Distributed Database; (2) provide reassurance that incidence rates of adverse outcomes are below a specified and meaningful level; (3) to compare reversal treatment for NOACs with those for warfarin; and (4) to evaluate the comparator situations that have been described elsewhere. With respect to the second item above, since serious bleeding on NOACs with use of an antidote is expected to occur infrequently, the database may or may not be able to meet the needed exposure occurrence levels.

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 characterizing actual use, and to provide further insight into benefit-risk, with a minimal lag in data availability. The questions such active surveillance might best address in the NOAC antidote arena include: usage of NOAC reversal agents (appropriate, inappropriate) events associated with NOAC antidotes, and a comparison to alternative approaches. Each is tied to the selection of patients for NOAC antidotes versus an alternative approach, the specific comparator used, the site of administration, and the rates of events for each leading to the use of a reversal strategy. The implementation of an active surveillance program is dependent upon the ability to capture exposure; upon the frequency of events; upon the ability to follow patients and “see” outcomes of interest; how representative the sample is; and what the comparison or control groups are. The ability to “see” requires specific reimbursement claims, particularly outpatient, where any procedure code would have to be billed separately. Potential comparators (e.g., vitamin K, PCC, etc.), dosage, who administered the NOAC antidote and where, site of bleed and severity, rationale for the reversal agent, and whether or not the NOAC was stopped and for how long may not be or are likely not to be visible, resulting in limitations to this approach. Possible study designs for active surveillance include prospective (including registries) and retrospective (including database or registry interrogations). However, the site of use (out-patient, in-patient on a standard floor,

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in the operating room, in the ED) will all influence the capture of information. It seemed likely that an active surveillance program could form part of the post-marketing evaluation of the NOAC antidotes, but that due to its limitations, it would not suffice as the prime or as a stand-alone method.

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 recognized that more than one test would likely be needed. For some agents, such as dabigatran, a plasma concentration or linearly related and sensitive coagulation parameter would likely be useful, despite some limitations as were presented above. For others, a broadly applicable and reliable factor Xa inhibition assay would apply. Whether such tests should be used to guide NOAC dosing remained unresolved or at least without consensus. Nonetheless, the concept of individualized dosing to improve outcomes is attractive, given the available data on edoxaban and dabigatran and the numerous clinical circumstances where fixed dosing may result in a wide range of plasma levels (such as with combinations of various metabolic inhibitors or inducers plus reduced or variable renal function). Moving to a monitoring process for determining dose can be contrasted with the current NOAC prescribing. This might appear to help clinicians who are struggling with the current dosing caveats and inconsistent list of metabolic altering agents from package insert to package insert but differences across NOACs and such caveats would potentially remain. Monitoring NOACs as a way to assess drug level/actions or to maximize dose flexibility or ultimately to benefit patient care remains unproven. Clinical outcome data are lacking. These issues will be further discussed in a follow-up CSRC think tank meeting. Second, after approval of the NOAC antidotes based on limited clinical data showing reversibility under their current fast-track and breakthrough therapy approach, there was a strong sense that Phase 4, post-marketing data in patients should be an essential part of the approval process. Likely, due to the relative infrequency of major bleeding events that might require a NOAC antidote, the relatively short half-life of the NOACs with a somewhat brief window of opportunity to give an antidote, and their anticipated significant price, it was generally felt that a prospective, active-comparator, randomized or cross­ over trial in severely bleeding

patients would not prove feasible. But, an uncontrolled trial in bleeding patients may be helpful to verify the pre-approval results in volunteers. Alternatively, and logistically more feasible, a registry to collect data on such infrequent events would be valuable. It was recommended that such a registry be established with mandatory inclusion of patient data whenever a reversal agent is used. Effectiveness, safety, longer-term outcomes, and costs should all be part of the data collected. Alternative means of assessment, such as active surveillance programs, review of electronic health records, and the like could be complementary and additive to registry­ provided data. However, and in addition, to further assess efficacy, safety, specific outcomes, and costs, some meeting participants suggested that a prospective phase 4 trial would be desirable in patients undergoing emergency or urgent surgery or other interventional procedure. Such a trial could be prospective, randomized, and against placebo and/or against currently used approaches, 63–68 e.g., 4 factor PCC +/− other procoagulants, depending on the population(s) included. Assessments in patients not actively bleeding could include bleeding events associated with the procedure, delays to the procedure, hospital or ICU length of stay, and the like. Moreover, in patients who are actively bleeding, such a protocol would ideally incorporate an agreed upon algorithm regarding hemodynamic support, approach to bleeding site, and transfusion requirements prior to the administration of the reversal agent. While data as could be forthcoming from the combination of a prospective trial and a registry might provide us with the best sense of the role for NOAC antidotes in our treatment of patients, from logistic and ethics points of view, as soon as the antidote is available in clinical practice and is shown to be efficacious in neutralizing the anticoagulant, patient recruitment for such a phase 4 prospective trial as a component of further data collection would be difficult. Nonetheless, additional data collection after marketing of each NOAC antidote being developed will be part of their approval process. Post Script: Since the date of this meeting, an antidote to dabigatran (Praxbind) has been approved in the U.S. as has a dabigatran dose of 110 mg (though only for orthopedic indication and not for AF).

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 relationships: http://www.aciclinical.com/about-us/disclosure/.

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Appendix (A). Agenda

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(B). List of Participants

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References 1. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361: 1139-51. 2. Schulman S, Kearon C, Kakkar AK, et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med 2009;361:2342-52. 3. Schulman S, Kakkar AK, Schellong S, et al. Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. N Engl J Med 2013;368:709-18. 4. Schulman S, Kakar AK, Goldhaber SZ, et al. Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis. Circulation 2014;129:764-72. 5. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365:883-91. 6. EINSTEIN Investigators, Bauersachs R, Berkowitz SD, et al. Oral rivaroxaban for symptomatic venous thromboembolism. N ENgl J Med 2010;363:2499-510. 7. EINSTEIN Investigators, Buller HR, Prins MH, et al. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 2012;366:1287-97. 8. Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011;365: 981-92. 9. Connolly SJ, Eikelboom J, Joyner C, et al. Apixaban in patients with atrial fibrillation. N Engl J Med 2011;364:806-17. 10. Agnelli G, Buller HR, Cohen A, et al. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med 2013;369: 799-808. 11. Agnelli G, Buller HR, Cohen A, et al. Apixaban for extended treatment of venous thromboembolism. N Engl J Med 2013;368:699-708. 12. Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2013;369:2093-104. 13. Hokusai-VTE Investigators, Buller HR, Decousus H, et al. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med 2013;369:1406-15. 14. Gallego P, Roldan V, Lip GY. Novel oral anticoagulants in cardiovascular disease. J Cardiovasc Pharmacol Ther 2014;19: 34-44. 15. Patel KK, Mehdirad AA, Lim MJ, et al. Beyond warfarin: a patient-centered approach to selecting novel oral anticoagulants for stroke prevention in atrial fibrillation. J Hosp Med 2014;9:400-6. 16. Reiffel JA. Novel oral anticoagulants. Am J Med 2014;127:e16-7. 17. Kirley K, Qato DM, Kornfield R, et al. National trends in oral anticoagulant use in the United States, 2007 to 2011. Circ Cardiovasc Qual Outcomes 2012;5:615-21. 18. Laffenburger JC, Farley JF, Gehi AK, et al. Factors driving anticoagulant selection in patients with atrial fibrillation in the United States. Am J Cardiol 2015;115:1095-101. 19. Cervelin G, Benatti M, Bonfanti L, et al. Quality and safety issues of direct oral anticoagulants in the emergency department. Semin Thromb Hemost 2015;41:348-54. 20. Levy S. Newer clinically available antithrombotics and their antidotes. J Interv Card Electrophysiol 2014;40:269-75. 21. Capodanno D, Giacchi G, Tamburino C. Current status and ongoing development of reversing agents for novel oral anticoagulants (NOACs). Recent Pat Cardiovasc Drug Discov 2013;8:2-9. 22. Gomes-Outes A, Suarez-Gea M, Lecumberri R, et al. Specific antidotes in development for reversal of novel anticoagulants: a review. Recent Pat Cardiovasc Drug Discov 2014;9:2-10.

Reiffel et al 85

23. Ebright J, Mousa SA. Oral anticoagulants and status of antidotes for the reversal of bleeding risk. Clin Appl Thromb Hemost 2015;21: 105-14. 24. Sarich TC, Seltzer JH, Berkowitz SD, et al. Novel oral anticoagulants and reversal agents: considerations for clinical development. Am Heart J 2015;169:751-7. 25. Lauw MN, Coppens M, Eikelboom JW. Recent advances in antidotes for direct oral anticoagulants: their arrival is imminent. Can J Cardiol 2014;30:381-4. 26. Siegal DM. Managing target-specific oral anticoagulant associated bleeding including an update on pharmacological reversal agents. J Thromb Thrombolysis 2015;39:395-402. 27. Greinacher A, Thiele T, Selling K. Reversal of anticoagulants: an overview of current developments. Thromb Haemost 2015;113: 931-42. 28. Costin J, Ansell J, Laulicht B, et al. Reversal agents in development for the new oral anticoagulants. Postgrad Med 2014;126:19-24. 29. Glund S, Moschetti V, Norris S, et al. A randomized study in healthy volunteers to investigate the safety, tolerability, and pharmacokinetics of idarucizumab, a specific antidote to dabigatran. Thromb Haemost 2015;113:943-51. 30. Pollack Jr CB, Reilly PA, Bernstein R, et al. Design and rational for RE-VERSE AD: a phase 3 study of idarucizumab, a specific reversal agent for dabigatran. Thromb Haemost 2015;114:198-205. 31. Glund S, Stangier J, Schmohl M, et al. Safety, tolerability, and efficacy of idarucizumab in healthy male volunteers: a randomized, placebo-controlled, double-blind phase 1 trial. Lancet 2015, http: //dx.doi.org/10.1016/S0140-6736(15)60732-2. 32. Jones D. Anticoagulant antidotes start yielding Phase III promise. Nat Rev Drug Discov 2015;14:5-6. 33. Portola Pharmeceuticals. Portola announces phase 3 ANNEXA-R study of andexanet alfa and factor Xa inhibitor XARELTO® (rivaroxaban) met primary endpoint with high statistical significance. http://investors.portola.com/phoenix.zhtml?c=198136&p=irolnewsArticle&ID=20054292015. 34. Pollack Jr CV, Reilly PA, Eikelboom J, et al. Idarucizumab for dabigatran reversal. N Engl J Med 2015;373:511-20. 35. Okubo K, Kuwahara T, Takagi K, et al. Relation between dabigatran concentration, as assessed using the direct thrombin inhibitor assay, and activated clotting time/activated partial thromboplastin time in patients with atrial fibrillation. Am J Cardiol 2015;115:1696-9. 36. Reilly PA, Lehr T, Haerttner S, et al. The effect of dabigatran plasma concentrations and patient characteristics on the frequency of ischemic stroke and major bleeding in atrial fibrillation patients: the RE-LY Trial (Randomized Evaluation of Long-Term Anticoagulation Therapy). J Am Coll Cardiol 2014;63:321-8. 37. Reilly PA, Connolly SJ, Yusuf S, et al. Reply: regarding the effect of dabigatran plasma concentrations. J Am Coll Cardiol 2014;63: 2885-6. 38. Jacksonll LR, Becker RC. Novel oral anticoagulatns: pharmacology, coagulation measures, and considerations for reversal. J Thromb Thrombolysis 2013;37:380-91. 39. Yamahira N, Frost C, Fukase H, et al. Safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple doses of apixaban in healthy Japanese male subjects. Int J Clin Pharmacol Ther 2014;52:564-73. 40. Dempfle CE. Direct oral anticoagulants-pharmacology, drug interactions, and side effects. Semin Hematol 2014;51:89-97. 41. Frost C, Nepal S, Wang J, et al. Safety, pharmacokinetics and pharmacodynamics of multiple oral doses of apixaban, a factor Xa inhibitor, in healthy subjects. Br J Clin Pharmacol 2013;76:776-86.

American Heart Journal July 2016

86 Reiffel et al

42. Camm AJ, Bounameaux H. Edoxaban: a new oral direct factor Xa inhibitor. Drugs 2011;71:1503-26. 43. Ruff CT, Giugliano RP, Braunwald E, et al. Association between edoxaban dose, concentration, anti-factor Xa activity, and outcomes: an analysis of data from the randomized, double-blind ENGAGE AF-TIMI 48 trial. Lancet 2015;385:2288-95. 44. Girgis IG, Patel MR, Peters GR, et al. Population pharmacokinetics and pharmacodynamics of rivaroxaban in patients with non-valvular atrial fibrillation: results from ROCKET-AF. J Clin Pharmacol 2014;54:917-27. 45. Winkler AM, Tormey CA. Pathology consultation on monitoring direct thrombin inhibitors and overcoming their effects in bleeding patients. Am J Clin Pathol 2013;140:610-22. 46. Stangier J, Feuring M. Using the HEMOCLOT direct thrombin inhibitor assay to determine plasma concentrations of dabigatran. Blood Coagul Fibrinolysis 2012;23:138-43. 47. Cuker A, Siegal DM, Crowther MA, et al. Laboratory measurement of the anticoagulant activity of the non-vitamin K oral anticoagulants. J Am Coll Cardiol 2014;64:1128-39. 48. Vanden Daelen S, Peetermans M, Vanassche T, et al. Monitoring and reversal strategies for new oral anticoagulants. Expert Rev Cardiovasc Ther 2015;13:95-103. 49. Hapgood G, Butler J, Malan E, et al. The effect of dabigatran on the activated partial thromboplastin time and thrombin time as determined by the Hemoclot thrombin inhibitor assay in patient plasma samples. Thromb Haemost 2013;110:308-15. 50. Jackson II LR, Becker RC. Novel oral anticoagulants: pharmacology, coagulation measures, and considerations for reversal. J Thromb Thrombolysis 2014;37:380-91. 51. van Ryn J, Baruch L, Clemens A. Interpretation of point-of-care INR results in patients treated with dabigatran. Am J Med 2011;125:417-20. 52. Samama MM, Meddahi S, Samama CM. Pharmacology and laboratory testing of the oral Xa inhibitors. Clin Lab Med 2014;34:503-17. 53. Barrett YC, Frost C, Shenker A. Clinical laboratory measurements of direct factor Xa inhibitors: anti-Xa assay is preferable to prothrombin time assay. Thromb Haemost 2010;104:1263-71. 54. Samama MM, Amiral J, Guinet C, et al. Monitoring plasma levels of factor Xa inhibitors: how, why, and when? Expert Rev Hematol 2013;6:155-64. 55. Douxfils J, Tamigniau A, Chatelain B, et al. Comparison of calibrated chromogenic anti-Xa assay and PT tests with LC-MS/MS for the

56. 57.

58.

59.

60.

61.

62.

63.

64. 65.

66.

67.

68.

therapeutic monitoring of patients treated with rivaroxaban. Thromb Haemost 2013;110:723-31. Blann AD, Lip GYH. Laboratory monitoring of the non-vitamin K oral anticoagulants. J Am Coll Cardiol 2014;64:1140-2. Lip GY, Clemens A, Noack H, et al. Patient outcomes using the European label for dabigatran: a post-hoc analysis from the RE-LY database. Thromb Haemost 2014;111:933-42. Mega JL, Walker JR, Ruff CT, et al. Genetics and the clinical response to warfarin and edoxaban: findings from the randomized, double-blind ENGAGE AF-TIMI 48 trial. Lancet 2015;385:2280-7. Hankey GJ. Unanswered questions and research priorities to optimise stroke prevention in atrial fibrillation with the new oral anticoagulants. Thromb Haemost 2014;111:808-16. Weimar C, Hohnloser SH, Eikelboom JW, et al. Preventing cardioembolic stroke in atrial fibrillation with dabigatran. Curr Neurol Neurosci Rep 2012;12:17-23. Meehan R, Tavares M, Sweeny J. Clinical experience with oral versus intravenous vitamin K for warfarin reversal. Transfusion 2013;53: 491-8. Watson HG, Baglin T, Laidlaw ST, et al. A comparison of the efficacy and rate of response to oral and IV vitamin K in reversal of over-anticoagulation with warfarin. Br J Haematol 2001;115:145-9. Dincq AS, Lessire S, Douxfils J, et al. Management of non-vitamin K antagonist oral anticoagulants in the perioperative setting. Biomed Res Int 2014;385014:2014. Lai A, Davidson N, Galloway SW, et al. Perioperative management of patients on new oral anticoagulants. Br J Surg 2014;101:742-9. Connolly G, Spyropoulos AC. Practical issues, limitations, and periprocedural management of the NOACs. J Thromb Thrombolysis 2013;36:212-22. Alikhan R, Rayment R, Keeling D, et al. The acute management of haemorrhage, surgery, and overdose in patients receiving dabigatran. Emerg Med J 2014;32:163-8. Tran H, Joseph J, Young L, et al. New oral anticoagulants: a practical guide on prescription, laboratory testing, and peri-procedural/bleeding management. Intern Med J 2014;44: 525-36. Krishnamoorthy A, Sherwood MW, Lopes RD, et al. The periprocedural management of novel oral anticoagulants in patients with nonvalvular atrial fibrillation: rational and a summary of the available evidence from phase 3 clinical trials. Am Heart J 2015;169:315-22.