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
American Heart Journal
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Reiffel et al 75
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
American Heart Journal
July 2016
76 Reiffel et al
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
American Heart Journal
Volume 177
Reiffel et al 77
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).
American Heart Journal
July 2016
78 Reiffel et al
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.
American Heart Journal
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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
Reiffel et al 79
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
80 Reiffel et al
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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July 2016
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
Reiffel et al 81
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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82 Reiffel et al
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/.
American Heart Journal
Volume 177
Appendix
(A). Agenda
Reiffel et al 83
84 Reiffel et al
(B). List of Participants
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American Heart Journal
Volume 177
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