RSC Health New Drug Approval Process Clinical Trial Discussion

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discuss the process by which drugs are taken from idea to wide scale use in humans or animals, and the factors that may limit or influence the overall quality of clinical trials. You can use rivaroxaban and the other oral anticoagulants as examples if you wish, or discuss another drug of your choosing.

In particular:

Discuss the approval process for a new drug

Discuss what you can learn from clinical trials that have been conducted and which are ongoing

https://www.xareltohcp.com/real-world-safety-side-effects-efficacy

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https://clinicaltrials.gov/ct2/results?term=rivaroxaban&Search=Search

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https://www.fda.gov/safety/medwatch/

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BMJ 2016;352:i575 doi: 10.1136/bmj.i575 (Published 3 February 2016)
Page 1 of 4
Feature
FEATURE
INVESTIGATION
Rivaroxaban: can we trust the evidence?
An investigation by The BMJ has uncovered the use of a faulty device in a regulatory drug trial,
potentially putting patients at unnecessary risk, Deborah Cohen reports
Deborah Cohen associate editor, The BMJ
Doctors and scientists are calling for an independent
investigation into the key trial underpinning use of rivaroxaban
to prevent ischaemic stroke in non-valvular atrial fibrillation
after The BMJ found that a defective point of care device was
used in the warfarin arm of the trial.
Doctors and scientists have also told The BMJ that the validity
of the trial—called ROCKET-AF and published in the New
England Journal of Medicine in 20111—is in question until such
independent analysis is done.
The drug was manufactured by Bayer and marketed in the
United States by Janssen, part of Johnson and Johnson, and the
companies relied on a single trial–ROCKET-AF—to gain
approval from the US and European regulators. The trial
included over 14 000 patients and found that rivaroxaban was
non-inferior to warfarin for preventing ischaemic stroke or
systemic embolism. There was no significant difference between
groups in the risk of major bleeding—although intracranial and
fatal bleeding occurred less often in the rivaroxaban group.
But there are now concerns about these outcomes. In a letter
submitted to the NEJM (as yet unpublished) and shown to The
BMJ, former FDA cardiovascular and renal drug reviewer,
Thomas Marcinicak, says: “The care for the warfarin control
arm patients [in ROCKET-AF] appears to have been
compromised.”
Earlier last year, The BMJ found that the point of care device
used to measure international normalised ratio (INR) in patients
taking warfarin in ROCKET-AF had been recalled in December
2014. An FDA class I recall notice (the most serious kind) said
that certain INR devices could deliver results that were
“clinically significantly lower” than a laboratory method. It
added that Alere—the device manufacturer—had received 18
924 reports of malfunctions, including 14 serious injuries. The
company confirmed to The BMJ that the fault went back to
2002, before the ROCKET-AF trial started.
A falsely low reading could mean that patients had their warfarin
dose unnecessarily increased, leading to a greater risk of
bleeding. In terms of the trial results, it could make rivaroxaban
seem safer than it was in terms of the risk of bleeding and throws
doubt on outcomes used to support the use of the world’s best
selling new oral anticoagulant.2
Back in September 2015, The BMJ asked the investigators
named in the NEJM paper about the recall. They included
researchers from Bayer, Johnson and Johnson, and the Duke
Clinical Research Institute, which carried out the trial on behalf
of the drug companies.
None of the authors responded, but a spokesperson for Johnson
and Johnson contacted The BMJ to say that they were “unaware
of this recall” and they took the journal’s concerns “seriously.”
But it took months of probing by The BMJ before the companies,
world drug regulators, and Duke began to investigate the
problem in earnest.
Joining the dots
As for the regulators, when The BMJ contacted the European
Medicines Agency in April 2015 and subsequently the Food
and Drug Administration, both said they did not know that the
recalled device had been used in ROCKET-AF. It’s new territory
for the regulators. What happens to a pivotal drug trial when a
device used is found to be defective?
In November the EMA told The BMJ it was investigating, and
the agency subsequently told journalists: “Due to the defect it
is now thought that the INR device may have impacted the
clotting results in some patients in the warfarin group.”4
Executive director of EMA, Guido Rasi, also called for further
independent investigation into direct oral anticoagulants. “It
would be nice to have some independent study carried out to
give confidence in the use of this medicine,” he said.
The FDA also told The BMJ that it is “aware of concerns
regarding the INR device and its use in the ROCKET-AF trial
and is reviewing relevant data.” It subsequently announced that
it will hold a public workshop about the safety and
effectiveness” of point of care INR devices in March “to seek
and identify potential solutions” to what it said were “scientific
and regulatory challenges.”
However, in the meantime spokespeople for Johnson and
Johnson and Bayer issued identical statements in December
2015: “We have conducted a number of sensitivity analyses.
dcohen@bmj.com
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BMJ 2016;352:i575 doi: 10.1136/bmj.i575 (Published 3 February 2016)
Page 2 of 4
FEATURE
Direct oral anticoagulants
Rivaroxaban is a factor Xa inhibitor and belongs to a class of medicines known as the direct oral anticoagulants (DOAC), which also
includes dabigatran, apixaban, and edoxaban. They have gained popularity in place of warfarin for the prevention of ischaemic stroke in
non-valvular atrial fibrillation because routine blood monitoring is not required.3
These sensitivity analyses confirm the results of the
ROCKET-AF study and the positive benefit-risk profile of
Xarelto (rivaroxaban) in patients with non valvular atrial
fibrillation.”
But what should happen amid the uncertainty?
Harlan Krumholz, professor of medicine (cardiology) at Yale
University, says that the NEJM should place an “immediate
expression of concern” on the paper to notify the medical
community.
“The study should be considered of uncertain validity until a
more thorough review can be done,” he says, adding that there
should be “an investigation by an independent group of experts
to quickly determine if there are grounds for retraction.”
Concerns about warfarin control
Even before rivaroxaban was approved in Europe and the US
in 2011 for use in non-valvular atrial fibrillation, regulatory
officials raised concerns about the warfarin control in the
ROCKET-AF trial. Two primary clinical FDA reviewers of the
drug recommended that it should not be approved for the US
market.
“ROCKET provides inadequate information to assess the relative
safety and efficacy of Xarelto in patients whose warfarin
administration can be well-controlled,” they wrote in an FDA
decisional memo—which outlines clinical reviewers’ view on
whether a drug should be approved.5
However, they were seemingly unaware that there are other
reasons to be concerned about the adequacy of the warfarin
control in the ROCKET-AF trial that have since emerged.
Lack of transparency over devices in trials
Currently, there is little public information about which
diagnostic point of care devices are used in any of the direct
oral anticoagulant trials (box). They are not named in the
published phase III trials. The BMJ became aware that the
problematic device was used in the ROCKET-AF trial only by
reviewing European regulatory documents in April last year.
Marciniak says that the NEJM, which published the trials for
three of the direct oral anticoagulants, should rectify that.
“You should require that the devices used in trials are clearly
and specifically identified in your publications,” he wrote in his
letter.
How has this come to happen?
In tracking the faulty recall and its potential effect on the
outcomes of a global clinical trial, The BMJ has once again
come across flaws in device regulation. A series of journal
investigations have highlighted the lack of clinical data required
by US and Europe regulators for high risk implants, such as
metal on metal hips, before they are put on the market.8 They
have also shown how slow regulators can be to act when
problems do emerge and shown how oversight can be lacking
on the performance diagnostic tests.9 10
In 2005, a warning letter from the FDA to HemoSense—the
company that marketed the faulty device before Alere bought
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it—reprimanded them for failing to investigate “clinically
significant erroneous” high and low INR results generated by
the point of care device.
“Both high and low test [INR] results have the potential to cause
or contribute to a death or serious injury, because: they may
result in erroneous dosing and thus improper control of
coagulation,” the letter said.11
Despite these warning letters, the FDA cleared subsequent
iterations of the device through its 510(k) regulatory system.
This system requires makers of such devices to show only that
the new version is “substantially equivalent,” or similar, to one
already on the market. It has been criticised by the likes of the
Institute of Medicine for not providing enough evidence that a
device is safe and effective.12
Johnson and Johnson, however, has lobbied against tightening
up this aspect of device regulation and the need to provide more
evidence.13 But the lack of a regulatory requirement for the
diagnostic accuracy of the device to be checked before it came
on to the market has allowed the fault to creep through the
system.
Alere has confirmed to The BMJ that the fault dates back to
2002 and it may occur in all devices and not just one batch.
However, neither it nor the FDA responded to questions about
why nothing had been done about the problem earlier.
Were the companies aware of any
problems during the trial?
The BMJ asked Johnson and Johnson, Bayer, and Duke if any
investigator complained to them about mismatched point of
care and laboratory INR readings if someone had a bleed in the
trial. The BMJ also asked if they had validated the device at any
point before or during the trial. None responded to the questions.
According to former FDA clinical pharmacologist, Bob Powell,
who has also worked with industry and academia, the specificity
and reproducibility of a diagnostic test or assay is vital to the
performance of a trial.
“The fact that this was apparently not previously done nor
reported in the primary publication is concerning as this is a
basic principle in drug development,” he says.
What next?
The EMA has told The BMJ that it has asked the companies for
analyses and would consider any analyses by Duke too. During
the trial INR at 12 and 24 weeks was measured at a central
laboratory as well as with the point of care device. Powell says
that “a comparison should be made between the defective point
of care readings and the two sets of ‘gold standard’ central lab
readings” as this would “determine whether this defective device
undermined the integrity of the trial results.”
It is not clear that this has happened. In December last year,
Duke issued a press release with a summary report of the results
of their “secondary analysis of the trial findings.”
“The findings from the analysis are consistent with the results
from the original trial and do not alter the conclusions of
ROCKET-AF—rivaroxaban is a reasonable alternative to
warfarin and is non-inferior for the prevention of stroke and
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BMJ 2016;352:i575 doi: 10.1136/bmj.i575 (Published 3 February 2016)
Page 3 of 4
FEATURE
Devices used in other trials
Given the lack of publicly available information about the point of care testing devices used in the other direct oral anticoagulant trials, The
BMJ sought to find out what they are.
Lars Wallentin, corresponding author of the phase III ARISTOTLE trial (Apixaban versus Warfarin in Patients with Atrial Fibrillation)6 said
that the trials used the ProTime POC device made by International Technidyne Corporation, Edison, NJ, USA.
Daiichi-Sankyo, the manufacturers of edoxaban, also said that the ProTime POC device was supplied to all study sites in the Edoxaban
versus Warfarin in Patients with Atrial Fibrillation Trial (ENGAGE AF)7 and in its venous thromboembolism trial.
systemic embolism with less intracranial hemorrhage and fatal
bleeding” it said.
But Powell says this statement is “misleading” because of the
lack of information.
Krumholz also thinks that this statement did not give enough
information about what Duke found in terms of the major safety
endpoint—major bleeds.
“The DCRI is among the most respected research institutions,
but this statement suggests that they know important information
that relates to the ROCKET-AF trial but are delaying in
disseminating the information until it can be published,” he
says.
Hugo ten Cate, medical director of the Maastricht thrombosis
anticoagulation clinic and coeditor in chief of Thrombosis
Journal, says that major bleeds have serious consequences.
“Large bleeds mostly occur in the gastrointestinal tract and can
be lethal if substantial blood loss occurs, especially in elderly
subjects with comorbidity; this can be a devastating
complication,” he says.
Any changes to the ROCKET-AF trial will have a broader effect
on the literature.
Carl Heneghan is an author on a forthcoming Cochrane
Collaboration review of “direct thrombin inhibitors and factor
Xa inhibitors for atrial fibrillation,” which includes the
ROCKET trial.
He has written to Duke to ask if the results for the main outcome
measures in the reanalysis are the same as in the original
published paper and, if not, what the differences are after the
reanalysis.
A spokesperson for Duke did not answer the question but said
that the ROCKET-AF executive committee “intends to publish
a full description of its analysis as rapidly as possible.”
Independent oversight
But given the lack of clarity over the outcomes and the methods
used, is a reanalysis by Duke enough?
Marciniak is unequivocal. He says that he would not rely on
any reanalyses done by Duke, Johnson and Johnson, or the FDA.
“Because they already missed the problems both in the trial and
with the public marketing, I would not trust them to publish
anything that is accurate—or that provides any details,” he told
The BMJ.
He added that the datasets need to be released as “the only
solution that would lead to unbiased analyses.”
But previous attempts to do this have been thwarted.
Krumholz has approached Johnson and Johnson for access to
the trial data. His Yale University Open Data Access (YODA)
project has an agreement with Johnson and Johnson to make
all of the clinical trial data available for its approved products.
However, although the company agreed to allow access to the
data, Bayer refused.
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“This is an ideal situation for data sharing. The evaluation of
the data in this trial should not go on behind the curtain. And it
seems imprudent to allow those who conducted the trial to be
the only ones who can touch the data,” Krumholz says.
But it doesn’t look like the data release is going to be sanctioned
by Bayer any time soon. A spokesperson for the company told
The BMJ that this is because they have signed up to sharing
information only on “study reports for new medicines approved
in the US and the EU after January 1, 2014.”
The request does not fit in their “current scope of clinical trial
data sharing.”
Good outcome for patients?
But in the end might this series of errors lead to a favourable
outcome for the regulators—and perhaps patients?
At the end of 2015, both the EMA and the FDA held meetings
to discuss the need to measure blood levels of direct oral
anticoagulants and adjust the dose accordingly to maximise
benefit and minimise harm—despite all the manufacturers
claiming that this is not necessary. The meetings were held after
The BMJ revealed that Boerhinger Ingelheim, manufacturers
of dabigatran, withheld analyses from the regulators that showed
how many major bleeds could be prevented by monitoring
anticoagulant activity and adjusting the dose.14
A presentation to EMA last year by Robert Temple, deputy
director for clinical science at the FDA’s Center for Drug
Evaluation and Research, suggests that the FDA believes there
is a scientific argument for measuring the blood levels of these
drugs and adjusting the dose.
“Being too low leads to a stroke, a very bad outcome, and being
too high leads to major bleeds, also bad, so that early
optimization [of the dose] seems worthwhile,” he said adding
that direct oral anticoagulants are “very good, but could probably
be better.”
But once a drug is on the market, regulators lack a mandate to
act unless there are safety concerns. However, according to
Powell, depending on the outcomes of any reanalysis of the
ROCKET-AF trial, this might allow them to take action.
“After a drug is approved, it usually takes a safety signal to
prompt significant action on the part of the FDA. It is this lack
of safety signal that appears to be hindering the FDA in their
desire to pursue tailored dosing for DOACs. If it turns out that
the issue with the [INR] device changes the safety profile of
rivaroxaban, this may constitute the safety signal necessary for
the FDA to act in this regard,” he said.
Competing interests: I have read and understood BMJ policy on
declaration of interests and have no relevant interests to declare.
Provenance and peer review: Commissioned; externally peer reviewed.
1
2
3
Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial
fibrillation. N Engl J Med 2011;365:883-91.
Top 50 pharmaceutical products by global sales. www.pmlive.com/top_pharma_list/Top_
50_pharmaceutical_products_by_global_sales.
Cohen D. Concerns over data in key dabigatran trial. BMJ 2014;349:g4670.
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BMJ 2016;352:i575 doi: 10.1136/bmj.i575 (Published 3 February 2016)
Page 4 of 4
FEATURE
4
5
6
7
8
9
10
Burger l. Trial for Bayer drug Xarelto under scrutiny over defective device. Reuters 2015
Dec 9.www.reuters.com/article/us-bayer-xarelto-idUSKBN0TR2DU20151209#
c4qYKB7bEseov2Fl.97.
FDA. Drug approval package Xarelto. 2015. www.accessdata.fda.gov/drugsatfda_docs/
nda/2011/202439toc.cfm.
Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients with
atrial fibrillation. N Engl J Med 2011;365:981-92.
Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban versus warfarin in patients with
atrial fibrillation. N Engl J Med 2013;369:2093-104.
Cohen D. How safe are metal-on-metal hip implants? BMJ 2012;344:e1410. (http://www.
bmj.com/content/346/bmj.f837
Cohen D. How a fake hip showed up failings in European device regulation. BMJ
2012;345:e7090.
Cohen D, Swift G. Laboratories and regulator misled over antibiotic susceptibility test
discs. BMJ 2013;346:f837.
For personal use only: See rights and reprints http://www.bmj.com/permissions
11
12
13
14
FDA. Warning letter. HemoSense Corporation, 4 Oct 2005. .www.fda.gov/ICECI/
EnforcementActions/WarningLetters/2005/ucm075594.htm
Meier B. Study faults approval process for medical devices. N Y Times 2011 Jul 29. www.
nytimes.com/2011/07/30/business/study-calls-approval-process-for-medical-devicesflawed.html?_r=0.
Mundy A. Firms warn of delays from FDA scrutiny. Wall Street J 2009 Sep 30. www.wsj.
com/articles/SB125426793950751021.
Cohen D. Dabigatran: how the drug company withheld important analyses. BMJ
2014;349:g4670.
Cite this as: BMJ 2016;352:i575
© BMJ Publishing Group Ltd 2016
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Clinical Therapeutics/Volume 40, Number 12, 2018
Review
A Review of the Efficacy and Safety Profiles of the
Novel Oral Anticoagulants in the Treatment and
Prevention of Venous Thromboembolism
Alexis A. Coulis, MS; and William C. Mackey, MD
Tufts University School of Medicine, Boston, MA, USA
ABSTRACT
Purpose: This study aims to review the published
literature concerning the use of novel oral anticoagulants
(NOACs) in the treatment and prevention of venous
thromboembolism (VTE) and to identify the appropriate
niche for each NOAC by comparing their behaviors in
Phase III and Phase IV clinical trial settings.
Methods: The ClinicalTrials.gov database was used to
identify Phase III and postmarketing (Phase IV)
randomized controlled trials concerning the efficacy and
safety profiles of the oral NOACs (apixaban, dabigatran
etexilate, exodaban, and rivaroxaban) for the treatment
or prevention of VTE. Studies of special interest included
those that compared the administration of a NOAC
versus standard anticoagulation therapy with lowmolecular-weight heparin and/or a vitamin K antagonist.
Findings: Overall, the NOACs offer a simplified
anticoagulation regimen that has noninferiority and
similar rates of bleeding when compared with standard
therapy throughout multiple studies. This finding held
true across several VTE conditions that required
anticoagulation, such as the treatment and prophylaxis
of acute VTE, including both deep vein thrombosis and
pulmonary embolism. Absence of dietary restrictions
and fixed oral dosing that does not require monitoring
makes NOACs ideal for the outpatient setting. Apparent
niches for each individual NOAC are discussed in detail;
however, the paucity of trials comparing NOAC
performance in specific clinical settings makes precise
definition of these niches problematic.
Implications: It now seems reasonable for clinicians
to consider NOACs as first-line agents for both the
treatment and prophylaxis of VTE and to attempt to
tailor their particular medication choices for each
patient scenario. More trials comparing NOAC
performance in specific clinical settings are essential to
2140
ensure these medications are being used to their full
potential. (Clin Ther. 2018;40:2140e2167) © 2018
Elsevier Inc. All rights reserved.
Keywords: NOACS, novel oral anticoagulants,
venous thromboembolism, VTE.
INTRODUCTION
Venous thromboembolism (VTE) is the third most
prevalent vascular diagnosis after myocardial infarction
and stroke. It is estimated to affect 300,000 to 600,000
persons in the United States each year.1 Deep vein
thrombosis (DVT) and pulmonary embolism (PE) are
the 2 acute manifestations of VTE. The mainstay of
treatment and prophylaxis of VTEdanticoagulation
therapydworks to inhibit blood clotting, lowering the
risks of DVT or PE. An overview of the coagulation
cascade and the antithrombotic therapy targets are
illustrated in Figure 1.
Conventional anticoagulants include heparin, a
naturally occurring anticoagulant produced by
basophils and mast cells that works by activating
antithrombin, an inhibitor of thrombin formation.
Unfractionated heparin (UFH), the pharmaceutical
version of heparin, contains polysaccharide molecular
chains of varying lengths. Low-molecular-weight
heparin (LMWH), commonly enoxaparin sodium,* is
®
* Trademark: Lovenox
Bridgewater, New Jersey).
(sanofi-aventis U.S., LLC,
Accepted for publication October 9, 2018
https://doi.org/10.1016/j.clinthera.2018.10.009
0149-2918/$ – see front matter
© 2018 Elsevier Inc. All rights reserved.
Volume 40 Number 12
December 2018
Coagulation Cascade and Antithrombotic Therapy Targets. Warfarin inhibits the synthesis of Vitamin K-dependent clotting factors
including FII (Prothrombin), FVII, FIX (not pictured), and FX. Direct Thrombin Inhibitors including Dabigatran inhibit FIIa (Thrombin).
Direct Factor Xa Inhibitors including Apixaban, Edoxaban, and Rivaroxaban inhibit FXa. Heparins facilitate the physiological anticoagulant Antithrombin (AT). Low Molecular Weight Heparin (LMWH) and Fondaparinux preferentially work through AT’s inhibition of
FXa while Unfractionated Heparin (UFH) preferentially works through AT’s inhibition of FIIa (Thrombin). Working to disrupt platelet
aggregation, Aspirin inhibits the generation of TxA2 while Clipidogrel inhibits the ADP receptor P2Y12.
2141
A.A. Coulis and W.C. Mackey
Figure 1.
Clinical Therapeutics
a further modified version of heparin that has
undergone fractionation to sequester only short-chain
polysaccharides. This helps to increase its
pharmacodynamic
predictability.
LMWH
preferentially works to activate antithrombin’s
inhibition of clotting factor Xa. Fondaparinux
sodiumy is a synthetic pentasaccharide factor Xa
inhibitor that also binds antithrombin but instead
accelerates its inhibition of thrombin. UFH, LMWH,
and fondaparinux must be administered by injection.
The effects of UFH and LMWH can be reversed with
protamine sulfate, a medication that binds to these
agents and inhibits their anticoagulant activity.
A second major class of conventional anticoagulants
includes the vitamin K antagonists (VKAs), most
notably warfarin.z By inhibiting the vitamin
Kedependent synthesis of several clotting factors,
VKAs effectively decrease patients’ coagulation
activity. Although given orally, and therefore easily
administered to outpatients, VKAs have a narrow
therapeutic window and require regular blood tests to
monitor their therapeutic effect. Prothrombin time and
the international normalized ratio (INR) are 2 values
obtained to ensure correct dosing. Failure to properly
monitor blood clotting parameters could result in
subtherapeutic anticoagulation, risking thrombus
propagation, or a supratherapeutic effect that
increases the risk of major bleeding. In addition,
because the effectiveness of VKAs is a direct result of
their ability to inhibit a vitamin Kedependent
pathway, this therapy is extremely sensitive to dietary
intake of vitamin K. Patients undergoing anticoagulant
treatment with VKAs must work daily to regulate their
diet to ensure their medication remains in a
therapeutic range. Although this often complicates
patients’ daily eating habits, one clinical benefit is
vitamin K’s ability to reverse VKA anticoagulation in
the event of major bleeding or VKA overdose.
Although these anticoagulation regimens have been
used in clinical practice for many years, they have
numerous limitations. Characteristics of an ideal
anticoagulant include a simple dosing regimen with a
y Trademark: Arixtra
United Kingdom).
®
(GlaxoSmithKline, Brentford,
®
z Trademark: Coumadin
York, New York).
2142
(Bristol-Myers-Squibb, New
wide therapeutic window that eliminates the need for
frequent clinical monitoring, easy oral administration,
minimal food and drug interactions, and the availability
of an antidote that quickly and effectively reverses
anticoagulation. Recently, pharmaceutical companies
developed novel oral anticoagulants (NOACs) with
many of these attributes.
Three of the 4, apixaban,x edoxaban,jj and
rivaroxaban,¶ are direct factor Xa inhibitors. Although
the heparins achieve anticoagulation by increasing
antithrombin’s inhibition of factor Xa, these
medications inhibit factor Xa directly. The fourth
NOAC, dabigatran etexilate,# is the prodrug of
dabigatran, which is a direct thrombin inhibitor.
Taken once or twice daily at fixed oral doses, these 4
medications are approved by the US Food and Drug
Administration (FDA) for a variety of anticoagulant
regimens in the treatment and prophylaxis of VTE as
well as in the prevention of stroke and systemic
embolism in adults with nonvalvular atrial fibrillation.
Figure 2 describes the current FDA dosing and
administration recommendations regarding NOAC
anticoagulation therapy for clinical conditions related
to VTE.
Benefits of anticoagulation with the NOACs include
ease of their oral administration, fewer drug and
dietary interactions, and predictable pharmacokinetic
properties that do not require clinical monitoring (see
Table I for a full comparison of anticoagulation
regimens). However, because less is known about
these newer medications and there is limited research
to speak to their behavior in clinical practice, efficacy
and complication rates in comparison with
traditional VKA or heparin therapies are of major
interest. Although these drugs have great promise,
further investigation is needed to firmly establish
their place in clinical practice and define the optimal
role(s) for each of the 4 agents.
®
x Trademark: Eliquis (Bristol-Myers-Squibb, New York,
New York).
®
jj Trademark: Savaysa (Daiichi Sankyo Co, Ltd, Tokyo,
Japan).
®
¶ Trademark: Xarelto (Janssen Pharmaceuticals Inc,
Raritan, New Jersey) .
®
# Trademark: Pradaxa (Boehringer Ingelheim Pharmaceuticals, Inc, Ingelheim am Rhein, Germany).
Volume 40 Number 12
December 2018
2143
A.A. Coulis and W.C. Mackey
Figure 2. Anticoagulation Regimens in Treatment and/or Prevention of VTE. Regimens are according to the FDA prescribing recommendations in
the United States. Of note, Edoxaban is not currently approved by the FDA for the extended treatment of VTE or prophylactic treatment
following Total Knee or Hip Arthroplasties (TKA/THA). Additionally, Dabigatran Etexilate is not approved by the FDA for prophylactic
treatment following a TKA. *Reduced 30mg dose is intended for patients with CRCL 15-50 mL/min, body weight £60kg, or those
taking concomitant P-gp inhibitors. **Reduced 2.5mg dose is intended for patients with at least 2 of the following characteristics: age
80, body weight £60kg, or serum creatinine 1.5 mg/dL.
Clinical Therapeutics
Table I.
Comparison of anticoagulants.
Variable
Heparins
Administration
Dosing
Food-drug
interactions
Reversal agent
Clinical
reliability
Vitamin K Antagonists
Novel Oral
Anticoagulants
Parenteral (intravenous or
Oral
Oral
subcutaneous)
Wide therapeutic
Dose adjusted to INR 2.0e3.0
Dose adjusted to INR 2.0e3.0
window and
requiring frequent monitoring
requiring frequent monitoring
because of a narrow therapeutic because of a narrow therapeutic predictable dose
response allows for
window and varied dose
window and varied dose
fixed dosing
response
response
Low potential for drug
Fewer drug interactions
Many drug interactions and
interactions and
directly affected by foods rich
unaffected by diet
in vitamin K
Protamine sulfate
Vitamin K
Andexanet alfa,*
idarucizumaby
Reliably used for years in clinical Reliably used for years in clinical Short history of clinical
practice
practice
use
INR ¼ international normalized ratio.
* Antidote for factor Xa inhibitors, approved by the US Food and Drug Administration in 2018 as a reversal agent for apixaban
and rivaroxaban.
y
Antidote for direct thrombin inhibitors, approved by the US Food and Drug Administration in 2015 as a reversal agent for
dabigatran etexilate.
METHODS
The ClinicalTrials.gov database was used to identify
published Phase III and postmarketing (Phase IV)
randomized controlled trials concerning the efficacy
and safety profiles of the oral NOACs (apixaban,
dabigatran etexilate, edoxaban, and rivaroxaban).
Each of these primary sources was subsequently
reviewed for their results concerning the treatment or
prevention of VTE. This process excluded active trials
that were not yet published during or after February
2018 and Phase I or Phase II trials. Particular studies
of interest included those that compared the
administration of a NOAC versus standard
anticoagulation therapy with LMWH and/or a VKA.
Additional exclusions included trials focused on the
prevention of stroke or systemic embolism in adults
with atrial fibrillation because this topic was beyond
the scope of the present review. In addition, although
the oral direct thrombin inhibitor ximelagatran** was
evaluated in Phase III clinical trials and was approved
** Trademark: Exanta
United Kingdom).
2144
®
(AstraZeneca, Cambridge,
for use internationally, it was also excluded from this
review because this medication did not gain approval
from the FDA because of concerns regarding
hepatotoxicity. Electronic searches to supplement the
reported data with additional relevant articles were
conducted as needed.
This review aimed to speak to the practical clinical
applications of each of these medications by
comparing their efficacy and safety profiles in Phase
III and Phase IV trial settings. As such, reported data
include the individual trial designs, study outcomes,
and trial authors’ commentary regarding the studied
drug in clinical practice. Specifically, the measured
efficacy end points included VTE progression or
recurrence in treatment studies and incidence of DVT
and PE in prophylaxis studies, whereas rates of
major bleeding and/or clinically relevant nonmajor
(CRNM) bleeding events were primary safety profile
end points.
The Phase III and Phase IV clinical trials, which
constituted most of the reported results, were funded
by the medications’ respective pharmaceutical
companies; however, a formal risk of bias assessment
was not performed.
Volume 40 Number 12
A.A. Coulis and W.C. Mackey
RESULTS
Medication Characteristics
Although the NOACs can be misinterpreted as a
homogeneous group of medications with similar routes
of administration and mechanisms of action, there are
slight variations that could have clinical relevance.
Table II provides an overview of these characteristics,
which are discussed below.
Adverse Effects
In Phase III clinical trials, all 4 NOAC regimens
revealed a relatively low adverse effect profile2e5
Besides bleeding, the only frequently reported significant
adverse effect was dyspepsia associated with dabigatran
etexilate. In clinical study, this affected 3% of patients.2
Drug Interactions
As substrates of the P-glycoprotein (P-gp) transporter,
all 4 NOACs interact with medications, inducing or
Table II.
inhibiting P-gp. Specifically, strong P-gp inhibitors (eg,
antifungals such as ketoconazole as well as the HIV
protease inhibitor ritonavir) increased medication
effect and therefore elevated the risk of bleeding.6e9
For this reason, coadministration of rivaroxaban or
dabigatran etexilate with the aforementioned
medications or other strong P-gp inhibitors is not
recommended.6,8 Conversely, P-gp inducers, such as
the antibiotic rifampicin, or hypericum (commonly
known as St. John’s wort, an herb thought to calm
feelings of anxiety or depression), decrease NOAC
effect and could lead to subtherapeutic levels of
anticoagulation.6e9
In addition, because apixaban, edoxaban, and
rivaroxaban are all metabolized by liver oxidative
pathways, including cytochrome P450 3A4 (CYP3A4),
medications that induce or inhibit this enzyme
will affect these anticoagulants. Including the
anticonvulsants carbamazepine and phenytoin as well
Medication characteristics according to the highlights of prescribing information published by the US
Food and Drug Administration.
Variable
Dosage forms
Adverse effects
Drug
interactions
Contraindicated
patient
populations
Antidote
Apixaban
Tablets: 2.5 and
5 mg
Bleeding
Dabigatran Etexilate
Capsules: 75 and
150 mg
Dyspepsia, bleeding
P-gp inducers
Strong dual
(rifampin), P-gp
inhibitors or
inhibitors
inducers of
(dronedarone,
CYP34A and Psystemic
gp
ketoconazole)
Elderly people
Breastfeeding
mothers,
pregnancy,
severe hepatic
impairment
Andexanet alfa
Idarucizumab
Edoxaban
Rivaroxaban
Tablets: 15, 30, and
Tablets: 10, 15, and
60 mg
20 mg
Bleeding
Rash, abnormal liver
function test results,
anemia, bleeding
Anticoagulants, P-gp
Strong dual inhibitors
inducers (rifampin)
or inducers of
CYP34A and P-gp,
anticoagulants
Breastfeeding mothers, Breastfeeding
mothers, renal
renal impairment,
impairment,
moderate-severe
hepatic impairment
hepatic impairment
Procoagulant agents
(prothrombin
complex,
recombinant factor
VIIa)
Andexanet alfa
CYP34A ¼ cytochrome P450 3A4; P-gp ¼ P-glycoprotein.
December 2018
2145
Clinical Therapeutics
as many of the same medications mentioned above,
coadministration with apixaban, edoxaban, or
rivaroxaban should be avoided.6,7,9 However, because
of its limited hepatic metabolism and primarily renal
elimination, dabigatran etexilate is not significantly
affected by pharmaceuticals that alter CYP3A4
activity.8
Finally, concomitant use of apixaban or rivaroxaban
with other medications that affect hemostasis is not
recommended.6,7 Because both these medications
are intended to be used as a monotherapeutic, singledrug approach to anticoagulation, overlapping
administration with an additional anticoagulant
increases the risk of bleeding. With regard to common
antiplatelet agents, such as aspirin or clopidogrel,yy
although coadministration with apixaban or
rivaroxaban is not specifically contraindicated, FDA
prescribing information in the United States includes a
warning regarding the increased risk of bleeding and
recommends that concomitant use be conducted with
caution.6,7
Specific Populations
Systemic anticoagulation effect increases with
decreasing renal function for all 4 NOACs.6e9 For this
reason, patients with severe renal insufficiency
(creatinine clearance [CLCR] 2 to 14 days before switching to
rivaroxaban) revealed that this patient population
experienced higher rates of major bleeding (1.4% vs
0.7%) and recurrent VTE (2.2% vs 1.4%) than the
original rivaroxaban cohort.17
In addition, all 4 NOACs depicted similar or
lowered bleeding profiles.2e5 Apixaban, however,
was the only NOAC to reveal a clinically relevant
reduction in major bleeding events. Specifically, only
0.6% of patients taking apixaban compared with
1.8% of those receiving conventional therapy
experienced major bleeding (relative risk ¼ 0.31;
95% CI, 0.17e0.55; P < 0.001 for superiority).4 The numerical results from each trial are given in Table III. In their investigations of NOACs versus standard anticoagulation therapy, 2 separate Cochrane reviews spoke to the effectiveness and tolerability of these oral medications for the treatment of acute DVT and PE. In the review concerning DVT, 11 randomized controlled trials in which participants had confirmed DVT were evaluated. Meta-analysis of the 3 studies (n ¼ 7596) concerning the oral direct thrombin inhibitors dabigatran etexilate and ximelagatran found no difference in the rates of recurrent VTE (odds ratio [OR] ¼ 1.12; 95% CI 0.80e1.49) and associated these 2 medications with reduced rates of bleeding (OR ¼ 0.68; 95% CI 0.47e0.98).18 2147 Variable Trial results for the treatment of acute VTE.* Apixaban AMPLIFY4 Dabigatran Etexilate AMPLIFY-J13 RE-COVER2 RE-COVER II14 Edoxaban Hokusai VTE Cancer Trial3 Rivaroxaban EINSTEIN-DVT5 EINSTEIN-PE15 Rivaroxaban 15 mg LMWH or UFH LMWH or UFH for Enoxaparin or UFH Rivaroxaban 15 Apixaban 10 mg Apixaban twice daily for 7 mg twice daily 5e11 days, then for up to 5 days, 10 mg twice for 5e11 days, twice daily for 7 for 7 weeks, then weeks, then then edoxaban then dabigatran dabigatran daily for 7 days, then 5 mg 20 mg/d for 3, 6, 20 mg/d for 3, 6, etexilate 150 mg 60 mg/d (or etexilate days, then twice daily for 6 30 mg/d) for 3e12 or 12 months vs or 12 months vs twice daily for 6 150 mg twice 5 mg twice months vs enoxaparin and months vs warfarin enoxaparin and months vs daily for 6 daily for 6 enoxaparin and VKA VKA warfarin months vs months vs warfarin warfarin UFH and warfarin Edoxaban (n ¼ Dabigatran Dabigatran Apixaban Patients Apixaban Rivaroxaban Rivaroxaban etexilate (n ¼ 40; 22 etexilate (n ¼ 2691; (n ¼ 2419 with (n ¼ 1731 with 4118; 2468 with (n ¼ 1273; 880 (n ¼ 1280; 877 with DVT, 1749 with DVT, PE), enoxaparin DVT), DVT, 1650 with with DVT, 298 18 with PE), with DVT, 270 678 with PE), or VKA enoxaparin or PE), warfarin with PE), with PE), UFH and enoxaparin and (n ¼ 2413 with VKA (n ¼ 1718 (n ¼ 4122; 2453 warfarin warfarin warfarin warfarin PE) with DVT) with DVT, 1669 (n ¼ 2704; 1783 (n ¼ 40; 23 (n ¼ 1266; 869 (n ¼ 1288; 873 with PE) with DVT, 297 with DVT, 271 with DVT, with DVT, 681 with PE) 17 with PE) with PE) with PE) Recurrent VTE Recurrent VTE Recurrent VTE or Recurrent VTE or Recurrent VTE Results Recurrent VTE Recurrent VTE occurred in 2.1% occurred in 2.1% occurred in 3.2% death occurred death occurred occurred in 2.3% occurred in of patients taking in 2.3% of in 2.4% of 0 patients of patients of patients of patients edoxaban and 3.5% taking patients taking patients taking taking taking apixaban taking of those receiving dabigatran dabigatran apixaban and 2.7% of rivaroxaban and rivaroxaban and warfarin etexilate and subjects and etexilate and those taking 1.8% of those 3.0% of those (HR ¼ 0.89; 95% 2.2% of those 2.1% receiving 1 patient enoxaparin and raking taking CI, 0.70e1.13; receiving warfarin taking UFH warfarin (−0.4% enoxaparin or enoxaparin or P < 0.001) warfarin (HR ¼ 1.10; difference in risk; or warfarin VKA (HR ¼ 0.68; VKA (HR ¼ 1.12; (HR ¼ 1.08; 95% 95%, CI 0.65 95% CI, −1.3 to 95% CI, 0.75 95% CI, 0.44 CI, 0.64e1.80; e1.84) 0.4; P < 0.001) e1.68; e1.04; P < 0.001) P ¼ 0.003) P < 0.001) Dosing Clinical Therapeutics 2148 Table III. Volume 40 Number 12 December 2018 Table III. Variable (Continued ) Apixaban AMPLIFY4 Dabigatran Etexilate AMPLIFY-J13 RE-COVER2 RE-COVER II14 Edoxaban Hokusai VTE Cancer Trial3 Rivaroxaban EINSTEIN-DVT5 EINSTEIN-PE15 2149 AMPLIFY ¼ Apixaban for the Initial Management of Pulmonary Embolism and Deep-Vein Thrombosis as First-Line Therapy; AMPLIFY-J ¼ Japanese AMPLIFY; CRNM ¼ clinical relevant nonmajor; DVT ¼ deep vein thrombosis; EINSTEIN-DVT ¼ Oral Direct Factor Xa Inhibitor Rivaroxaban in Patients With Deep Vein Thrombosis; EINSTEIN-PE ¼ Oral Direct Factor Xa Inhibitor Rivaroxaban in Patients With Acute Symptomatic Pulmonary Embolism; HR ¼ hazard ratio; LMWH ¼ low-molecular-weight heparin; PE ¼ pulmonary embolism; RE-COVER ¼ Randomized Trial of Dabigatran Versus Warfarin in the Treatment of Acute Venous Thromboembolism; RR ¼ relative risk; UFH ¼ unfractionated heparin; VKA ¼ vitamin K agonist; VTE ¼ venous thromboembolism. * Major bleeding and clinically relevant nonmajor bleeding were defined according to the International Society on Thrombosis Haemostasis and bleeding scale. LMWH and VKA were dose adjusted to INR of 2.0e3.0. A.A. Coulis and W.C. Mackey Major or CRNM Major bleeding ¼Major bleeding Major or CRNM Major bleeding Major or Major bleeding or CRNM bleeding occurred in 1.2% bleeding occurred occurred in occurred in 0.6% CRNM occurred in 8.1% bleeding in 8.5% of patients 1.6% of patients of patients bleeding of patients occurred in of patients taking edoxaban taking taking occurred in taking apixaban 10.3% of and 10.3% of those taking dabigatran dabigatran 7.5% of and 1.8% of patients rivaroxaban and receiving warfarin etexilate and etexilate and patients those taking 8.1% of those (HR ¼ 0.81; 95% 1.7% of those 1.9% of those taking undergoing rivaroxaban taking CI, 0.71e0.94; receiving receiving apixaban enoxaparin and and 11.4% of enoxaparin or P ¼ 0.004) warfarin warfarin warfarin therapy and 28.2% those taking VKA (HR ¼ 0.69; 95% (HR ¼ 0.82; (RR ¼ 0.31; 95% of those enoxaparin or CI, 0.36e1.32) 95% CI, 0.45 taking UFH CI, 0.17e0.55; VKA e1.48) or warfarin P < 0.001) (HR ¼ 0.90; 95% CI, 0.76 e1.07; P ¼ 0.23) Pooled analysis revealed HRs of 1.09 Pooled analysis revealed HRs of 0.89 for recurrent VTE (95% CI, 0.66 (95% CI, 0.76e1.57) for recurrent e1.19; P < 0.001) and 0.54 for VTE and 0.73 for major bleeding major bleeding (95% CI, 0.37e0.79; (95% CI, 0.48e1.11) P ¼ 0.002) Noninferior Noninferior efficacy Noninferior Noninferior No clinically Noninferior Outcome Noninferior efficacy with a efficacy with a with significantly efficacy with a efficacy with a important efficacy with a potentially potentially less bleeding lowered risk of clinically relevant difference in similar safety improved improved bleeding efficacy with profile reduction in benefit-risk benefit-risk a favorable major bleeding profile profile safety profile Clinical Therapeutics Concerning the oral factor Xa inhibitors apixaban, edoxaban, and rivaroxaban, meta-analysis of 8 studies (n ¼ 16356) found similar rates of recurrent VTE (OR ¼ 0.89; 95% CI, 0.73e1.07) and reduced rates bleeding (OR ¼ 0.84; 95% CI, 0.43e0.76).18 In the review concerning PE, 5 randomized controlled trials in which participants had confirmed PE were evaluated. For direct thrombin inhibitors, analysis of 2 studies (n ¼ 1602) indicated no difference in the effectiveness of dabigatran etexilate or ximelagatran versus standard anticoagulation in the prevention of recurrent VTE (OR ¼ 0.93; 95% CI, 0.52e1.66) or in the number of major bleeding events (OR ¼ 0.50; 95% CI, 0.15e1.68).19 In the analysis of direct factor Xa inhibitors, 3 studies (n ¼ 6295) also indicated no significant difference in the rates of recurrent VTE (OR ¼ 0.85; 95% CI, 0.63e1.15) or major bleeding (OR ¼ 0.97; 95% CI, 0.59e1.62).19 Summarizing their results, the Cochrane review authors concluded that both oral direct thrombin inhibitors and oral factor Xa inhibitors may be tolerable and effective alternatives to conventional anticoagulation for the treatment of both acute DVT and PE.18,19 Subgroup Analysis Subgroup analysis of the Phase III trials investigated whether the results reported above could be generalized to vulnerable populations, specifically patients with active cancer, impaired renal function, or advanced age. Active Cancer Although patients with cancer are at risk for developing VTE, anticoagulant treatment with VKAs in this population is associated with an elevated risk of recurrent VTE and higher rates of bleeding. As such, current guidelines recommend that patients with cancer and VTE be treated with a monotherapy of LMWH for 6 months. However, because a longterm regimen of this subcutaneous injection is extremely inconvenient, many patients with cancer and VTE continue to be treated with VKAs. If NOACs had noninferiority with respect to VKAs in the prevention of recurrent VTE while additionally exhibiting fewer rates of bleeding, these medications could be convenient options for patients with active cancer and VTE who decide against LMWH monotherapy as per current recommendations. On 2150 subgroup analysis for each NOAC regarding its performance in patients with active cancer, these 4 medications remained noninferior to warfarin in the prevention of recurrent VTE and continued to be associated with a lower risk of bleeding (Table IV).20e23 Edoxaban was the only medication to undergo further research to investigate its performance against the recommended long-term LMWH monotherapy. Evaluating the efficacy and tolerability of edoxaban 60 mg/d after a 5-day regimen of LMWH, the Hokusai VTE Cancer trial established edoxaban's noninferiority to LMWH monotherapy in the prevention of recurrent VTE in patients with cancer (12.8% in the edoxaban group compared with 13.5% in the dalteparin group; HR ¼ 0.97; 95% CI, 0.70e1.35; P ¼ 0.006 for noninferiority and P ¼ 0.87 for superiority).24 However, the rate of major bleeding was significantly higher with edoxaban (6.9% in the edoxaban group compared with 4.0% in the dalteparin group; 2.9% difference in risk; 95% CI, 0.1e5.6).24 Impaired Renal Function Because renal function directly affects the rate at which a medication is eliminated from the body, renal impairment could increase NOAC exposure and potentially result in more adverse bleeding events. Acknowledging this, subgroup analyses of renally impaired patients in the RE-COVER II and the Oral Direct Factor Xa Inhibitor Rivaroxaban in Patients With Deep Vein Thrombosis (EINSTEIN-DVT) and in Patients With Acute Symptomatic Pulmonary Embolism (EINSTEIN-PE) studies examined the effect of decreased renal function on dabigatran etexilate's (primarily renal clearance) and rivaroxaban's (both hepatic and renal clearance) efficacy and tolerability compared with the warfarin standard (primarily hepatic clearance). On subgroup analysis of patients taking dabigatran etexilate with mild (CRCL 50e80 mL/min) to moderate (CRCL 30e50 mL/min) renal impairment, decreasing renal function was associated with lowered rates of recurrent VTE. This trend was not reflected in the warfarin group. In both the dabigatran etexilate and warfarin groups, however, the rates of bleeding increased with decreased renal function.25 Similar subgroup analysis of patients taking rivaroxaban revealed slightly different results because decreased renal function was associated with increased rates of recurrent VTE and bleeding for both rivaroxaban and Volume 40 Number 12 A.A. Coulis and W.C. Mackey Table IV. Results of subgroup analysis for patients with active cancer.* Variable Apixaban (AMPLIFY4) Dabigatran Etexilate (RE-COVER II2,14) Edoxaban (Hokusai VTE Cancer Trial3) Rivaroxaban (EINSTEINDVT and EINSTEINPE5,15) Edoxaban (n ¼ 378), Rivaroxaban (n ¼ 354), Dabigatran etexilate Patients Apixaban (n ¼ 88), warfarin (n ¼ 393) enoxaparin or VKA (n ¼ 114), warfarin enoxaparin and (n ¼ 301) (n ¼ 107) warfarin (n ¼ 81) Recurrent VTE occurred Recurrent VTE occurred in Results Recurrent VTE occurred in Recurrent VTE or 5% of patients taking in 4% of patients 3.7% of patients taking related death rivaroxaban and 7% of taking edoxaban and occurred in 5.8% of apixaban and 6.4% of those receiving 7% of those taking those taking enoxaparin patients taking enoxaparin or VKA warfarin (HR ¼ 0.53; or warfarin (RR ¼ 0.56; dabigatran etexilate (HR ¼ 0.67; 95% CI, and 7.4% of patients 95% CI, 0.28e1.00; 95% CI, 0.13e2.37) 0.35e1.30) P ¼ 0.0007) taking warfarin Major and CRNM Major bleeding Major bleeding Major bleeding occurred bleeding occurred in occurred in 3.8% of occurred in 2.3% of in 2% of patients taking 12% of patients taking patients taking patients taking rivaroxaban and 5% of edoxaban and 19% of dabigatran etexilate apixaban patients and those receiving those taking warfarin and 4.6% of those 5.0% of those taking enoxaparin or VKA (HR ¼ 0.64; 95% CI, taking warfarin enoxaparin and (HR ¼ 0.42; 95% CI, 0.45e0.92; P ¼ 0.017) 0.19e0.99) warfarin (RR ¼ 0.45; 95% CI, 0.08e2.46) AMPLIFY ¼ Apixaban for the Initial Management of Pulmonary Embolism and Deep-Vein Thrombosis as First-Line Therapy; CRNM ¼ clinically relevant nonmajor; EINSTEIN-DVT ¼ Oral Direct Factor Xa Inhibitor Rivaroxaban in Patients With Deep Vein Thrombosis; EINSTEIN-PE ¼ Oral Direct Factor Xa Inhibitor Rivaroxaban in Patients With Acute Symptomatic Pulmonary Embolism; HR ¼ hazard ratio; RE-COVER ¼ Randomized Trial of Dabigatran Versus Warfarin in the Treatment of Acute Venous Thromboembolism; RR ¼ relative risk; VKA ¼ vitamin K agonist; VTE ¼ venous thromboembolism. * Major bleeding and CRNM bleeding were defined according to the International Society on Thrombosis Haemostasis bleeding scale. VKA was dose adjusted to international normalized ratio of 2.0e3.0. warfarin.26 In both subgroup analyses, however, the rates of recurrent VTE and bleeding were lower in the NOAC groups than in their warfarin counterparts, maintaining their noninferiority to standard anticoagulation treatment in patients with mild-to-moderate renal impairment (Table V).25,26 Advanced Age In conjunction with the investigations on the effect of renal impairment, subgroup analyses regarding elderly patients (75 years old) were additionally performed for dabigatran etexilate and rivaroxaban. Analysis of the RE-COVER II subgroups revealed no increase in VTE recurrence or bleeding in older (75 years old) versus younger (75 years, CLCR