RSC Health New Drug Approval Process Clinical Trial Discussion


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

  • Discuss  real-world safety issues that may  appear after approval and how they might be mitigated
  • What could have been done differently?
  • Students often ask how long I want the assignment to be. I am not going to set a target for that, it really depends on your writing style and what you have to say. I am looking for original thought, not just repeating what you read in the powerpoint. A highly insightful and concise paper can be less than a page, where another might be two or three. I will be looking for structure, grammar and logical thinking.
  • Some web sites that may be helpful include:

    Links to an external site.

    Links to an external site.

    Links to an external site.

  • BMJ 2016;352:i575 doi: 10.1136/bmj.i575 (Published 3 February 2016)
    Page 1 of 4
    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
    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.
    For personal use only: See rights and reprints
    BMJ 2016;352:i575 doi: 10.1136/bmj.i575 (Published 3 February 2016)
    Page 2 of 4
    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
    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
    “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
    “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
    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
    For personal use only: See rights and reprints
    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
    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
    BMJ 2016;352:i575 doi: 10.1136/bmj.i575 (Published 3 February 2016)
    Page 3 of 4
    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
    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
    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.
    For personal use only: See rights and reprints
    “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.
    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.
    Cohen D. Concerns over data in key dabigatran trial. BMJ 2014;349:g4670.
    BMJ 2016;352:i575 doi: 10.1136/bmj.i575 (Published 3 February 2016)
    Page 4 of 4
    Burger l. Trial for Bayer drug Xarelto under scrutiny over defective device. Reuters 2015
    FDA. Drug approval package Xarelto. 2015.
    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.
    Cohen D. How a fake hip showed up failings in European device regulation. BMJ
    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
    FDA. Warning letter. HemoSense Corporation, 4 Oct 2005.
    Meier B. Study faults approval process for medical devices. N Y Times 2011 Jul 29. www.
    Mundy A. Firms warn of delays from FDA scrutiny. Wall Street J 2009 Sep 30. www.wsj.
    Cohen D. Dabigatran: how the drug company withheld important analyses. BMJ
    Cite this as: BMJ 2016;352:i575
    © BMJ Publishing Group Ltd 2016
    Clinical Therapeutics/Volume 40, Number 12, 2018
    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
    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 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
    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.
    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
    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.
    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
    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).
    (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,
    ¶ Trademark: Xarelto (Janssen Pharmaceuticals Inc,
    Raritan, New Jersey) .
    # Trademark: Pradaxa (Boehringer Ingelheim Pharmaceuticals, Inc, Ingelheim am Rhein, Germany).
    Volume 40 Number 12
    December 2018
    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.
    Reversal agent
    Vitamin K Antagonists
    Novel Oral
    Parenteral (intravenous or
    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
    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,*
    Reliably used for years in clinical Reliably used for years in clinical Short history of clinical
    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.
    Antidote for direct thrombin inhibitors, approved by the US Food and Drug Administration in 2015 as a reversal agent for
    dabigatran etexilate.
    The 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).
    (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
    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
    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.
    Dosage forms
    Adverse effects
    Tablets: 2.5 and
    5 mg
    Dabigatran Etexilate
    Capsules: 75 and
    150 mg
    Dyspepsia, bleeding
    P-gp inducers
    Strong dual
    (rifampin), P-gp
    inhibitors or
    inducers of
    CYP34A and Psystemic
    Elderly people
    severe hepatic
    Andexanet alfa
    Tablets: 15, 30, and
    Tablets: 10, 15, and
    60 mg
    20 mg
    Rash, abnormal liver
    function test results,
    anemia, bleeding
    Anticoagulants, P-gp
    Strong dual inhibitors
    inducers (rifampin)
    or inducers of
    CYP34A and P-gp,
    Breastfeeding mothers, Breastfeeding
    mothers, renal
    renal impairment,
    hepatic impairment
    hepatic impairment
    Procoagulant agents
    recombinant factor
    Andexanet alfa
    CYP34A ¼ cytochrome P450 3A4; P-gp ¼ P-glycoprotein.
    December 2018
    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
    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
    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

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