Download Suggestion from a pharmaceutical company

Dabigatran
Addition to the list
Explanation for addition
Pharmaceutical company suggestion: “Dabigatran is the only novel oral anticoagulant with an approved
reversal agent when specific reversal of the anticoagulant effects of Dabigatran is required for emergency
surgery/urgent procedures or life-threatening or uncontrolled bleeding. The antidote, Praxbind
(idarucizumab), provides immediate, complete and sustained reversal of the anticoagulant effects of
Pradaxa within minutes.
Dabigatran is an oral direct thrombin inhibitor for the prevention of stroke and systemic embolism in
patients with Atrial Fibrillation, and for the treatment of venous thromboembolism events (deep vein
thrombosis [DVT], pulmonary embolism [PE], and prevention of recurrent DVT and PE.”
anticoagulants in Clean Meds Essential Medication List
 warfarin
 rivaroxaban
Note: In August of 2015, the NOAC were reviewed and rivaroxaban was added to the list (weak
recommendation). We are now revisiting that decision based on the antidote. The previous literature
search on NOACs is included at the end of this package. We have also included the results from a recent
network meta-analysis comparing the efficacy and safety of rivaroxaban vs. dabigatran in patients with
atrial fibrillation.
Proietti, M. and G.Y. Lip, Antidotes to non-vitamin K oral anticoagulants: necessary or not? Expert
Opin Pharmacother, 2015. 16(11): p. 1573-6.
Health Canada approved Praxbind™ (idarucizumab) on May 16th, 2016. Other targeted antidotes have not
been approved for use in Canada.
Syed, Y.Y., Idarucizumab: A Review as a Reversal Agent for Dabigatran. Am J Cardiovasc Drugs,
2016. 16(4): p. 297-304.
Idarucizumab is a humanized monoclonal antibody fragment developed as a specific reversal agent for
dabigatran.
Idarucizumab Therapeutic efficacy
In the ongoing, multicentre, prospective, single-arm, phase 3 trial (RE-VERSE AD), a total of 90 patients
were enrolled into 1 of 2 groups: group A patients (n = 51) experienced uncontrolled, life-threatening
bleeding, whereas group B patients (n = 39) required urgent surgery that could not be delayed. Patients
received idarucizumab 5 g intravenously as two 2.5-g per 50-mL bolus infusions. An interim analysis
demonsrated Idarucizumab 5 g reversed dabigatran-induced prolongation of dilute thrombin time (dTT)
and ecarin clotting time (ECT) within minutes. The median maximum percentage reversal was 100 % for
both assays (primary endpoint). After idarucizumab administration, bleeding stopped in 97 % of
evaluable patients in the bleeding cohort within 24 h (median time to cessation of bleeding was 11.4 h),
and the rate of normal intraoperative haemostasis was 92 % in the surgical cohort.”
Yogaratnam, D., et al., Idarucizumab for Reversal of Dabigatran. Ann Pharmacother, 2016
Safety
In the RE-VERSE AD trial, the most frequent AEs were the following: hypokalemia
(7%), delirium (7%), constipation (7%), pyrexia (6%), and pneumonia (7/123, 6%). Thromboembolic
events (3 deep vein thromboses, 2 PEs, 1 ischemic stroke, and 1 non–ST-elevation myocardial infarction)
occurred in 5 patients receiving idarucizumab. None of these patients received antithrombotic therapy at
onset of these events. [3]
Ruff, C.T., R.P. Giugliano, and E.M. Antman, Management of Bleeding With Non-Vitamin K
Antagonist Oral Anticoagulants in the Era of Specific Reversal Agents. Circulation, 2016. 134(3): p.
248-61.
Andexanet Alfa
“Andexanet alfa (andexanet) is a specific reversal agent for direct (apixaban, rivaroxaban, and edoxaban)
and indirect (low-molecular-weight heparins and fondaparinux) FXa inhibitors that act through
antithrombin. It is a modified human recombinant FXa decoy protein that is catalytically inactive.”
“In phase 2 studies, andexanet demonstrated rapid, dose-dependent reversal of anticoagulant effects (antiFXa activity, unbound FXa concentrations, restoration of thrombin potential) in healthy volunteers
administered apixaban, rivaroxaban, or enoxaparin.” In 2 parallel RCTs, Andexanet Alfa were given to
healthy older volunteers 50-75 years of age pretreated with apixaban and rivaroxaban. “Anti-FXa activity
was rapidly (within 2–5 minutes) reduced by 92% to 94% with andexanet bolus in comparison with 18%
to 21% for placebo (P<0.001for both studies)… Similar decreases were observed for unbound plasma
concentrations of apixaban and rivaroxaban. No thrombotic or serious adverse events were reported”
“The ongoing ANNEXA-4 phase 3b to 4 study (http://www.clinicaltrials.gov, NCT02329327) is
evaluating the efficacy and safety of andexanet in patients taking FXa inhibitors with acute major
bleeding. Andexanet has been granted breakthrough therapy designation by the FDA, in which expedited
review is provided for therapies to treat serious or life-threatening conditions, often based on preliminary
clinical evidence demonstrating substantial improvement over other therapies/existing care. The
Prescription Drug User Fee Act date for andexanet is August 17, 2016, which is the target date for the
FDA to complete its review and take action on the application.”
Ciraparantag
Ciraparantag is a small synthetic water-soluble molecule developed as a reversal agent for unfractionated
heparin, low-molecular-weight heparins, fondaparinux, and the oral direct Xa and IIa inhibitors.
“When added to whole blood spiked with rivaroxaban or apixaban from healthy human volunteers,
ciraparantag reversed anti-FXa activity in a dose-dependent fashion… In a phase 1 dose-ranging study in
healthy volunteers (n=80) administered a single dose of edoxaban 60 mg, ciraparantag decreased wholeblood clotting times to within 10% of baseline values within 10 minutes with single intravenous doses of
100 to 300 mg.84 Reversal was sustained for 24 hours.” It was granted the fast track designation by the
FDA but has not been approved.
Literature Review Question: What is the comparative efficacy and safety of rivaroxaban vs. dabigatran
in patients with atrial fibrillation?
Morimoto, T., et al., Comparative efficacy and safety of novel oral anticoagulants in patients with
atrial fibrillation: A network meta-analysis with the adjustment for the possible bias from open label
studies. J Cardiol, 2015. 66(6): p. 466-74.
Objective
This study was designed to compare efficacy and safety among novel oral anticoagulants (NOACs),
Data collection
Network meta-analyses of RCTs in preventing thromboembolic events and major bleeding in patients
with atrial fibrillation, 9 studies were included in the primary analysis.
Endpoints
The primary endpoint was a composite of stroke and systemic embolism. Secondary endpoints included
stroke and myocardial infarction. We included major bleeding as a safety endpoint. Other endpoints of
interest included: all-cause death, ischemic stroke (including stroke of unknown origin), hemorrhagic
stroke, and intracranial hemorrhage.
Results
“Primary composite endpoint (stroke and systemic embolism): All NOACs were found to perform
similarly except for dabigatran 110mg and edoxaban 30mg.” (Figure 3 B, C and F). Higher odds ratio =
worse outcome
“Major bleeding risk was similar between dabigatran 110 mg and 150 mg, and rivaroxaban” (Fig. 4B, C,
and F). Higher odds ratio = worse outcome
“Rivaroxaban was superior in reducing myocardial infarction compared to both dabigatran 110mg and
150mg.” (Figure 6 B, C, F). Higher odds ratio = worse outcome.
“Apixaban and rivaroxaban were found to be superior to dabigatran 110 mg in reducing ischemic stroke
and stroke of unknown origin” Figure not shown here.
LITERATURE PACKAGE FROM AUGUST 2015
Literature Review Question:
What is the efficacy of novel OACs for stroke prevention in atrial fibrillation?
Literature Search:
eCPS – Cardiovascular Disorders: Supraventricular Tachycardia
CPG via CMA - Guidelines for the Management of Atrial Fibrillation
Meta-analysis taken from references of the CPG
Medline: “novel anticoagulants AND atrial fibrillation AND 2014-2015 AND meta-analysis/review”
A major challenge for clinicians in following this recommendation (#5) is that the current reimbursement
systems in Canada are not aligned with it.
Verma, Atul, et al. "2014 focused update of the Canadian Cardiovascular Society guidelines for the
management of atrial fibrillation." Canadian Journal of Cardiology 30.10 (2014): 1114-1130.
Systematic review of stroke prevention in AF (2015)
With the availability of 4 different NOACs as well as the VKAs, physicians now have a choice and can fit
the drug to the patient. Various patient characteristics may influence the initial choice of one drug over
another (Table 4). In the absence of head-to-head clinical trials, clinicians cannot directly compare one
NOAC against another. Nevertheless, regulatory bodies and health economic analyses have performed
indirect comparisons of one agent against another using warfarinas the comparator; such indirect
comparisons (or network metaanalyses) should be interpreted with some caution given heterogeneity in
trial inclusion-exclusion criteria, quality of INR control.73Overall, there are few substantial differences in
efficacy, although 150mg of dabigatran twice daily may offer the greatest potency by reducing both
ischemic and hemorrhagic stroke, and it has a similar risk of major bleeding as warfarin. For safety, the
best bleeding profile is seen with 110 mg of dabigatran twice daily, apixaban, and edoxaban.74-76
Lip, Gregory YH, and Deirdre A. Lane. "Stroke Prevention in Atrial Fibrillation: A Systematic
Review." JAMA 313.19 (2015): 1950-1962.
Guidelines for the Management of Atrial Fibrillation (2014)
Note: OAC – oral anticoagulants, NOAC - novel direct oral anticoagulants
The NOACs apixaban, dabigatran, edoxaban, and rivaroxaban were developed to overcome the major
limitations associated with warfarin and other vitamin K antagonists. All 4 agents have been evaluated in
large, blinded, RCTs involving > 70,000 patients.15-18 The trials of apixaban, dabigatran, and
rivaroxaban were summarized in the 2012 CCS update2 and since then numerous publications have
provided details about interactions with age, time in the therapeutic range, renal dysfunction, and previous
stroke or transient ischemic attack (TIA). Edoxaban, the most recent agent, was compared with warfarin
in the Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in
Myocardial Infarction 48 (ENGAGE AF-TIMI 48) trial.18 There were 21,105 patients (mean CHADS2
score ¼ 2.8) randomized double blind to edoxaban 30 mg once daily, edoxaban 60 mg once daily, or
warfarin. The principal outcome rates (stroke or systemic embolism) were noninferior to warfarin for both
doses of edoxaban and neither dose was superior to warfarin, although there was a trend toward benefit
with the higher dose. Bleeding rates were significantly lower for both doses of edoxaban. Intracranial
bleeding was significantly less with both doses of edoxaban than warfarin.
Each of the NOACs was found to be noninferior to warfarin for the outcome of all stroke or systemic
embolism. None of them caused more major bleeding and all were superior for the outcome of
intracranial hemorrhage. A meta-analysis of the 4 RCTs19 found the following for the higher-dose
regimens vs warfarin: stroke or systemic embolism (RR, 0.81; 95% confidence interval [CI], 0.73-0.91; P
< 0.0001), intracranial hemorrhage (RR, 0.48; 95% CI, 0.39-0.59; P < 0.0001), gastrointestinal bleeding
(RR, 1.25; 95% CI, 1.01-1.55; P ¼ 0.04), all-cause mortality (RR, 0.90; 95% CI, 0.85-0.95; P ¼ 0.0003).
Comparison of the lower-dose regimens with warfarin showed similar rates of stroke or systemic
embolism, significantly less intracranial bleeding, and significantly less mortality. Based on these
observations coupled with greater convenience for patients and physicians, the Guidelines Committee
continues to recommend NOACs over warfarin for nonvalvular AF.
There have been no published trials directly comparing the various NOACs, and it is unlikely that any
will be conducted in the near future. In the absence of any such direct comparative data, the CCS expert
panel discussed the possibility that the balance of efficacy and safety might influence clinicians to choose
one agent over another. Indirect comparisons using appropriate statistical methods have been performed
but their limitations have to be acknowledged.20,21 Differences in baseline populations and in the
designs of the key RCTs affect the ability to make any definitive comparisons between the NOACs. Any
differences in efficacy that might exist among the NOACs, and even the difference in efficacy between
warfarin and each of the NOACs, is very small compared with the reduction of stroke with any OAC
compared with no OAC.
The panel also reviewed the data within various subgroups of patients in the RCTs. It appears that the
benefit-to-risk ratio of dabigatran 150 mg vs warfarin is more favourable among patients aged < 75 years,
but less favourable in those aged 75 years, among whom dabigatran 110 mg is the better choice.22 For
apixaban and rivaroxaban, the balance of efficacy and safety does not differ between patients 75 vs < 75
years. Dabigatran elimination is more dependent on renal clearance, so rivaroxaban and apixaban might
be preferred for estimated glomerular filtration rates (eGFRs) of 30-50 mL/ min/1.73 m2. The initial
publication from the Randomized Evaluation of Long-term Anticoagulation Therapy (RE-LY) trial
showed an excess of myocardial infarction with dabigatran over warfarin but the difference was
insignificant when additional events were considered. Meta-analyses have consistently shown more
myocardial infarction with dabigatran, although less total mortality, but a recent Food and Drug
Administration study showed equivalent rates of myocardial infarction in patients taking dabigatran
compared with patients taking warfarin.23 Gastrointestinal bleeding is more common in patients taking
dabigatran 150 mg twice daily and rivaroxaban vs warfarin. The finding for dabigatran was confirmed by
a large Food and Drug Administration cohort study.23 Patients taking dabigatran also had significantly
more dyspepsia and earlier discontinuation of study
Meta-analysis of NOACs (2014)
Our results show that stroke and systemic embolic events were significantly reduced in patients receiving
new oral anticoagulants. This benefit was mainly driven by substantial protection against haemorrhagic
stroke, which was reduced by half. Conceptually, haemorrhagic stroke is a complication of anticoagulant
treatment even though it is part of the overall efficacy assessment of these drugs. Importantly, overall
intracranial haemorrhage (which includes haemorrhagic stroke) was reduced by roughly half, which
represents a substantial benefit of treatment with new oral anticoagulants. Intracranial haemorrhage is a
feared and often fatal complication of anticoagulant treatment and about one in six first hospital
admissions for this disorder are related to such treatment.26 For the prevention of ischaemic stroke, the
new oral anticoagulants had similar efficacy to warfarin, which itself is very effective in this regard and
reduces ischaemic stroke by two-thirds compared with placebo.27 In general, the new oral anticoagulants
had a favourable safety profile compared with warfarin; however, they were associated with an increase
in gastrointestinal bleeding. They were also associated with a significant reduction in all cause-mortality
compared with warfarin.
Ruff, Christian T., et al. "Comparison of the efficacy and safety of new oral anticoagulants with warfarin
in patients with atrial fibrillation: a meta-analysis of randomised trials." The Lancet 383.9921 (2014):
955-962.
eCPS (2014)
Warfarin and ASA have been used for many years, although ASA is less effective than
warfarin. Apixaban, dabigatran and rivaroxaban are approved for prevention of systemic embolism in
patients with atrial fibrillation (see Table 8). Approval of dabigatran was based largely on the RE-LY
study, which randomized patients to warfarin or dabigatran.17 Dabigatran 150 mg twice a day was
superior to warfarin in preventing stroke and systemic embolism. Rivaroxaban was compared to warfarin
in the ROCKET-AF trial and was found noninferior to warfarin.18 Apixaban was shown to be superior to
ASA in the AVERROES study19 and to warfarin in the ARISTOTLE study.20 CCS guidelines suggest that
when an oral anticoagulant is indicated, most patients should receive apixaban, dabigatran or
rivaroxaban.5 The preference for 1 of the new oral anticoagulants over warfarin is less marked among
patients already receiving warfarin with stable INRs and no bleeding complications. Other factors (e.g.,
cost, renal function) may also influence drug choice.
The combination of clopidogrel and ASA is recommended by the CCS for stroke prevention in low-risk
patients with stable coronary artery disease, acute coronary syndrome or percutaneous coronary
intervention.13 The summary of recommendations for antithrombotic therapy in patients
with atrial fibrillation or atrial flutter and coronary artery disease is shown in Figure 5 - Summary of
Recommendations for Antithrombotic Management in Patients with Coronary Artery Disease .
Table 8: Drug Therapy for Prevention of Systemic Embolism in Patients with Supraventricular
Tachycardia
Class
Drug
Direct Factor apixaban
Xa
Eliquis
Inhibitors
Dose
Usual: 5 mg BID po
If serum creatinine >133
mmoL/L and patient
either >80 y or ≤60 kg:
2.5 mg BID po
Adverse Effects
Bleeding.
Drug Interactions
Contraindicated in combination
with strong inhibitors of both
CYP3A4 and P-gp (e.g.,
itraconazole, ritonavir).
Costa
$$$$
Class
Drug
Dose
Adverse Effects
Costa
Drug Interactions
Direct Factor rivaroxaban 20 mg daily po
Xa
Xarelto
Moderate renal
Inhibitors
impairment (ClCr 30–49
mL/min): 15 mg daily po
Bleeding.
Contraindicated in combination
with strong inhibitors of both
CYP3A4 and P-gp (e.g.,
itraconazole, ritonavir).
Direct
Thrombin
Inhibitors
dabigatran
Pradaxa
Usual: 150 mg BID po
Patients with increased
bleeding risk or >80 y:
110 mg BID po
Bleeding, gastric
intolerance.
Contraindicated in combination
$$$$
with strong inhibitors of P-gp (e.g.,
ketoconazole). Caution with other
drugs acting on P-gp.
Vitamin K
Antagonists
warfarin
Coumadin,
generics
Dose to maintain INR
between 2 and 3
Bleeding, skin necrosis. Many potential interactions.
Contraindicated in
Substrate for CYP2C9 and other
pregnancy.
isoenzymes.
Legend: $ <$10
$$ $10–50
$$$ $50–90
$$$
$
$$$$ $90–130
Cardiovascular Disorders: Supraventricular Tachycardia; David Birnie, MD and Pablo Nery, MD; Date of
revision: May 2014
ODB Formulary
Generic Name
APIXABAN
Brand Name,
Strength & Dosage MFR
Form
Eliquis
2.5mg, 5mg Tab
Xarelto
RIVAROXABAN 10mg, 15mg, 20 mg
Tab
Drug
Benefit
Price
Amount
InterLimited Therapeutic
MOHLTC
changeables Use
Notes
Pays
BQU
1.6000
1.6000
NO
YES
NO
BAH
2.8400
2.8400
NO
YES
NO
DABIGATRAN
ETEXILATE
Pradaxa
110mg, 150mg Cap
BOE
1.6000
1.6000
NO
YES
NO
WARFARIN
Apo-Warfarin
1mg -10mg Tab
APX
0.0674 0.1211
0.0674 0.1211
YES
NO
YES