Download Suggestion from clinicians

Dabigatran/Rivaroxaban/Apixaban
Addition to the List
Peer Feedback:
“commonly used in place of Warfain for stroke prevetion in AF”
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”
therapy.
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 causemortality 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
Adverse Effects
Costa
Bleeding.
Contraindicated in combination
with strong inhibitors of both
CYP3A4 and P-gp (e.g.,
itraconazole, ritonavir).
$$$$
Direct Factor rivaroxaban 20 mg daily po
Xa
Xarelto
Moderate renal
Inhibitors
impairment (ClCr 30–49
mL/min): 15 mg daily
po
Bleeding.
Contraindicated in combination
with strong inhibitors of both
CYP3A4 and P-gp (e.g.,
itraconazole, ritonavir).
$$$
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 Pgp.
$$$$
Vitamin K
Antagonists
warfarin
Coumadin,
generics
Dose to maintain INR
between 2 and 3
Bleeding, skin
necrosis.
Contraindicated in
pregnancy.
Many potential interactions.
Substrate for CYP2C9 and other
isoenzymes.
$
Legend:
$ <$10
Usual: 5 mg BID po
If serum creatinine
>133 mmoL/L and
patient either >80 y or
≤60 kg: 2.5 mg BID po
Drug Interactions
$$ $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
Brand Name, Strength &
MFR
Dosage Form
Drug Benefit
Price
Amount
InterLimited Therapeutic
MOHLTC Pays changeables Use
Notes
APIXABAN
Eliquis
2.5mg, 5mg Tab
BQU
1.6000
1.6000
NO
YES
NO
RIVAROXABAN
Xarelto
10mg, 15mg, 20 mg Tab
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
Medication
warfarin
Uses
atrial
Fibrillation,
deep vein
thrombosis,
pulmonary
embolism
Contraindications (CI), drug
interactions (DI) or cautions
CI: pregnancy, active bleeding,
hemorrhagic disorders, previous
warfarin induced skin necrosis,
recent surgery, noncompliant
patients
DI: alcohol, allopurinol, amiodarone,
cimetidine, fibrates, NSAIDs/Coxibs,
phenobarbital, st. john’s
wort
Adverse Effects
(common and
severe)
bleeding, bruising,
nausea, diarrhea,
abdominal
cramping, fever
Initial dose;
typical dose
2mg; 210mg one time a
day
Monitoring
LFTs