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New Anticoagulants for Stroke Prevention in Patients with Atrial Fibrillation

Source agency:

CADTH

Date of Submission:

13/08/2012

Date of Printing:

18/05/2013

Disclaimer:

This report is work in progress and should not be used for external distribution without permission from the originating agency. Users should be aware that reports are based on information available at the time of research and often on a limited literature search.

Technology, Company & Licensing

Technology name:

Dabigatran etexilate (Pradax) rivaroxaban (Xarelto)

Technology - description:

The new anticoagulants dabigatran etexilate (Pradax, Boehringer Ingelheim) and rivaroxaban (Xarelto, Bayer)impact the
coagulation cascade more specifically than do VKAs, with dabigatran being a direct inhibitor of thrombin and rivaroxaban a direct inhibitor of factor Both have a rapid onset of action (peak concentrations in
two to four hours, versus 72 hours for warfarin) and short half-lives (14 to 17 and five to 13 hours respectively, versus 40 hours for warfarin), making management before procedures easier.

Company or developer:

Pradax, Boehringer Ingelheim and rivaroxaban Xarelto, Bayer

Reason for database entry:

Potential alternatives to vitamin K antagonists (VKAs) such as warfarin for stroke prevention in patients
with atrial fibrillation (AF)

Technology - stage in early warning process:

Prioritised for assessment

Technology - stage of development:

Nearly established

Licensing, reimbursement and other approval:

Dabigatran received a Health Canada Notice of
Compliance (NOC) in June 2008, and rivaroxaban in September 2008; both are approved for prevention of VTE after elective total hip or knee replacement
surgery.10,11 They have been considered for public coverage for this indication by the Canadian Expert Drug Advisory Committee, which supported rivaroxaban12 but not dabigatran. Both drugs were approved in 2008 in the European Union for the postsurgical
indication approved in Canada.Neither
drug is yet approved by the Food and Drug
Administration in the United States.

Technology - type(s):

Drug

Technology - use(s):

Therapeutic

Patient Indication & Setting

Patient indications:

In Canada, AF is the most prevalent, sustained cardiac dysrhythmia, affecting 200,000 to 250,000 people. The prevalence of AF rises sharply with age, being 0.2% at age 30 and > 12% at age 75; lifetime risk is about 25%.1,20 AF is estimated to cause up to 15% of all strokes and AF-related strokes are more severe, cause greater disability, and have a worse prognosis than strokes in patients without AF. Patients considered to be at risk of stroke and advised to take
long-term prophylactic VKAs include those with prior ischemic stroke, transient ischemic attack (TIA), or
systemic embolism; or two or more risk factors including age >75 and history of hypertension, diabetes mellitus, moderately or severely impaired left ventricular systolic function, and/or heart failure (with
one risk factor, patients may be advised to use a VKA or aspirin).

Disease description and associated mortality and morbidity:

 

Number of Patients:

 

Technology - specialities(s):

Cardiovascular disease & vascular surgery

Technology - setting(s):

Community and primary care

Setting - further information:

 

Impact

Alternative and/or complementary technology:

 

Current Technology:

The most commonly used VKA in North
America is warfarin, but the related VKAs,
acenocoumarol and phenprocoumon, see some uptake in Europe.

Health Impact:

The drugs do not have the limitations of
VKAs; i.e., narrow therapeutic window,
variable dose-response relationship, slow
onset and offset of action, food and drug
interactions, and the need for regular
laboratory monitoring and dose adjustment
of international normalized ratio (INR).

Diffusion:

 

Cost, infrastructure and economic consequences:

The current price of these drugs is higher
than that of warfarin and laboratory
monitoring, highlighting the need for full
economic evaluations that consider offset
costs due to potential clinical benefits.

Ethical, social, legal, political and cultural impact:

 

Evidence & Policy

Clinical evidence and safety:

Dabigatran: Randomized Evaluation of Longterm
anticoagulant therapY (RE-LY) was a
phase III, industry-sponsored trial (n = 18,113) that randomized patients with AF and at least one risk factor for stroke to dabigatran 110 mg or 150 mg twice daily (b.i.d.), or adjusted-dose warfarin.4,26 Patients were recruited from 951
clinical centres in 44 countries. Half had been on long-term VKA therapy and about 40% on aspirin; continued aspirin use was allowed. The primary efficacy outcome was annual stroke or systemic embolization rate, and median followup was two years. Blinding was applied to dabigatran dose but not to the warfarin group due to the latter’s need for INR monitoring; detection bias is therefore possible.22 The
efficacy of dabigatran 110 mg b.i.d. versus
warfarin was 1.53% versus 1.69% (relative risk [RR] 0.91, 95% confidence interval [CI] 0.74 to 1.11; P < 0.001); i.e., not significantly different.
b.i.d. versus warfarin (1.11% versus 1.69%; RR
0.66, 95% CI 0.53 to 0.82; P < 0.001).4
Number-needed-to-treat (NNT) with dabigatran
150 mg b.i.d. to prevent one non-hemorrhagic
stroke was 357 and NNT to prevent one
hemorrhagic stroke was 370.22 For the warfarin
group, INR was within the therapeutic range
64% of the time. Subsequent calculations
showed that the stroke risk for the dabigatran
150 mg b.i.d. versus warfarin groups would be
similar at TTRs of at least 79%, although this
may not be realistically achievable.22,25 RELYABLE
is a long-term extension of the RE-LY
trial focusing on drug safety, primarily
occurrence of major bleeding.27 Estimated
enrollment is 6,200 patients with expected
completion of data collection in July 2011.
 Rivaroxaban: The ROCKET-AF study is a
phase III, industry-sponsored, randomized,
double-blind, double-dummy trial (n = 14,266)
comparing the efficacy and safety of
rivaroxaban 20 mg once daily to that of
adjusted-dose warfarin in patients with nonvalvular AF and risk factors for stroke.28,29

The study is powered to show non-inferiority
of rivaroxaban versus warfarin for the primaryefficacy end point, the composite of stroke and non-Central Nervous System systemic embolism, followed by a superiority test if non-inferiority for rivaroxaban is
demonstrated.29 Patients were recruited up to
mid-2009 and data collection is expected to
end in May 2010.12,21 Treatment will span a
mean of 18 months with a range of 12 to
> 24 months.30

Economic evaluation:

 

Ongoing research:

 

Ongoing or planned HTA:

 

Web link:

http://www.cadth.ca/media/pdf/R0004_Anticoagulants_Atrial_Fibrillation_cetap_e.pdf

References and sources:

1. Lam J. Clinical guide - stroke prevention in
atrial fibrillation [Internet]. Mississauga (ON):
Thrombosis Interest Group of Canada; 2008. 3 p.
[cited 2009 Feb 18]. Available from:
http://www.tigc.org/pdf/thrombAF2008.pdf
2. Lindsay P, et al. CMAJ [Internet]. 2008 Dec 2
[cited 2009 Feb 19];179(12 Suppl):S1-S25.
Available from:
http://www.pubmedcentral.nih.gov/picrender.fcg
i?artid=2586332&blobtype=pdf
3. Singer DE, et al. Chest. 2008 Jun;133(6
Suppl):546S-92S.
4. Connolly SJ, et al. N Engl J Med. 2009 Sep
17;361(12):1139-51.
5. Zikria J, et al. Discovery medicine [Internet].
2009 Dec;8(43):196-203. Available from:
http://www.discoverymedicine.com/Jennifer-
Zikria/2009/11/17/oral-anticoagulation-withfactor-
xa-and-thrombin-inhibitors-is-there-analternative-
to-warfarin/
6. Garcia D, et al. Blood. 2010 Jan 7;115(1):15-20.
7. Umer Usman MH, et al. J Interv Card
Electrophysiol. 2008 Aug;22(2):129-37.
8. Leung LLK. Anticoagulants other than heparin
and warfarin. 2009 Sep 24 [cited 2010 Jan 11].
In: UpToDate [database on the Internet]. Version
17.3. Waltham (MA): UpToDate; c2005 - .
Available from: http://www.uptodate.com
Subscription required.
9. Gross PL, et al. Arterioscler Thromb Vasc Biol.
2008 Mar;28(3):380-6.
10. Notice of compliance database [Internet].
Ottawa: Health Canada; 1994 -. Notice of
Compliance Information: Pradax; 2008 Jun 10
[cited 2009 Nov 5]. Available from:
http://www.hc-sc.gc.ca/dhpmps/
prodpharma/notices-avis/index-eng.php
11. Notice of compliance database [Internet].
Ottawa: Health Canada; 1994 -. Notice of
Compliance Information: Xarelto; 2008 Sep 15
[cited 2009 Nov 5]. Available from:
http://www.hc-sc.gc.ca/dhpmps/
prodpharma/notices-avis/index-eng.php
12. Common Drug Review. Rivaroxaban (Xarelto -
Bayer, Inc.) [Internet]. Ottawa: Canadian Agency
for Drugs and Technologies in Health; 2008. 3 p.
[cited 2009 Feb 17]. Available from:
http://www.cadth.ca/media/cdr/complete/cdr_xar
elto_complete-dec17-08.pdf
13. Common Drug Review. Dabigatran etexilate
(Pradax - Boehringer Ingelheim Canada Ltd.)
[Internet]. Ottawa: Canadian Agency for Drugs
and Technologies in Health; 2008. 3 p. [cited
2009 Feb 17]. Available from:
http://www.cadth.ca/media/cdr/complete/cdr_co
mplete_Pradax_January-28-2009.pdf
14. Commission of the European Communities.
Commission decision of 18-III-2008 granting
marketing authorisation under Regulation (EC)
no 726/2004 of the European Parliament and of
the Council for "Pradaxa - dabigatran etexilate
mesilate", a medicinal product for human use
[Internet]. Brussels: European Commission;
2008 Mar 18. [cited 2010 Jan 13]. Available
from:
http://ec.europa.eu/enterprise/sectors/pharmaceut
icals/documents/communityregister/
2008/2008040845828/dec_45828_en.pdf
Decision no. C(2008)1180.
15. Commission of the European Communities.
Commission decision of 30.9.2008 granting
marketing authorisation under Regulation (EC)
No 726/2004 of the European Parliament and of
the Council for "Xarelto - rivaroxaban", a
medicinal product for human use [Internet].
Brussels: European Commission; 2008 Sep 30.
[cited 2010 Jan 13]. Available from:
http://ec.europa.eu/enterprise/sectors/pharmaceut
icals/documents/communityregister/
2008/2008093049239/dec_49239_en.pdf
Decision no. C(2008)5680.
16. Drugs@FDA [database on the Internet]. Silver
Spring (MD): U.S. Food and Drug
Administration, Center for Drug Evaluation and
Research; [2004] - [cited 2010 Jan 14]. Available
from:
http://www.accessdata.fda.gov/Scripts/cder/Drug
satFDA/
17. Boehringer Ingelheim. Dabigatran Etexilate:
U.S. Fact Sheet [Internet]. Ridgefield (CT):
Boehringer Ingelheim; 2009. [cited 2010 Jan 11].
Available from:
http://www.bicorporation.com/newsroom/2009/fi
les/dabigatran_factsheet.pdf
The Canadian Agency for Drugs and Technologies in Health (CADTH)
is funded by Canadian federal, provincial, and territorial governments. (www.cadth.ca)
18. Heart and Stroke Foundation of Canada.
Statistics [Internet]. In: News. Ottawa: Heart and
Stroke Foundation of Canada; 2009 [cited 2009
Jan 21]. Available from:
http://www.heartandstroke.com/site/c.ikIQLcM
WJtE/b.3483991/k.34A8/Statistics.htm.
19. Heart and Stroke Foundation of Canada. The
growing burden of heart disease and stroke in
Canada 2003 [Internet]. Ottawa: The
Foundation; 2003 May. [cited 2010 Jan 11].
Available from:
http://www.cvdinfobase.ca/cvdbook/CVD_En03.
pdf Prepared in Collaboration with the Centre for
Chronic Disease Prevention and Control, Health
Canada, the Canadian Cardiovascular Society,
and the Heart and Stroke Foundation of Canada.
20. Humphries KH, et al. Population rates of
hospitalization for atrial fibrillation/flutter in
Canada [Internet]. In: Tu JV, Ghali WA, Pilote
L, Brien S, editors. CCORT Canadian
Cardiovascular Atlas. Oakville (ON): Pulsus
Group; 2006. p. 127-34. Chapter 16 [cited 2010
Jan 11]. Available from:
http://www.ccort.ca/Portals/0/atlas/PDF/16_Hum
phries_20_9_04.pdf.
21. viva.vita international [Internet]. Leverkusen
(DE): Bayer HealthCare AG. Bayer completes
enrollment into major phase III study with
rivaroxaban (ROCKET AF); 2009 [cited 2009
Nov 5]. Available from:
http://www.viva.vita.bayerhealthcare.com/index.
php?id=36&no_cache=1&tx_ttnews%5Btt_news
%5D=13318
22. Gage BF. N Engl J Med [Internet]. 2009 Sep
17;361(12):1200-2. Available from:
http://content.nejm.org/cgi/reprint/361/12/1200.p
df
23. Manning WJ, et al. Antithrombotic therapy to
prevent embolization in nonvalvular atrial
fibrillation. 2009 Oct 16 [cited 2010 Jan 11]. In:
UpToDate [database on the Internet]. Version
17.3. Waltham (MA): UpToDate; c2005 - .
Available from: http://www.uptodate.com
Subscription required.
24. National Horizon Scanning Centre. Dabigatran
etexilate (Pradaxa) for stroke prevention in
atrial fibrillation [Internet]. Birmingham:
University of Birmingham; 2008. [cited 2009
Feb 17]. Available from:
http://www.pcpoh.bham.ac.uk/publichealth/horiz
on/outputs/documents/2008/mayaugust/
Dabigatran_etexilate__Pradaxa__for_stro
ke_prevention.pdf
25. Connolly SJ, et al. Circulation [Internet]. 2008
Nov 11 [cited 2010 Feb 26];118(20):2029-37.
Available from:
http://circ.ahajournals.org/cgi/reprint/118/20/202
9
26. Ezekowitz MD, et al. Am Heart J. 2009
May;157(5):805-10, e1-2.
27. ClinicalTrials.gov [Internet]. Bethesda (MD):
National Library of Medicine (US); 2000 Feb -.
Identifier NCT00808067, RELY-ABLE Long
Term Multi-center Extension of Dabigatran
Treatment in Patients With Atrial Fibrillation
Who Completed RE-LY Trial; 2008 Dec 12
[cited 2010 Jan 11; updated 2009 Dec 8].
Available from:
http://www.clinicaltrials.gov/ct2/show/NCT0080
8067
28. ClinicalTrials.gov [Internet]. Bethesda (MD):
National Library of Medicine (US); 2000 Feb -.
Identifier NCT00403767, Randomized, Double-
Blind Study Comparing Once Daily Oral
Rivaroxaban With Adjusted-Dose Oral Warfarin
for the Prevention of Stroke in Subjects With
Non-Valvular Atrial Fibrillation; 2006 Nov 23
[cited 2010 Jan 11; updated 2009 Nov 6].
Available from:
http://www.clinicaltrials.gov/ct2/show/NCT0040
3767
29. Patel M, et al. P4198: Rationale and design of the
ROCKET AF study: comparison of rivaroxaban
with warfarin for the prevention of stroke and
systemic embolism in patients with atrial
fibrillation [Internet]. Abstract presented at: ESC
Congress 2009 (European Society of
Cardiology). 2010 Aug 29 - Sept 2; Barcelona.
Available from: http://spo.escardio.org/abstractbook/
presentation.aspx?id=69133
30. Bayer Health Care. About rivaroxaban clinical
studies [Internet]. Leverkusen (Germany): Bayer
Schering Pharma AG; 2009. [cited 2010 Jan 11].
Available from:
http://www.xarelto.com/html/press/pdf/About_Ri
varoxaban_Clinical_Studies.pdf
31. Tomoda H. N Engl J Med. 2009 Dec
31;361(27):2671-2. Comment on: N Engl J Med.
2009 Sep 17;361(12):1139-51.
32. Xarelto® [product monograph on the Internet].
Toronto: Bayer; 2008 Sep 10. [cited 2009 Nov
5]. Available from:
http://www.bayer.ca/files/XARELTO-PM-ENG-
10SEP2008-119111.pdf
33. Pradax™ [product monograph on the Internet].
Burlington (ON): Boehringer Ingelheim Canada;
2009 Jul 31. [cited 2009 Nov 5]. Available from:
http://www.boehringeringelheim.
ca/en/Home/Human_Health/Our_Prod
ucts/Product_Monographs/Pradax-pm.pdf
The Canadian Agency for Drugs and Technologies in Health (CADTH)
is funded by Canadian federal, provincial, and territorial governments. (www.cadth.ca)
34. Oldgren J, et al. Randomised dabigatran etexilate
dose finding study in patients with acute
coronary syndromes post index event with
additional risk factors for cardiovascular
compications also receiving aspirin and
clopidogrel: RE-DEEM [slides on the Internet].
Poster presented at: American Heart Association
Scientific Sessions. 2009 Nov 14-18; Orlando
(FL). [cited 2010 Mar 16]. Available from:
http://directnews.americanheart.org/extras/sessio
ns2009/slides/165_pslides.pdf
35. van Ryn J, et al. Dabigatran etexilate - a novel,
reversible, oral direct thrombin inhibitor:
Interpretation of coagulation assays and reversal
of anticoagulant activity. Thromb Haemost.
Forthcoming 2010.
36. Hankey GJ. Curr Opin Neurol. 2010
Feb;23(1):65-72.
37. Camm AJ. Eur Heart J. 2009 Nov;30(21):2554-
5.

Notes: