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{{Short description|Anticoagulant}}
{{Drugbox
{{Drugbox
| Verifiedfields = changed
| Verifiedfields = changed
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<!--Pharmacokinetic data-->
<!--Pharmacokinetic data-->
| bioavailability = 20%
| bioavailability = 20%
| metabolism = to melagatran
| metabolism = to [[melagatran]]
| elimination_half-life = 3–5 hours
| elimination_half-life = 3–5 hours
| excretion = Renal (80%)
| excretion = Renal (80%)
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| StdInChIKey = ZXIBCJHYVWYIKI-PZJWPPBQSA-N
| StdInChIKey = ZXIBCJHYVWYIKI-PZJWPPBQSA-N
}}
}}
'''Ximelagatran''' ('''Exanta''' or '''Exarta''', H 376/95) is an [[anticoagulant]] that has been investigated extensively as a replacement for [[warfarin]]<ref>{{cite journal |vauthors=Hirsh J, O'Donnell M, Eikelboom JW |title=Beyond unfractionated heparin and warfarin: current and future advances |journal=Circulation |volume=116 |issue=5 |pages=552–560 |date=July 2007 |pmid=17664384 |doi=10.1161/CIRCULATIONAHA.106.685974 |url=http://circ.ahajournals.org/cgi/content/full/116/5/552}}</ref> that would overcome the problematic [[Diet (nutrition)|dietary]], [[drug interaction]], and [[therapeutic drug monitoring|monitoring]] issues associated with warfarin therapy. In 2006, its manufacturer [[AstraZeneca]] announced that it would withdraw pending applications for marketing approval after reports of [[hepatotoxicity]] (liver damage) during trials, and discontinue its distribution in countries where the drug had been approved (Germany, Portugal, Sweden, Finland, Norway, Iceland, Austria, Denmark, France, Switzerland, Argentina and Brazil).<ref name="az">{{cite press release
'''Ximelagatran''' ('''Exanta''' or '''Exarta''', H 376/95) is an [[anticoagulant]] that has been investigated extensively as a replacement for [[warfarin]]<ref>{{cite journal | vauthors = Hirsh J, O'Donnell M, Eikelboom JW | title = Beyond unfractionated heparin and warfarin: current and future advances | journal = Circulation | volume = 116 | issue = 5 | pages = 552–560 | date = July 2007 | pmid = 17664384 | doi = 10.1161/CIRCULATIONAHA.106.685974 | doi-access = free }}</ref> that would overcome the problematic [[Diet (nutrition)|dietary]], [[drug interaction]], and [[therapeutic drug monitoring|monitoring]] issues associated with warfarin therapy. In 2006, its manufacturer [[AstraZeneca]] announced that it would withdraw pending applications for marketing approval after reports of [[hepatotoxicity]] (liver damage) during trials, and discontinue its distribution in countries where the drug had been approved (Germany, Portugal, Sweden, Finland, Norway, Iceland, Austria, Denmark, France, Switzerland, Argentina and Brazil).<ref name="az">{{cite press release
|publisher=AstraZeneca |date=February 14, 2006
|publisher=AstraZeneca |date=February 14, 2006
|url=http://www.astrazeneca.com/Media/Press-releases/Article/20060214--AstraZeneca-Decides-to-Withdraw-Exanta
|url=http://www.astrazeneca.com/Media/Press-releases/Article/20060214--AstraZeneca-Decides-to-Withdraw-Exanta
|title=AstraZeneca Decides to Withdraw Exanta
|title=AstraZeneca Decides to Withdraw Exanta
|accessdate=2012-07-16
|access-date=2012-07-16
}}</ref>
}}</ref>


==Method of action==
==Method of action==
Ximelagatran, a [[direct thrombin inhibitor]],<ref name="pmid17319469">{{cite journal |vauthors=Ho SJ, Brighton TA |title=Ximelagatran: direct thrombin inhibitor |journal=Vasc Health Risk Manag |volume=2 |issue=1 |pages=49–58 |year=2006 |pmid=17319469 |pmc=1993972 |doi= 10.2147/vhrm.2006.2.1.49|url=}}</ref> was the first member of this class that can be taken orally. It acts solely by inhibiting the actions of [[thrombin]]. It is taken orally twice daily, and rapidly absorbed by the [[small intestine]]. Ximelagatran is a [[prodrug]], being converted ''[[in vivo]]'' to the active agent '''melagatran'''. This conversion takes place in the liver and many other tissues through [[hydrolysis]] and [[dehydroxylation]] (replacing the [[ethyl group|ethyl]] and [[hydroxyl]] groups with [[hydrogen]]).
Ximelagatran, a [[direct thrombin inhibitor]],<ref name="pmid17319469">{{cite journal | vauthors = Ho SJ, Brighton TA | title = Ximelagatran: direct thrombin inhibitor | journal = Vascular Health and Risk Management | volume = 2 | issue = 1 | pages = 49–58 | year = 2006 | pmid = 17319469 | pmc = 1993972 | doi = 10.2147/vhrm.2006.2.1.49 | doi-access = free }}</ref> was the first member of this class that can be taken orally. It acts solely by inhibiting the actions of [[thrombin]]. It is taken orally twice daily, and rapidly absorbed by the [[small intestine]]. Ximelagatran is a [[prodrug]], being converted ''[[in vivo]]'' to the active agent melagatran. This conversion takes place in the liver and many other tissues through [[hydrolysis]] and [[dehydroxylation]] (replacing the [[ethyl group|ethyl]] and [[hydroxyl]] groups with [[hydrogen]]).

[[File:Ximelagatran activation.svg|thumb|left|upright=1.5|The conversion of ximelagatran to melagatran. This conversion includes [[dealkylation]] and [[dehydroxylation]].]]
{{clear left}}


==Uses==
==Uses==
Ximelagatran was expected to replace [[warfarin]] and sometimes [[aspirin]] and [[heparin]] in many therapeutic settings, including [[deep venous thrombosis]], prevention of secondary venous [[thromboembolism]] and complications of [[atrial fibrillation]] such as stroke. The efficacy of ximelagatran for these indications had been well documented,<ref>{{cite journal | vauthors = Eriksson H, Wåhlander K, Gustafsson D, Welin LT, Frison L, Schulman S | collaboration = THRIVE Investigators | title = A randomized, controlled, dose-guiding study of the oral direct thrombin inhibitor ximelagatran compared with standard therapy for the treatment of acute deep vein thrombosis: THRIVE I | journal = Journal of Thrombosis and Haemostasis | volume = 1 | issue = 1 | pages = 41–47 | date = January 2003 | pmid = 12871538 | doi = 10.1046/j.1538-7836.2003.00034.x | s2cid = 20556829 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Francis CW, Berkowitz SD, Comp PC, Lieberman JR, Ginsberg JS, Paiement G, Peters GR, Roth AW, McElhattan J, Colwell CW | display-authors = 6 | title = Comparison of ximelagatran with warfarin for the prevention of venous thromboembolism after total knee replacement | journal = The New England Journal of Medicine | volume = 349 | issue = 18 | pages = 1703–1712 | date = October 2003 | pmid = 14585938 | doi = 10.1056/NEJMoa035162 | s2cid = 26026547 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Schulman S, Wåhlander K, Lundström T, Clason SB, Eriksson H | title = Secondary prevention of venous thromboembolism with the oral direct thrombin inhibitor ximelagatran | journal = The New England Journal of Medicine | volume = 349 | issue = 18 | pages = 1713–1721 | date = October 2003 | pmid = 14585939 | doi = 10.1056/NEJMoa030104 | doi-access = free }}</ref> except for non valvular atrial fibrillation.
Ximelagatran was expected to replace [[warfarin]] and sometimes [[aspirin]] and [[heparin]] in many therapeutic settings, including [[deep venous thrombosis]], prevention of secondary venous [[thromboembolism]] and complications of [[atrial fibrillation]] such as stroke. The efficacy of ximelagatran for these indications had been well documented,<ref>{{cite journal

| last = Eriksson | first = H
⚫
An advantage, according to early reports by its manufacturer, was that it could be taken orally without any monitoring of its anticoagulant properties. This would have set it apart from [[warfarin]] and [[heparin]], which require monitoring of the [[international normalized ratio]] (INR) and the [[partial thromboplastin time]] (PTT), respectively. A disadvantage recognised early was the absence of an [[antidote]] in case acute bleeding develops, while warfarin can be antagonised by [[prothrombin complex concentrate]] and/or [[vitamin K]] and heparin by [[protamine sulfate]].
|author2=Wahlander K |author3=Gustafsson D |author4=Welin LT |author5=Frison L |author6=Schulman S |author7=THRIVE Investigators
|date=January 2003
| title = A randomized, controlled, dose-guiding study of the oral direct thrombin inhibitor ximelagatran compared with standard therapy for the treatment of acute deep vein thrombosis: THRIVE I
| journal = [[Journal of Thrombosis and Haemostasis]] | volume = 1 | pages = 41&ndash;47
| pmid = 12871538
| doi = 10.1046/j.1538-7836.2003.00034.x
| issue = 1
}}</ref><ref>{{cite journal
|vauthors=Francis CW, Berkowitz SD, Comp PC, Lieberman JR, Ginsberg JS, Paiement G, Peters GR, Roth AW, McElhattan J, Colwell CW Jr, ((EXULT A Study Group))
|date=October 2003
| title = Comparison of ximelagatran with warfarin for the prevention of venous thromboembolism after total knee replacement
| journal = [[New England Journal of Medicine]] | volume = 349 | issue = 18 | pages = 1703&ndash;1712
| pmid = 14585938 | doi = 10.1056/NEJMoa035162
}}</ref><ref>{{cite journal
| last = Schulman | first = S |author2=Wåhlander K |author3=Lundström T |author4=Clason SB |author5=Eriksson H |author6=THRIVE III investigators
|date=October 2003
| title = Secondary prevention of venous thromboembolism with the oral direct thrombin inhibitor ximelagatran
| journal = [[New England Journal of Medicine]]
| volume = 349 | issue = 18 | pages = 1713&ndash;1721 | pmid = 14585939
| doi = 10.1056/NEJMoa030104
}}</ref> except for non valvular atrial fibrillation.


⚫
==Side effects==
⚫
An advantage, according to early reports by its manufacturer, was that it could be taken orally without any monitoring of its anticoagulant properties. This would have set it apart from [[warfarin]] and [[heparin]], which require monitoring of the [[international normalized ratio]] (INR) and the [[partial thromboplastin time]] (PTT), respectively. A disadvantage recognised early was the absence of an [[antidote]] in case acute bleeding develops, while warfarin can be antagonised by [[vitamin K]] and heparin by [[protamine sulfate]].
⚫
Ximelagatran was generally well tolerated in the trial populations, but a small proportion (5–6%) developed elevated [[liver enzyme]] levels, which prompted the [[U.S. Food and Drug Administration|FDA]] to reject an initial application for approval in 2004. The further development was discontinued in 2006 following reports of hepatotoxicity. Subsequent analysis of Phase 2 clinical study data using [[extreme value theory|extreme value modelling]] showed that the elevated [[liver enzyme]] levels observed in Phase 3 clinical studies could have been predicted; if this had been known at the time, it might have affected decisions on future development of the compound.<ref name="Southworth 2014">{{cite journal | vauthors = Southworth H | title = Predicting potential liver toxicity from phase 2 data: a case study with ximelagatran | journal = Statistics in Medicine | volume = 33 | issue = 17 | pages = 2914–2923 | date = July 2014 | pmid = 24623062 | doi = 10.1002/sim.6142 | ref = Southworth 2014 | s2cid = 36324117 }}</ref>


A chemically different but pharmacologically similar substance, [[AZD-0837]], was developed by AstraZeneca for similar indications.<ref name="az" /> It is a prodrug of a potent, competitive, reversible inhibitor of free and fibrin-bound thrombin called [[ARH0637]].<ref name=Ahrens>{{cite journal | vauthors = Ahrens I, Peter K, Lip GY, Bode C | title = Development and clinical applications of novel oral anticoagulants. Part II. Drugs under clinical investigation | journal = Discovery Medicine | volume = 13 | issue = 73 | pages = 445–450 | date = June 2012 | pmid = 22742650 }}</ref> The development of AZD-0837 has been discontinued. Due to a limitation identified in long-term stability of the extended-release AZD-0837 drug product, a follow-up study from ASSURE on stroke prevention in patients with non-valvular atrial fibrillation, was prematurely closed in 2010 after 2 years. There was also a numerically higher mortality against warfarin.<ref>{{cite web|url=http://www.astrazenecaclinicaltrials.com/other-drug-products/in_development_drugs/AZD0837/ |title=AZD0837 |publisher=Astrazenecaclinicaltrials.com |access-date=2012-10-16}}</ref><ref>{{cite web | work = Clinical Study Report Synopsis | publisher = AstraZeneca | date = 21 January 2010 | title = Long-term treatment with the oral direct thrombin inhibitor AZD0837, compared to Vitamin-K antagonists, as stroke prevention in patients with non-valvular atrial fibrillation and one or more risk factors for stroke and systemic embolic events. A 5-year follow-up study study | id = Trial D1250C0004221 | url = http://www.astrazenecaclinicaltrials.com/_mshost800325/content/clinical-trials/resources/pdf/D1250C00042 | archive-url = https://web.archive.org/web/20131110014536/http://www.astrazenecaclinicaltrials.com/_mshost800325/content/clinical-trials/resources/pdf/D1250C00042 | archive-date = 10 November 2013 }}</ref><ref>{{cite journal | vauthors = Eikelboom JW, Weitz JI | title = New anticoagulants | journal = Circulation | volume = 121 | issue = 13 | pages = 1523–1532 | date = April 2010 | pmid = 20368532 | doi = 10.1161/CIRCULATIONAHA.109.853119 | doi-access = free }}</ref> In a Phase 2 trial for AF the mean serum creatinine concentration increased by about 10% from baseline in patients treated with AZD-0837, which returned to baseline after cessation of therapy.<ref name="pmid19690349">{{cite journal | vauthors = Lip GY, Rasmussen LH, Olsson SB, Jensen EC, Persson AL, Eriksson U, Wåhlander KF | title = Oral direct thrombin inhibitor AZD0837 for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation: a randomized dose-guiding, safety, and tolerability study of four doses of AZD0837 vs. vitamin K antagonists | journal = European Heart Journal | volume = 30 | issue = 23 | pages = 2897–2907 | date = December 2009 | pmid = 19690349 | pmc = 2785945 | doi = 10.1093/eurheartj/ehp318 }}</ref>
⚫
==Side-effects==
⚫
Ximelagatran was generally well tolerated in the trial populations, but a small proportion (5-6%) developed elevated [[liver enzyme]] levels, which prompted the [[U.S. Food and Drug Administration|FDA]] to reject an initial application for approval in 2004. The further development was discontinued in 2006 following reports of hepatotoxicity. Subsequent analysis of Phase 2 clinical study data using extreme value modelling (see [[Extreme value theory]]) showed that the elevated [[liver enzyme]] levels observed in Phase 3 clinical studies could have been predicted; if this had been known at the time, it might have affected decisions on future development of the compound.<ref name="Southworth 2014">{{cite journal|last1=Southworth|first1=Harry|title=Predicting potential liver toxicity from phase 2 data: a case study with ximelagatran|journal=Statistics in Medicine|date=30 Jul 2014|volume=33|issue=17|pages=2914–2923|doi=10.1002/sim.6142|url=http://onlinelibrary.wiley.com/doi/10.1002/sim.6142/full|accessdate=6 January 2017|ref=Southworth 2014}}</ref>


⚫
== References ==
According to AstraZeneca, a chemically different but pharmacologically similar substance, AZD0837, is undergoing testing for similar indications.<ref name="az" />
⚫
{{reflist}}


== External links ==
⚫
==References==
* {{cite web | url = https://druginfo.nlm.nih.gov/drugportal/name/ximelagatran | publisher = U.S. National Library of Medicine | work = Drug Information Portal | title = Ximelagatran }}
⚫
{{reflist|2}}


{{Antithrombotics}}
{{Antithrombotics}}
{{AstraZeneca}}
{{AstraZeneca}}
{{Portal bar | Medicine}}


[[Category:Direct thrombin inhibitors]]
[[Category:Direct thrombin inhibitors]]
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[[Category:Prodrugs]]
[[Category:Prodrugs]]
[[Category:Hepatotoxins]]
[[Category:Hepatotoxins]]
[[Category:AstraZeneca]]
[[Category:Drugs developed by AstraZeneca]]
[[Category:Azetidines]]
[[Category:Azetidines]]

Latest revision as of 19:24, 20 December 2023

Ximelagatran
Clinical data
Trade namesExanta
Pregnancy
category
  • Uncategorized
Routes of
administration		Oral (tablets)
ATC code
Legal status
Legal status
  • Withdrawn from market
Pharmacokinetic data
Bioavailability20%
Metabolismto melagatran
Elimination half-life3–5 hours
ExcretionRenal (80%)
Identifiers
  • ethyl 2-[[(1R)-1-cyclohexyl-2-
    [(2S)-2-[[4-(N'-hydroxycarbamimidoyl)
    phenyl]methylcarbamoyl]azetidin-1-yl]-
    2-oxo-ethyl]amino]acetate
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC24H35N5O5
Molar mass473.574 g·mol−1 (429 g/mol after conversion)
3D model (JSmol)
  • O=C(NCc1ccc(C(=N\O)\N)cc1)[C@H]3N(C(=O)[C@H](NCC(=O)OCC)C2CCCCC2)CC3
  • InChI=1S/C24H35N5O5/c1-2-34-20(30)15-26-21(17-6-4-3-5-7-17)24(32)29-13-12-19(29)23(31)27-14-16-8-10-18(11-9-16)22(25)28-33/h8-11,17,19,21,26,33H,2-7,12-15H2,1H3,(H2,25,28)(H,27,31)/t19-,21+/m0/s1 checkY
  • Key:ZXIBCJHYVWYIKI-PZJWPPBQSA-N checkY
 ☒NcheckY (what is this?)  (verify)

Ximelagatran (Exanta or Exarta, H 376/95) is an anticoagulant that has been investigated extensively as a replacement for warfarin[1] that would overcome the problematic dietary, drug interaction, and monitoring issues associated with warfarin therapy. In 2006, its manufacturer AstraZeneca announced that it would withdraw pending applications for marketing approval after reports of hepatotoxicity (liver damage) during trials, and discontinue its distribution in countries where the drug had been approved (Germany, Portugal, Sweden, Finland, Norway, Iceland, Austria, Denmark, France, Switzerland, Argentina and Brazil).[2]

Method of action

[edit]

Ximelagatran, a direct thrombin inhibitor,[3] was the first member of this class that can be taken orally. It acts solely by inhibiting the actions of thrombin. It is taken orally twice daily, and rapidly absorbed by the small intestine. Ximelagatran is a prodrug, being converted in vivo to the active agent melagatran. This conversion takes place in the liver and many other tissues through hydrolysis and dehydroxylation (replacing the ethyl and hydroxyl groups with hydrogen).

The conversion of ximelagatran to melagatran. This conversion includes dealkylation and dehydroxylation.

Uses

[edit]

Ximelagatran was expected to replace warfarin and sometimes aspirin and heparin in many therapeutic settings, including deep venous thrombosis, prevention of secondary venous thromboembolism and complications of atrial fibrillation such as stroke. The efficacy of ximelagatran for these indications had been well documented,[4][5][6] except for non valvular atrial fibrillation.

An advantage, according to early reports by its manufacturer, was that it could be taken orally without any monitoring of its anticoagulant properties. This would have set it apart from warfarin and heparin, which require monitoring of the international normalized ratio (INR) and the partial thromboplastin time (PTT), respectively. A disadvantage recognised early was the absence of an antidote in case acute bleeding develops, while warfarin can be antagonised by prothrombin complex concentrate and/or vitamin K and heparin by protamine sulfate.

Side effects

[edit]

Ximelagatran was generally well tolerated in the trial populations, but a small proportion (5–6%) developed elevated liver enzyme levels, which prompted the FDA to reject an initial application for approval in 2004. The further development was discontinued in 2006 following reports of hepatotoxicity. Subsequent analysis of Phase 2 clinical study data using extreme value modelling showed that the elevated liver enzyme levels observed in Phase 3 clinical studies could have been predicted; if this had been known at the time, it might have affected decisions on future development of the compound.[7]

A chemically different but pharmacologically similar substance, AZD-0837, was developed by AstraZeneca for similar indications.[2] It is a prodrug of a potent, competitive, reversible inhibitor of free and fibrin-bound thrombin called ARH0637.[8] The development of AZD-0837 has been discontinued. Due to a limitation identified in long-term stability of the extended-release AZD-0837 drug product, a follow-up study from ASSURE on stroke prevention in patients with non-valvular atrial fibrillation, was prematurely closed in 2010 after 2 years. There was also a numerically higher mortality against warfarin.[9][10][11] In a Phase 2 trial for AF the mean serum creatinine concentration increased by about 10% from baseline in patients treated with AZD-0837, which returned to baseline after cessation of therapy.[12]

References

[edit]
  1. ^ Hirsh J, O'Donnell M, Eikelboom JW (July 2007). "Beyond unfractionated heparin and warfarin: current and future advances". Circulation. 116 (5): 552–560. doi:10.1161/CIRCULATIONAHA.106.685974. PMID 17664384.
  2. ^ a b "AstraZeneca Decides to Withdraw Exanta" (Press release). AstraZeneca. February 14, 2006. Retrieved 2012-07-16.
  3. ^ Ho SJ, Brighton TA (2006). "Ximelagatran: direct thrombin inhibitor". Vascular Health and Risk Management. 2 (1): 49–58. doi:10.2147/vhrm.2006.2.1.49. PMC 1993972. PMID 17319469.
  4. ^ Eriksson H, Wåhlander K, Gustafsson D, Welin LT, Frison L, Schulman S, et al. (THRIVE Investigators) (January 2003). "A randomized, controlled, dose-guiding study of the oral direct thrombin inhibitor ximelagatran compared with standard therapy for the treatment of acute deep vein thrombosis: THRIVE I". Journal of Thrombosis and Haemostasis. 1 (1): 41–47. doi:10.1046/j.1538-7836.2003.00034.x. PMID 12871538. S2CID 20556829.
  5. ^ Francis CW, Berkowitz SD, Comp PC, Lieberman JR, Ginsberg JS, Paiement G, et al. (October 2003). "Comparison of ximelagatran with warfarin for the prevention of venous thromboembolism after total knee replacement". The New England Journal of Medicine. 349 (18): 1703–1712. doi:10.1056/NEJMoa035162. PMID 14585938. S2CID 26026547.
  6. ^ Schulman S, Wåhlander K, Lundström T, Clason SB, Eriksson H (October 2003). "Secondary prevention of venous thromboembolism with the oral direct thrombin inhibitor ximelagatran". The New England Journal of Medicine. 349 (18): 1713–1721. doi:10.1056/NEJMoa030104. PMID 14585939.
  7. ^ Southworth H (July 2014). "Predicting potential liver toxicity from phase 2 data: a case study with ximelagatran". Statistics in Medicine. 33 (17): 2914–2923. doi:10.1002/sim.6142. PMID 24623062. S2CID 36324117.
  8. ^ Ahrens I, Peter K, Lip GY, Bode C (June 2012). "Development and clinical applications of novel oral anticoagulants. Part II. Drugs under clinical investigation". Discovery Medicine. 13 (73): 445–450. PMID 22742650.
  9. ^ "AZD0837". Astrazenecaclinicaltrials.com. Retrieved 2012-10-16.
  10. ^ "Long-term treatment with the oral direct thrombin inhibitor AZD0837, compared to Vitamin-K antagonists, as stroke prevention in patients with non-valvular atrial fibrillation and one or more risk factors for stroke and systemic embolic events. A 5-year follow-up study study". Clinical Study Report Synopsis. AstraZeneca. 21 January 2010. Trial D1250C0004221. Archived from the original on 10 November 2013.
  11. ^ Eikelboom JW, Weitz JI (April 2010). "New anticoagulants". Circulation. 121 (13): 1523–1532. doi:10.1161/CIRCULATIONAHA.109.853119. PMID 20368532.
  12. ^ Lip GY, Rasmussen LH, Olsson SB, Jensen EC, Persson AL, Eriksson U, Wåhlander KF (December 2009). "Oral direct thrombin inhibitor AZD0837 for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation: a randomized dose-guiding, safety, and tolerability study of four doses of AZD0837 vs. vitamin K antagonists". European Heart Journal. 30 (23): 2897–2907. doi:10.1093/eurheartj/ehp318. PMC 2785945. PMID 19690349.
[edit]
  • "Ximelagatran". Drug Information Portal. U.S. National Library of Medicine.
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