Anticoagulant: Difference between revisions

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'''Anticoagulants''' are "agents that prevent [[coagulation|blood clotting]]".<ref name="title">{{MeSH|Anticoagulants}}</ref> They may be used to prevent [[embolism and thrombosis]].
'''Anticoagulants''' are "agents that prevent [[coagulation|blood clotting]]".<ref name="title">{{MeSH|Anticoagulants}}</ref> They interfere with [[coagulation]] and may be used to prevent [[embolism and thrombosis]].
 
Anticoagulation is dangerous due to drug toxicity and should be managed in a systematic manner.<ref name="pmid16685005">{{cite journal| author=van Walraven C, Jennings A, Oake N, Fergusson D, Forster AJ| title=Effect of study setting on anticoagulation control: a systematic review and metaregression. | journal=Chest | year= 2006 | volume= 129 | issue= 5 | pages= 1155-66 | pmid=16685005 | doi=10.1378/chest.129.5.1155 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16685005  }} </ref>
 
==Vitamin K antagonists==
==Vitamin K antagonists==
===Warfarin===
===Warfarin===
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[[Warfarin]] is a commonly used oral anticoagulant that interferes with the Vitamin K dependent coagulation co-factors.
[[Warfarin]] is a commonly used oral anticoagulant that interferes with the Vitamin K dependent coagulation co-factors.


==Heparins==
==Indirect thrombin inhibitors==
===Unfractionated heparin===
===Heparins===
Heparins bind to and activate the enzyme inhibitor [[antithrombin III]]. The activated [[antithrombin III]] then inactivates thrombin, factor Xa, and components of coagulation.
 
====Unfractionated heparin====
Details of the usage of heparin are available in [[clinical practice guideline]]s by the [[American College of Chest Physicians]]<ref name="pmid15383472">{{cite journal |author=Hirsh J, Raschke R |title=Heparin and low-molecular-weight heparin: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy |journal=Chest |volume=126 |issue=3 Suppl |pages=188S-203S |year=2004 |pmid=15383472 |doi=10.1378/chest.126.3_suppl.188S|url=http://www.chestjournal.org/cgi/content/full/126/3_suppl/204S}}</ref>:
Details of the usage of heparin are available in [[clinical practice guideline]]s by the [[American College of Chest Physicians]]<ref name="pmid15383472">{{cite journal |author=Hirsh J, Raschke R |title=Heparin and low-molecular-weight heparin: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy |journal=Chest |volume=126 |issue=3 Suppl |pages=188S-203S |year=2004 |pmid=15383472 |doi=10.1378/chest.126.3_suppl.188S|url=http://www.chestjournal.org/cgi/content/full/126/3_suppl/204S}}</ref>:
* [http://www.chestjournal.org/cgi/content/full/126/3_suppl/188S/T4 Non-weight based heparin dose adjustment]
* [http://www.chestjournal.org/cgi/content/full/126/3_suppl/188S/T4 Non-weight based heparin dose adjustment]
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is related to heparin levels. The goal heparin level is 0.3 to 0.7 U/mL for unfractionated heparin but a higher level for low molecular weight heparin.<ref name="pmid15222660">{{cite journal |author=Rosborough TK, Shepherd MF |title=Achieving target antifactor Xa activity with a heparin protocol based on sex, age, height, and weight |journal=Pharmacotherapy |volume=24 |issue=6 |pages=713–9 |year=2004 |month=June |pmid=15222660 |doi=10.1592/phco.24.8.713.36067 |url=http://www.atypon-link.com/doi/abs/10.1592/phco.24.8.713.36067 |issn=}}</ref><ref name="pmid10391423">{{cite journal |author=Rosborough TK |title=Monitoring unfractionated heparin therapy with antifactor Xa activity results in fewer monitoring tests and dosage changes than monitoring with the activated partial thromboplastin time |journal=Pharmacotherapy |volume=19 |issue=6 |pages=760–6 |year=1999 |month=June |pmid=10391423 |doi= |url= |issn=}}</ref><ref name="pmid8267489">{{cite journal |author=Levine MN, Hirsh J, Gent M, ''et al.'' |title=A randomized trial comparing activated thromboplastin time with heparin assay in patients with acute venous thromboembolism requiring large daily doses of heparin |journal=Arch. Intern. Med. |volume=154 |issue=1 |pages=49–56 |year=1994 |month=January |pmid=8267489 |doi= |url=http://archinte.ama-assn.org/cgi/pmidlookup?view=long&pmid=8267489 |issn=}}</ref>
is related to heparin levels. The goal heparin level is 0.3 to 0.7 U/mL for unfractionated heparin but a higher level for low molecular weight heparin.<ref name="pmid15222660">{{cite journal |author=Rosborough TK, Shepherd MF |title=Achieving target antifactor Xa activity with a heparin protocol based on sex, age, height, and weight |journal=Pharmacotherapy |volume=24 |issue=6 |pages=713–9 |year=2004 |month=June |pmid=15222660 |doi=10.1592/phco.24.8.713.36067 |url=http://www.atypon-link.com/doi/abs/10.1592/phco.24.8.713.36067 |issn=}}</ref><ref name="pmid10391423">{{cite journal |author=Rosborough TK |title=Monitoring unfractionated heparin therapy with antifactor Xa activity results in fewer monitoring tests and dosage changes than monitoring with the activated partial thromboplastin time |journal=Pharmacotherapy |volume=19 |issue=6 |pages=760–6 |year=1999 |month=June |pmid=10391423 |doi= |url= |issn=}}</ref><ref name="pmid8267489">{{cite journal |author=Levine MN, Hirsh J, Gent M, ''et al.'' |title=A randomized trial comparing activated thromboplastin time with heparin assay in patients with acute venous thromboembolism requiring large daily doses of heparin |journal=Arch. Intern. Med. |volume=154 |issue=1 |pages=49–56 |year=1994 |month=January |pmid=8267489 |doi= |url=http://archinte.ama-assn.org/cgi/pmidlookup?view=long&pmid=8267489 |issn=}}</ref>


===Low molecular weight heparin===
====Low molecular weight heparin====
{{main|Low molecular weight heparin}}
{{main|Low molecular weight heparin}}


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The last dose of low molecular weight heparin prior to [[coronary artery bypass]] surgery should occur 24 hours before the procedure in order to prevent high residual anti-Xa levels.<ref name="pmid17588394">{{cite journal |author=Whitlock RP, Crowther MA, Warkentin TE, Blackall MH, Farrokhyar F, Teoh KH |title=Warfarin cessation before cardiopulmonary bypass: lessons learned from a randomized controlled trial of oral vitamin K |journal=Ann. Thorac. Surg. |volume=84 |issue=1 |pages=103–8 |year=2007 |pmid=17588394 |doi=10.1016/j.athoracsur.2007.03.014}}</ref>
The last dose of low molecular weight heparin prior to [[coronary artery bypass]] surgery should occur 24 hours before the procedure in order to prevent high residual anti-Xa levels.<ref name="pmid17588394">{{cite journal |author=Whitlock RP, Crowther MA, Warkentin TE, Blackall MH, Farrokhyar F, Teoh KH |title=Warfarin cessation before cardiopulmonary bypass: lessons learned from a randomized controlled trial of oral vitamin K |journal=Ann. Thorac. Surg. |volume=84 |issue=1 |pages=103–8 |year=2007 |pmid=17588394 |doi=10.1016/j.athoracsur.2007.03.014}}</ref>


==Direct thrombin inhibitors==
==Direct thrombin inhibitors (antithrombins)==
Direct thrombin inhibitors bind directly to thrombin<ref name="pmid16148288">{{cite journal |author=Di Nisio M, Middeldorp S, Büller HR |title=Direct thrombin inhibitors |journal=N. Engl. J. Med. |volume=353 |issue=10 |pages=1028–40 |year=2005 |pmid=16148288 |doi=10.1056/NEJMra044440|url=http://content.nejm.org/cgi/content/full/353/10/1028}}</ref> and are used for [[heparin-induced thrombocytopenia]] and during [[percutaneous coronary intervention]]s.<ref name="pmid18956996">{{cite journal| author=Baetz BE, Spinler SA| title=Dabigatran etexilate: an oral direct thrombin inhibitor for prophylaxis and treatment of thromboembolic diseases. | journal=Pharmacotherapy | year= 2008 | volume= 28 | issue= 11 | pages= 1354-73 | pmid=18956996  
Direct thrombin inhibitors ([[antithrombin]]s) bind directly to thrombin<ref name="pmid16148288">{{cite journal |author=Di Nisio M, Middeldorp S, Büller HR |title=Direct thrombin inhibitors |journal=N. Engl. J. Med. |volume=353 |issue=10 |pages=1028–40 |year=2005 |pmid=16148288 |doi=10.1056/NEJMra044440|url=http://content.nejm.org/cgi/content/full/353/10/1028}}</ref> and are used for [[heparin-induced thrombocytopenia]] and during [[percutaneous coronary intervention]]s.<ref name="pmid18956996">{{cite journal| author=Baetz BE, Spinler SA| title=Dabigatran etexilate: an oral direct thrombin inhibitor for prophylaxis and treatment of thromboembolic diseases. | journal=Pharmacotherapy | year= 2008 | volume= 28 | issue= 11 | pages= 1354-73 | pmid=18956996  
| url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=clinical.uthscsa.edu/cite&email=badgett@uthscdsa.edu&retmode=ref&cmd=prlinks&id=18956996 | doi=10.1592/phco.28.11.1354 }} <!--Formatted by http://sumsearch.uthscsa.edu/cite/--></ref>
| url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=clinical.uthscsa.edu/cite&email=badgett@uthscdsa.edu&retmode=ref&cmd=prlinks&id=18956996 | doi=10.1592/phco.28.11.1354 }}</ref>
* [[Argatroban]] is for treating [[heparin-induced thrombocytopenia]] (HIT)
* [[Argatroban]] is for treating [[heparin-induced thrombocytopenia]] (HIT)
* [[Bivalirudin]] is a recombinant protein
* [[Bivalirudin]] is a recombinant protein
* [[Dabigatran]] is given orally and may be as effective as [[warfarin]] and with less bleeding but increased [[dyspepsia]] for the treatment of [[embolism and thrombosis]].<ref name="pmid19966341">{{cite journal| author=Schulman S, Kearon C, Kakkar AK, Mismetti P, Schellong S, Eriksson H et al.| title=Dabigatran versus warfarin in the treatment of acute venous thromboembolism. | journal=N Engl J Med | year= 2009 | volume= 361 | issue= 24 | pages= 2342-52 | pmid=19966341  
* [[Dabigatran]] is given orally and may be as effective as [[warfarin]] and with less bleeding but increased [[dyspepsia]] for the treatment of [[embolism and thrombosis]].<ref name="pmid19966341">{{cite journal| author=Schulman S, Kearon C, Kakkar AK, Mismetti P, Schellong S, Eriksson H et al.| title=Dabigatran versus warfarin in the treatment of acute venous thromboembolism. | journal=N Engl J Med | year= 2009 | volume= 361 | issue= 24 | pages= 2342-52 | pmid=19966341 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=clinical.uthscsa.edu/cite&retmode=ref&cmd=prlinks&id=19966341 | doi=10.1056/NEJMoa0906598 }}  [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=clinical.uthscsa.edu/cite&retmode=ref&cmd=prlinks&id=20404376 Review in: Ann Intern Med. 2010 Apr 20;152(8):JC4-7] </ref> However, dabigatran my increase [[acute coronary syndrome]].<ref name="pmid22231617">{{cite journal| author=Uchino K, Hernandez AV| title=Dabigatran Association With Higher Risk of Acute Coronary Events: Meta-analysis of Noninferiority Randomized Controlled Trials. | journal=Arch Intern Med | year= 2012 | volume=  | issue=  | pages=  | pmid=22231617 | doi=10.1001/archinternmed.2011.1666 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22231617  }} </ref>
| url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=clinical.uthscsa.edu/cite&retmode=ref&cmd=prlinks&id=19966341 | doi=10.1056/NEJMoa0906598 }}  [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=clinical.uthscsa.edu/cite&retmode=ref&cmd=prlinks&id=20404376 Review in: Ann Intern Med. 2010 Apr 20;152(8):JC4-7] </ref>
* [[Desirudin]]  
* [[Desirudin]]  
* [[Hirudin]] is a recombinant protein for treating [[heparin-induced thrombocytopenia]] (HIT)
* [[Hirudin]] is a recombinant protein for treating [[heparin-induced thrombocytopenia]] (HIT)
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==Factor Xa inhibitors==
==Factor Xa inhibitors==
* [[Apixaban]] is taken orally and can prevent can prevent [[embolism and thrombosis]] during [[perioperative care]] according to [[randomized controlled trial]]s of knee<ref name="pmid19657123">{{cite journal| author=Lassen MR, Raskob GE, Gallus A, Pineo G, Chen D, Portman RJ| title=Apixaban or enoxaparin for thromboprophylaxis after knee replacement. | journal=N Engl J Med | year= 2009 | volume= 361 | issue= 6 | pages= 594-604 | pmid=19657123 | doi=10.1056/NEJMoa0810773 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19657123  }} </ref> and hip<ref name="pmid21175312">{{cite journal| author=Lassen MR, Gallus A, Raskob GE, Pineo G, Chen D, Ramirez LM et al.| title=Apixaban versus enoxaparin for thromboprophylaxis after hip replacement. | journal=N Engl J Med | year= 2010 | volume= 363 | issue= 26 | pages= 2487-98 | pmid=21175312 | doi=10.1056/NEJMoa1006885 | pmc= | url= }} </ref> surgery. May also reduce embolism better than warfarin in [[atrial fibrillation]].<ref>{{Cite journal
* [[Apixaban]] is taken orally and can prevent can prevent [[embolism and thrombosis]] during [[perioperative care]] according to [[randomized controlled trial]]s of knee<ref name="pmid19657123">{{cite journal| author=Lassen MR, Raskob GE, Gallus A, Pineo G, Chen D, Portman RJ| title=Apixaban or enoxaparin for thromboprophylaxis after knee replacement. | journal=N Engl J Med | year= 2009 | volume= 361 | issue= 6 | pages= 594-604 | pmid=19657123 | doi=10.1056/NEJMoa0810773 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19657123  }} </ref> and hip<ref name="pmid21175312">{{cite journal| author=Lassen MR, Gallus A, Raskob GE, Pineo G, Chen D, Ramirez LM et al.| title=Apixaban versus enoxaparin for thromboprophylaxis after hip replacement. | journal=N Engl J Med | year= 2010 | volume= 363 | issue= 26 | pages= 2487-98 | pmid=21175312 | doi=10.1056/NEJMoa1006885 | pmc= | url= }} </ref> surgery. May also reduce embolism better than warfarin in [[atrial fibrillation]]. Hepatic metabolism.
| doi = 10.1056/NEJMoa1007432
| issn = 0028-4793
| pages = 110210075948054
| last = Connolly
| first = Stuart J.
| coauthors = John Eikelboom, Campbell Joyner, Hans-Christoph Diener, Robert Hart, Sergey Golitsyn, Greg Flaker, Alvaro Avezum, Stefan H. Hohnloser, Rafael Diaz, Mario Talajic, Jun Zhu, Prem Pais, Andrzej Budaj, Alexander Parkhomenko, Petr Jansky, Patrick Commerford, Ru San Tan, Kui-Hian Sim, Basil S. Lewis, Walter Van Mieghem, Gregory Y.H. Lip, Jae Hyung Kim, Fernando Lanas-Zanetti, Antonio Gonzalez-Hermosillo, Antonio L. Dans, Muhammad Munawar, Martin O'Donnell, John Lawrence, Gayle Lewis, Rizwan Afzal, Salim Yusuf
| title = Apixaban in Patients with Atrial Fibrillation
| journal = New England Journal of Medicine
| accessdate = 2011-02-10
| date = 2011
| url = http://www.nejm.org/doi/full/10.1056/NEJMoa1007432?query=OF
}}</ref>
* [[Fondaparinux]] can prevent [[embolism and thrombosis]] during [[perioperative care]] according to [[randomized controlled trial]]s of hip fracture surgery<ref name="pmid11794148">{{cite journal |author=Eriksson BI, Bauer KA, Lassen MR, Turpie AG |title=Fondaparinux compared with enoxaparin for the prevention of venous thromboembolism after hip-fracture surgery |journal=The New England journal of medicine |volume=345 |issue=18 |pages=1298–304 |year=2001 |month=November |pmid=11794148 |doi= |url=http://content.nejm.org/cgi/pmidlookup?view=short&pmid=11794148&promo=ONFLNS19 |issn=}}</ref>.  
* [[Fondaparinux]] can prevent [[embolism and thrombosis]] during [[perioperative care]] according to [[randomized controlled trial]]s of hip fracture surgery<ref name="pmid11794148">{{cite journal |author=Eriksson BI, Bauer KA, Lassen MR, Turpie AG |title=Fondaparinux compared with enoxaparin for the prevention of venous thromboembolism after hip-fracture surgery |journal=The New England journal of medicine |volume=345 |issue=18 |pages=1298–304 |year=2001 |month=November |pmid=11794148 |doi= |url=http://content.nejm.org/cgi/pmidlookup?view=short&pmid=11794148&promo=ONFLNS19 |issn=}}</ref>.  
* [[Idraparinux]] is a synthetic derivative of heparin that has a long half life that allows once-weekly dosage. A [[randomized controlled trial]] compared idraparinux to warfarin and found that [[idraparinux]] is equivalent for [[deep venous thrombosis]] but is inferior for [[pulmonary embolism]].<ref name="pmid17855670">{{cite journal |author=Buller HR, Cohen AT, Davidson B, ''et al'' |title=Idraparinux versus standard therapy for venous thromboembolic disease |journal=N. Engl. J. Med. |volume=357 |issue=11 |pages=1094–104 |year=2007 |pmid=17855670 |doi=10.1056/NEJMoa064247}}</ref>
* [[Idraparinux]] is a synthetic derivative of heparin that has a long half life that allows once-weekly dosage. A [[randomized controlled trial]] compared idraparinux to warfarin and found that [[idraparinux]] is equivalent for [[deep venous thrombosis]] but is inferior for [[pulmonary embolism]].<ref name="pmid17855670">{{cite journal |author=Buller HR, Cohen AT, Davidson B, ''et al'' |title=Idraparinux versus standard therapy for venous thromboembolic disease |journal=N. Engl. J. Med. |volume=357 |issue=11 |pages=1094–104 |year=2007 |pmid=17855670 |doi=10.1056/NEJMoa064247}}</ref>
** [[Idrabiotaparinux]] is idraparinux with biotin added to allow rapid reversal of anticoagulation with [[avidin]]. Idrabiotaparinux may be more effective than warfarin for [[pulmonary embolism]].<ref name="pmid22130488">{{cite journal| author=Büller HR, Gallus AS, Pillion G, Prins MH, Raskob GE, Cassiopea Investigators| title=Enoxaparin followed by once-weekly idrabiotaparinux versus enoxaparin plus warfarin for patients with acute symptomatic pulmonary embolism: a randomised, double-blind, double-dummy, non-inferiority trial. | journal=Lancet | year= 2012 | volume= 379 | issue= 9811 | pages= 123-9 | pmid=22130488 | doi=10.1016/S0140-6736(11)61505-5 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22130488  }} </ref>
* [[Rivaroxaban]] can be given orally. It can prevent [[embolism and thrombosis]] during [[perioperative care]] according to [[randomized controlled trial]]s of two weeks of therapy after knee arthoplasty<ref name="pmid18579812">{{cite journal |author=Lassen MR, Ageno W, Borris LC, ''et al'' |title=Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty |journal=The New England journal of medicine |volume=358 |issue=26 |pages=2776–86 |year=2008 |month=June |pmid=18579812 |doi=10.1056/NEJMoa076016 |url=http://content.nejm.org/cgi/content/full/358/26/2776 |issn=}}</ref> or 5 weeks of therapy after hip arthroplasty.<ref name="pmid18579811">{{cite journal |author=Eriksson BI, Borris LC, Friedman RJ, ''et al'' |title=Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty |journal=The New England journal of medicine |volume=358 |issue=26 |pages=2765–75 |year=2008 |month=June |pmid=18579811 |doi=10.1056/NEJMoa0800374 |url=http://content.nejm.org/cgi/pmidlookup?view=short&pmid=18579811&promo=ONFLNS19 |issn=}}</ref><ref name="pmid18582928">{{cite journal |author=Kakkar AK, Brenner B, Dahl OE, ''et al'' |title=Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind, randomised controlled trial |journal=Lancet |volume=372 |issue=9632 |pages=31–9 |year=2008 |month=July |pmid=18582928 |doi=10.1016/S0140-6736(08)60880-6 |url=http://linkinghub.elsevier.com/retrieve/pii/S0140-6736(08)60880-6 |issn=}}</ref>
* [[Rivaroxaban]] can be given orally. It can prevent [[embolism and thrombosis]] during [[perioperative care]] according to [[randomized controlled trial]]s of two weeks of therapy after knee arthoplasty<ref name="pmid18579812">{{cite journal |author=Lassen MR, Ageno W, Borris LC, ''et al'' |title=Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty |journal=The New England journal of medicine |volume=358 |issue=26 |pages=2776–86 |year=2008 |month=June |pmid=18579812 |doi=10.1056/NEJMoa076016 |url=http://content.nejm.org/cgi/content/full/358/26/2776 |issn=}}</ref> or 5 weeks of therapy after hip arthroplasty.<ref name="pmid18579811">{{cite journal |author=Eriksson BI, Borris LC, Friedman RJ, ''et al'' |title=Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty |journal=The New England journal of medicine |volume=358 |issue=26 |pages=2765–75 |year=2008 |month=June |pmid=18579811 |doi=10.1056/NEJMoa0800374 |url=http://content.nejm.org/cgi/pmidlookup?view=short&pmid=18579811&promo=ONFLNS19 |issn=}}</ref><ref name="pmid18582928">{{cite journal |author=Kakkar AK, Brenner B, Dahl OE, ''et al'' |title=Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind, randomised controlled trial |journal=Lancet |volume=372 |issue=9632 |pages=31–9 |year=2008 |month=July |pmid=18582928 |doi=10.1016/S0140-6736(08)60880-6 |url=http://linkinghub.elsevier.com/retrieve/pii/S0140-6736(08)60880-6 |issn=}}</ref>


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==Adverse effects==
==Adverse effects==
The risk of bleeding when [[heparin]] is used in patients with [[acute coronary syndrome]] can be estimated with a [[clinical prediction rule]] (http://www.crusadebleedingscore.org/). Additional [[clinical prediction rule]]s are available.<ref name="pmid17099015">{{cite journal| author=Shireman TI, Mahnken JD, Howard PA, Kresowik TF, Hou Q, Ellerbeck EF| title=Development of a contemporary bleeding risk model for elderly warfarin recipients. | journal=Chest | year= 2006 | volume= 130 | issue= 5 | pages= 1390-6 | pmid=17099015 | doi=10.1378/chest.130.5.1390 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17099015  }}  [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17335175 Review in: ACP J Club. 2007 Mar-Apr;146(2):52]  [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17400649 Review in: Evid Based Med. 2007 Apr;12(2):57] </ref>
===Risk factors===
Various risk factors, such as history of [[chronic obstructive pulmonary disease]], prior [[gastrointestinal hemorrhage]] and [[anemia]], have been identified.<ref name="pmid24315894">{{cite journal| author=Goodman SG, Wojdyla DM, Piccini JP, White HD, Paolini JF, Nessel CC et al.| title=Factors associated with major bleeding events: insights from the ROCKET AF trial (rivaroxaban once-daily oral direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation). | journal=J Am Coll Cardiol | year= 2014 | volume= 63 | issue= 9 | pages= 891-900 | pmid=24315894 | doi=10.1016/j.jacc.2013.11.013 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24315894  }} </ref>
 
Bleeding is more likely when more than one antithrombotic is used.<ref name="pmid10386508">{{cite journal| author=Gulløv AL, Koefoed BG, Petersen P| title=Bleeding during warfarin and aspirin therapy in patients with atrial fibrillation: the AFASAK 2 study. Atrial Fibrillation Aspirin and Anticoagulation. | journal=Arch Intern Med | year= 1999 | volume= 159 | issue= 12 | pages= 1322-8 | pmid=10386508 }} </ref><ref name="pmid20006130">{{cite journal| author=Sørensen R, Hansen ML, Abildstrom SZ, Hvelplund A, Andersson C, Jørgensen C et al.| title=Risk of bleeding in patients with acute myocardial infarction treated with different combinations of aspirin, clopidogrel, and vitamin K antagonists in Denmark: a retrospective analysis of nationwide registry data. | journal=Lancet | year= 2009 | volume= 374 | issue= 9706 | pages= 1967-74 | pmid=20006130 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=clinical.uthscsa.edu/cite&email=badgett@uthscdsa.edu&retmode=ref&cmd=prlinks&id=20006130 | doi=10.1016/S0140-6736(09)61751-7 }}</ref>
 
[[Accidental fall]]s may not increase rate of major bleeding.<ref name="pmid22840664">{{cite journal| author=Donzé J, Clair C, Hug B, Rodondi N, Waeber G, Cornuz J et al.| title=Risk of falls and major bleeds in patients on oral anticoagulation therapy. | journal=Am J Med | year= 2012 | volume= 125 | issue= 8 | pages= 773-8 | pmid=22840664 | doi=10.1016/j.amjmed.2012.01.033 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22840664  }} </ref>
 
===Prediction===
In [[atrial fibrillation]], the risk of bleeding can be estimated with the HAS-BLED clinical prediction rule.<ref name="pmid20299623">{{cite journal| author=Pisters R, Lane DA, Nieuwlaat R, de Vos CB, Crijns HJ, Lip GY| title=A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey. | journal=Chest | year= 2010 | volume= 138 | issue= 5 | pages= 1093-100 | pmid=20299623 | doi=10.1378/chest.10-0134 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20299623  }} </ref>
 
In acute [[acute coronary syndrome]], the risk of bleeding with [[heparin]] can be estimated with a [[clinical prediction rule]] (http://www.crusadebleedingscore.org/). Additional [[clinical prediction rule]]s are available.<ref name="pmid17099015">{{cite journal| author=Shireman TI, Mahnken JD, Howard PA, Kresowik TF, Hou Q, Ellerbeck EF| title=Development of a contemporary bleeding risk model for elderly warfarin recipients. | journal=Chest | year= 2006 | volume= 130 | issue= 5 | pages= 1390-6 | pmid=17099015 | doi=10.1378/chest.130.5.1390 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17099015  }}  [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17335175 Review in: ACP J Club. 2007 Mar-Apr;146(2):52]  [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17400649 Review in: Evid Based Med. 2007 Apr;12(2):57] </ref>


Bleeding is more likely when more than one antithrombotic is used.<ref name="pmid10386508">{{cite journal| author=Gulløv AL, Koefoed BG, Petersen P| title=Bleeding during warfarin and aspirin therapy in patients with atrial fibrillation: the AFASAK 2 study. Atrial Fibrillation Aspirin and Anticoagulation. | journal=Arch Intern Med | year= 1999 | volume= 159 | issue= 12 | pages= 1322-8 | pmid=10386508 }} </ref><ref name="pmid20006130">{{cite journal| author=Sørensen R, Hansen ML, Abildstrom SZ, Hvelplund A, Andersson C, Jørgensen C et al.| title=Risk of bleeding in patients with acute myocardial infarction treated with different combinations of aspirin, clopidogrel, and vitamin K antagonists in Denmark: a retrospective analysis of nationwide registry data. | journal=Lancet | year= 2009 | volume= 374 | issue= 9706 | pages= 1967-74 | pmid=20006130
| url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=clinical.uthscsa.edu/cite&email=badgett@uthscdsa.edu&retmode=ref&cmd=prlinks&id=20006130 | doi=10.1016/S0140-6736(09)61751-7 }} <!--Formatted by http://sumsearch.uthscsa.edu/cite/--></ref>


===Prevention===
[[Proton pump inhibitor]]s may reduce the risk of [[gastrointestinal hemorrhage]] among patients undergoing anticoagulation.<ref name="pmid18616644">{{cite journal| author=Massó González EL, García Rodríguez LA| title=Proton pump inhibitors reduce the long-term risk of recurrent upper gastrointestinal bleeding: an observational study. | journal=Aliment Pharmacol Ther | year= 2008 | volume= 28 | issue= 5 | pages= 629-37 | pmid=18616644  
[[Proton pump inhibitor]]s may reduce the risk of [[gastrointestinal hemorrhage]] among patients undergoing anticoagulation.<ref name="pmid18616644">{{cite journal| author=Massó González EL, García Rodríguez LA| title=Proton pump inhibitors reduce the long-term risk of recurrent upper gastrointestinal bleeding: an observational study. | journal=Aliment Pharmacol Ther | year= 2008 | volume= 28 | issue= 5 | pages= 629-37 | pmid=18616644  
| url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=clinical.uthscsa.edu/cite&email=badgett@uthscdsa.edu&retmode=ref&cmd=prlinks&id=18616644 | doi=10.1111/j.1365-2036.2008.03780.x }} <!--Formatted by http://sumsearch.uthscsa.edu/cite/--></ref>
| url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=clinical.uthscsa.edu/cite&email=badgett@uthscdsa.edu&retmode=ref&cmd=prlinks&id=18616644 | doi=10.1111/j.1365-2036.2008.03780.x }}</ref>
 
===Treatment===
"Prothrombin complex concentrate immediately and completely reverses the anticoagulant effect of rivaroxaban in healthy subjects but has no influence on the anticoagulant action of dabigatran at the PCC dose used in this study" according to a [[randomized controlled trial]]. <ref name="pmid21900088">{{cite journal| author=Eerenberg ES, Kamphuisen PW, Sijpkens MK, Meijers JC, Buller HR, Levi M| title=Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects. | journal=Circulation | year= 2011 | volume= 124 | issue= 14 | pages= 1573-9 | pmid=21900088 | doi=10.1161/CIRCULATIONAHA.111.029017 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21900088  }} </ref>


==References==
==References==
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==External links==
==External links==
* [http://www.chestjournal.org/content/vol133/6_suppl/ The Eighth ACCP Conference on Antithrombotic and Thrombolytic Therapy: Evidence-Based Guidelines]
* [http://journal.publications.chestnet.org/issue.aspx?journalid=99&issueid=23443 The Ninth ACCP Conference on Antithrombotic and Thrombolytic Therapy: Evidence-Based Guidelines] 2012
* [http://www.chestjournal.org/content/vol133/6_suppl/ The Eighth ACCP Conference on Antithrombotic and Thrombolytic Therapy: Evidence-Based Guidelines][[Category:Suggestion Bot Tag]]

Latest revision as of 11:00, 11 July 2024

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https://en.citizendium.org/wiki/index.php?title=Anticoagulant&printable=yes
This editable Main Article is under development and subject to a disclaimer.

Anticoagulants are "agents that prevent blood clotting".[1] They interfere with coagulation and may be used to prevent embolism and thrombosis.

Anticoagulation is dangerous due to drug toxicity and should be managed in a systematic manner.[2]

Vitamin K antagonists

Warfarin

For more information, see: warfarin.

Warfarin is a commonly used oral anticoagulant that interferes with the Vitamin K dependent coagulation co-factors.

Indirect thrombin inhibitors

Heparins

Heparins bind to and activate the enzyme inhibitor antithrombin III. The activated antithrombin III then inactivates thrombin, factor Xa, and components of coagulation.

Unfractionated heparin

Details of the usage of heparin are available in clinical practice guidelines by the American College of Chest Physicians[3]:

Heparin dose may also be adjusted by using an anti-Xa assay to measure heparin function, which is related to heparin levels. The goal heparin level is 0.3 to 0.7 U/mL for unfractionated heparin but a higher level for low molecular weight heparin.[4][5][6]

Low molecular weight heparin

For more information, see: Low molecular weight heparin.


Selected low molecular weight heparins
  Prophylaxis dose Full dose Comments
Enoxiparin
(Lovenox)		 Either:
30 mg twice daily
40 mg once daily		 Either:
1 mg/kg/dose every 12 hours
1.5 mg/kg once daily
more information is at Enoxaparin		  
Dalteparin
(Framin)		 After loading, 2500 to 5000 int. units daily 150 int. units/kg up to 18,000 int. units) once daily
dosing is complicated and more information is at DailyMed		 If creatinine clearance is less then 30 mL/minute, monitor anti-Xa levels

The last dose of low molecular weight heparin prior to coronary artery bypass surgery should occur 24 hours before the procedure in order to prevent high residual anti-Xa levels.[7]

Direct thrombin inhibitors (antithrombins)

Direct thrombin inhibitors (antithrombins) bind directly to thrombin[8] and are used for heparin-induced thrombocytopenia and during percutaneous coronary interventions.[9]

Low molecular weight heparins may provide better anticoagulation for prophylaxis of deep venous thrombosis among orthopedic patients than direct thrombin inhibitors because the latter may increase bleeding complications.[12] However, if anticoagulation is started before surgery, direct thrombin inhibitors may be more effective.

Factor Xa inhibitors

Warfarin combined with heparin

Warfarin combined with heparin did not benefit survivors of acute myocardial infarction in a randomized controlled trial.[21]

Warfarin combined with heparin reduced events, but increased bleeding, among survivors of acute myocardial infarction in a randomized controlled trial.[22]

Adverse effects

Risk factors

Various risk factors, such as history of chronic obstructive pulmonary disease, prior gastrointestinal hemorrhage and anemia, have been identified.[23]

Bleeding is more likely when more than one antithrombotic is used.[24][25]

Accidental falls may not increase rate of major bleeding.[26]

Prediction

In atrial fibrillation, the risk of bleeding can be estimated with the HAS-BLED clinical prediction rule.[27]

In acute acute coronary syndrome, the risk of bleeding with heparin can be estimated with a clinical prediction rule (http://www.crusadebleedingscore.org/). Additional clinical prediction rules are available.[28]


Prevention

Proton pump inhibitors may reduce the risk of gastrointestinal hemorrhage among patients undergoing anticoagulation.[29]

Treatment

"Prothrombin complex concentrate immediately and completely reverses the anticoagulant effect of rivaroxaban in healthy subjects but has no influence on the anticoagulant action of dabigatran at the PCC dose used in this study" according to a randomized controlled trial. [30]

References

  1. ↑ Anonymous (2024), Anticoagulants (English). Medical Subject Headings. U.S. National Library of Medicine.
  2. ↑ van Walraven C, Jennings A, Oake N, Fergusson D, Forster AJ (2006). "Effect of study setting on anticoagulation control: a systematic review and metaregression.". Chest 129 (5): 1155-66. DOI:10.1378/chest.129.5.1155. PMID 16685005. Research Blogging.
  3. ↑ Hirsh J, Raschke R (2004). "Heparin and low-molecular-weight heparin: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy". Chest 126 (3 Suppl): 188S-203S. DOI:10.1378/chest.126.3_suppl.188S. PMID 15383472. Research Blogging.
  4. ↑ Rosborough TK, Shepherd MF (June 2004). "Achieving target antifactor Xa activity with a heparin protocol based on sex, age, height, and weight". Pharmacotherapy 24 (6): 713–9. DOI:10.1592/phco.24.8.713.36067. PMID 15222660. Research Blogging.
  5. ↑ Rosborough TK (June 1999). "Monitoring unfractionated heparin therapy with antifactor Xa activity results in fewer monitoring tests and dosage changes than monitoring with the activated partial thromboplastin time". Pharmacotherapy 19 (6): 760–6. PMID 10391423. [e]
  6. ↑ Levine MN, Hirsh J, Gent M, et al. (January 1994). "A randomized trial comparing activated thromboplastin time with heparin assay in patients with acute venous thromboembolism requiring large daily doses of heparin". Arch. Intern. Med. 154 (1): 49–56. PMID 8267489. [e]
  7. ↑ Whitlock RP, Crowther MA, Warkentin TE, Blackall MH, Farrokhyar F, Teoh KH (2007). "Warfarin cessation before cardiopulmonary bypass: lessons learned from a randomized controlled trial of oral vitamin K". Ann. Thorac. Surg. 84 (1): 103–8. DOI:10.1016/j.athoracsur.2007.03.014. PMID 17588394. Research Blogging.
  8. ↑ Di Nisio M, Middeldorp S, Büller HR (2005). "Direct thrombin inhibitors". N. Engl. J. Med. 353 (10): 1028–40. DOI:10.1056/NEJMra044440. PMID 16148288. Research Blogging.
  9. ↑ Baetz BE, Spinler SA (2008). "Dabigatran etexilate: an oral direct thrombin inhibitor for prophylaxis and treatment of thromboembolic diseases.". Pharmacotherapy 28 (11): 1354-73. DOI:10.1592/phco.28.11.1354. PMID 18956996. Research Blogging.
  10. ↑ Schulman S, Kearon C, Kakkar AK, Mismetti P, Schellong S, Eriksson H et al. (2009). "Dabigatran versus warfarin in the treatment of acute venous thromboembolism.". N Engl J Med 361 (24): 2342-52. DOI:10.1056/NEJMoa0906598. PMID 19966341. Research Blogging. Review in: Ann Intern Med. 2010 Apr 20;152(8):JC4-7
  11. ↑ Uchino K, Hernandez AV (2012). "Dabigatran Association With Higher Risk of Acute Coronary Events: Meta-analysis of Noninferiority Randomized Controlled Trials.". Arch Intern Med. DOI:10.1001/archinternmed.2011.1666. PMID 22231617. Research Blogging.
  12. ↑ Salazar CA, Malaga G, Malasquez G (2010). "Direct thrombin inhibitors versus vitamin K antagonists or low molecular weight heparins for prevention of venous thromboembolism following total hip or knee replacement.". Cochrane Database Syst Rev 4: CD005981. DOI:10.1002/14651858.CD005981.pub2. PMID 20393944. Research Blogging.
  13. ↑ Lassen MR, Raskob GE, Gallus A, Pineo G, Chen D, Portman RJ (2009). "Apixaban or enoxaparin for thromboprophylaxis after knee replacement.". N Engl J Med 361 (6): 594-604. DOI:10.1056/NEJMoa0810773. PMID 19657123. Research Blogging.
  14. ↑ Lassen MR, Gallus A, Raskob GE, Pineo G, Chen D, Ramirez LM et al. (2010). "Apixaban versus enoxaparin for thromboprophylaxis after hip replacement.". N Engl J Med 363 (26): 2487-98. DOI:10.1056/NEJMoa1006885. PMID 21175312. Research Blogging.
  15. ↑ Eriksson BI, Bauer KA, Lassen MR, Turpie AG (November 2001). "Fondaparinux compared with enoxaparin for the prevention of venous thromboembolism after hip-fracture surgery". The New England journal of medicine 345 (18): 1298–304. PMID 11794148. [e]
  16. ↑ Buller HR, Cohen AT, Davidson B, et al (2007). "Idraparinux versus standard therapy for venous thromboembolic disease". N. Engl. J. Med. 357 (11): 1094–104. DOI:10.1056/NEJMoa064247. PMID 17855670. Research Blogging.
  17. ↑ Büller HR, Gallus AS, Pillion G, Prins MH, Raskob GE, Cassiopea Investigators (2012). "Enoxaparin followed by once-weekly idrabiotaparinux versus enoxaparin plus warfarin for patients with acute symptomatic pulmonary embolism: a randomised, double-blind, double-dummy, non-inferiority trial.". Lancet 379 (9811): 123-9. DOI:10.1016/S0140-6736(11)61505-5. PMID 22130488. Research Blogging.
  18. ↑ Lassen MR, Ageno W, Borris LC, et al (June 2008). "Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty". The New England journal of medicine 358 (26): 2776–86. DOI:10.1056/NEJMoa076016. PMID 18579812. Research Blogging.
  19. ↑ Eriksson BI, Borris LC, Friedman RJ, et al (June 2008). "Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty". The New England journal of medicine 358 (26): 2765–75. DOI:10.1056/NEJMoa0800374. PMID 18579811. Research Blogging.
  20. ↑ Kakkar AK, Brenner B, Dahl OE, et al (July 2008). "Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind, randomised controlled trial". Lancet 372 (9632): 31–9. DOI:10.1016/S0140-6736(08)60880-6. PMID 18582928. Research Blogging.
  21. ↑ Fiore LD, Ezekowitz MD, Brophy MT, Lu D, Sacco J, Peduzzi P (2002). "Department of Veterans Affairs Cooperative Studies Program Clinical Trial comparing combined warfarin and aspirin with aspirin alone in survivors of acute myocardial infarction: primary results of the CHAMP study". Circulation 105 (5): 557–63. PMID 11827919. [e]
  22. ↑ Hurlen M, Abdelnoor M, Smith P, Erikssen J, Arnesen H (2002). "Warfarin, aspirin, or both after myocardial infarction". N. Engl. J. Med. 347 (13): 969–74. DOI:10.1056/NEJMoa020496. PMID 12324552. Research Blogging.
  23. ↑ Goodman SG, Wojdyla DM, Piccini JP, White HD, Paolini JF, Nessel CC et al. (2014). "Factors associated with major bleeding events: insights from the ROCKET AF trial (rivaroxaban once-daily oral direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation).". J Am Coll Cardiol 63 (9): 891-900. DOI:10.1016/j.jacc.2013.11.013. PMID 24315894. Research Blogging.
  24. ↑ Gulløv AL, Koefoed BG, Petersen P (1999). "Bleeding during warfarin and aspirin therapy in patients with atrial fibrillation: the AFASAK 2 study. Atrial Fibrillation Aspirin and Anticoagulation.". Arch Intern Med 159 (12): 1322-8. PMID 10386508.
  25. ↑ Sørensen R, Hansen ML, Abildstrom SZ, Hvelplund A, Andersson C, Jørgensen C et al. (2009). "Risk of bleeding in patients with acute myocardial infarction treated with different combinations of aspirin, clopidogrel, and vitamin K antagonists in Denmark: a retrospective analysis of nationwide registry data.". Lancet 374 (9706): 1967-74. DOI:10.1016/S0140-6736(09)61751-7. PMID 20006130. Research Blogging.
  26. ↑ Donzé J, Clair C, Hug B, Rodondi N, Waeber G, Cornuz J et al. (2012). "Risk of falls and major bleeds in patients on oral anticoagulation therapy.". Am J Med 125 (8): 773-8. DOI:10.1016/j.amjmed.2012.01.033. PMID 22840664. Research Blogging.
  27. ↑ Pisters R, Lane DA, Nieuwlaat R, de Vos CB, Crijns HJ, Lip GY (2010). "A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey.". Chest 138 (5): 1093-100. DOI:10.1378/chest.10-0134. PMID 20299623. Research Blogging.
  28. ↑ Shireman TI, Mahnken JD, Howard PA, Kresowik TF, Hou Q, Ellerbeck EF (2006). "Development of a contemporary bleeding risk model for elderly warfarin recipients.". Chest 130 (5): 1390-6. DOI:10.1378/chest.130.5.1390. PMID 17099015. Research Blogging. Review in: ACP J Club. 2007 Mar-Apr;146(2):52 Review in: Evid Based Med. 2007 Apr;12(2):57
  29. ↑ Massó González EL, García Rodríguez LA (2008). "Proton pump inhibitors reduce the long-term risk of recurrent upper gastrointestinal bleeding: an observational study.". Aliment Pharmacol Ther 28 (5): 629-37. DOI:10.1111/j.1365-2036.2008.03780.x. PMID 18616644. Research Blogging.
  30. ↑ Eerenberg ES, Kamphuisen PW, Sijpkens MK, Meijers JC, Buller HR, Levi M (2011). "Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects.". Circulation 124 (14): 1573-9. DOI:10.1161/CIRCULATIONAHA.111.029017. PMID 21900088. Research Blogging.

See also

External links

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