Apixaban

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Apixaban
Apixaban.svg
Systematic (IUPAC) name
1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4,5-dihydropyrazolo[5,4-c]pyridine-3-carboxamide
Clinical data
Trade names Eliquis
AHFS/Drugs.com entry
Licence data EMA:Link, US FDA:link
Pregnancy cat. B (US)
Legal status POM (UK) -only (US)
Routes Oral
Pharmacokinetic data
Bioavailability ca. 50%
Half-life 9–14 h
Excretion 75% biliary, 25% renally
Identifiers
CAS number 503612-47-3 YesY
ATC code B01AF02
PubChem CID 10182969
DrugBank DB07828
ChemSpider 8358471 YesY
UNII 3Z9Y7UWC1J YesY
KEGG D03213 YesY
ChEBI CHEBI:72296 N
ChEMBL CHEMBL231779 YesY
Synonyms BMS-562247-01
Chemical data
Formula C25H25N5O4 
Mol. mass 459.497 g/mol
 N (what is this?)  (verify)

Apixaban (INN, trade name Eliquis) is an anticoagulant for the prevention of venous thromboembolism and the prevention of stroke in atrial fibrillation. It is a direct factor Xa inhibitor. Apixaban has been available in Europe since May 2011. The drug was developed in a joint venture by Pfizer and Bristol-Myers Squibb.[1][2]

Medical uses[edit]

Apixaban is a factor Xa inhibitor (anticoagulant) indicated to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. [3] A systematic review of new anticoagulants states the treatment benefits of apixaban and other new anticoagulants compared with warfarin are small and vary depending on the control achieved by warfarin treatment.[4] Patients already taking warfarin with excellent international normalized ratio (INR) control may have little to gain by switching to new oral anticoagulants in atrial fibrillation.[5]

In Europe apixaban can also be used to prevent the formation of blood clots in the veins (deep venous thrombosis) in adults who have had an operation to replace a hip or knee. In a systematic review of new oral anticoagulants (Noacs) against low-molecular-weight heparin (LMWH) there is marginal clinical benefit over LMWH and it is offset by increased risk for major bleeding. New oral anticoagulants have not been compared with warfarin.[6]

Apixaban is not indicated for prosthetic heart valves or for mitral stenosis.

Apixaban is not indicated as add-on treatment for dual antiplatelet therapy in secondary prevention of coronary incidents.(Triple therapy).[7][8]

Non valvular atrial fibrillation[edit]

A systematic review of new anticoagulants (dabigatran, rivaroxaban and apixaban) stated that the treatment benefits of apixaban and other new anticoagulants compared with warfarin were small and varied depending on the control achieved by warfarin treatment. In atrial fibrillation, the new anticoagulants decreased all-cause mortality. The new anticoagulants, compared with warfarin, showed lower incidents of fatal bleeding and hemorrhagic stroke, numerically lower incidents for major bleeding, numerically higher incidents for gastrointestinal bleeding, and higher numbers of patients discontinuing treatments due to adverse events. Bleeding risks may be increased for persons older than 75 years or those receiving warfarin who have good control over their symptoms. No head-to-head trials of new anticoagulants or large-scale observational studies have been conducted to reflect routine and long-term use of these agents.[9]

The new oral anticoagulants seem no more effective than warfarin for prevention of nonhemorrhagic stroke and systemic embolic events in the overall non-valvular atrial fibrillation population, but are generally associated with a lower risk of intracranial bleeding than warfarin. The numbers of all strokes and systemic embolic events avoided per 1000 patients per year were highly dependent on the geographic region and quality of warfarin therapy, with no significant differences in European patients or in centres with TTR ≥65%. The absolute risk reduction in major bleedings was mainly observed in centres with TTR <65%. The absolute risk difference in all-cause death per 1000 patients treated per year was highly dependent on quality of warfarin therapy. No significant differences between the NOAC and warfarin were seen in centres with TTR ≥65%, while a significant absolute risk reduction was achieved in centres with TTR <65%. The absolute benefit of the new oral anticoagulants tends to be of a lesser magnitude in Europe than in other regions, which might be due to regional differences in quality of oral anticoagulation and overall management of associated risk factors for thrombosis. [10]

A systematic review on data of clinical trials with dabigatran, rivaroxaban and apixaban in atrial fibrillation suggests all three agents are at least as efficacious as dose-adjusted warfarin, with similar major bleeding profiles. For patients who are unwilling to adhere to regular coagulation monitoring or whose therapeutic effect using warfarin is not optimal despite adequate monitoring and management, the new anticoagulants may provide alternatives in anticoagulation treatment.[11]

According a Cochrane analysis Factor Xa inhibitors like apixaban, significantly reduced the number of strokes and systemic embolic events compared with warfarin in patients with atrial fibrillation and a number needed to treat of approximately 100 patients per year. Factor Xa inhibitors also seem to reduce the number of major bleedings and intracranial haemorrhages compared with warfarin, though the evidence for a reduction of major bleedings is somewhat less robust. There is currently no conclusive evidence to determine which factor Xa inhibitor is more effective and safer for long-term anticoagulant treatment of patients with AF as head-to-head studies of the different factor Xa inhibitors have not yet been performed.[12]

Deep venous thrombosis[edit]

New oral anticoagulants are effective for thromboprophylaxis after total hip repair and total knee repair. Their clinical benefits over LMWH are marginal and offset by increased risk for major bleeding. There is no evidence that new anticoagulants have a better harm-benefit balance than LMWH. They have not been compared with warfarin in hip and knee operations.[6] In a systematic review comparing dabigatran, rivaroxaban and apixaban with enoxaparin for thromboprophylaxis after total hip or knee replacement, the new anticoagulants did not differ significantly for efficacy and safety. The risk of symptomatic venous thromboembolism was lower with rivaroxaban and similar with dabigatran and apixaban; compared with enoxaparin, the relative risk of clinically relevant bleeding was higher with rivaroxaban, similar with dabigatran and lower with apixaban. A higher efficacy of new anticoagulants was generally associated with a higher bleeding tendency.[13]

Adverse effects[edit]

According to a systematic review, adverse effects of new anticoagulants (dabigatran, rivaroxaban and apixaban) compared with warfarin were lower for fatal bleeding and hemorrhagic stroke, numerically lower for major bleeding, numerically higher for gastrointestinal bleeding, and higher for discontinuation due to adverse events. Bleeding risks may be increased for persons older than 75 years or those receiving warfarin who have good control.[9]

Bleeding risk[edit]

Apixaban increases the risk of bleeding and can cause serious, potentially fatal bleeding. The overall incidence of adverse reactions related to bleeding with apixaban was 24.3% in the Aristotle trial for atrial fibrillation. Common adverse reactions for apixaban were nose bleedings, contusion, haematuria, vaginal bleeding, haematoma, eye bleedings, anaemia and gastrointestinal bleeding.[14]

In people with deep venous thrombosis or pulmonary embolism, or the acute coronary syndrome, new oral anticoagulants increase risk for gastrointestinal bleeding compared with standard care. Number needed to harm 92 and 26. In people with acute coronary syndrome risk for clinically relevant bleeding was increased also. Number needed to harm 27[15]

Concomitant use of drugs affecting hemostasis increases the risk of bleeding including aspirin and other anti-platelet agents, other anticoagulants, heparin, thrombolytic agents, SSRIs, SNRIs, and NSAIDs.

Concomitant use of aspirin increased the major bleeding risk on apixaban with 1,6% (from 1.8% per year to 3.4% per year) and increased the bleeding risk on warfarin with 1,9% (from 2.7% per year to 4.6% per year) in a atrial fibrillation trial. [16]

Overdose[edit]

Overdose of apixaban may result in a higher risk of bleeding. In the event of haemorrhagic complications, treatment must be discontinued. There is no established way to reverse the anticoagulant effect of apixaban, which can be expected to persist for about 24 hours after the last dose (i.e., about two half-lives). A specific antidote is not available. [17] Although treatment with apixaban does not require routine monitoring of exposure, the Rotachrom® anti-FXa assay may be useful in exceptional situations where knowledge of apixaban exposure may help to inform clinical decisions, e.g., overdose and emergency surgery.[18]

Discontinuation[edit]

There is increased risk of (mainly ischemic) stroke with discontinuation of apixaban. Discontinuing apixaban in the absence of adequate alternative anticoagulation increases the risk of thrombotic events. An increased rate of stroke was observed during the transition from apixaban to warfarin in clinical trials in patients with nonvalvular atrial fibrillation within the first 30 days of transition. This resumption of events was probably related to inadequate control of anticoagulation, but induction of a hypercoagulable state by long-term treatment with the NOAC has not been ruled out.[19] If apixaban must be discontinued for a reason other than pathological bleeding, consider coverage with another anticoagulant.[17]

Drug interactions[edit]

Strong dual Inhibitors of CYP3A4 and P-gp (e.g., ketoconazole (Nizoral), itraconazole (Sporanox), ritonavir, or clarithromycin) increase the exposure to apixaban and increase the risk of bleeding . These medicinal products may increase apixaban exposure by 2-fold. Less potent inhibitors of CYP3A4 and/or P-gp as diltiazem and naproxen led to a 1.4-fold and 1,5 fold increase in mean apixaban concentration.

Strong dual inducers of CYP3A4 and P-gp decrease exposure to apixaban and increase the risk of stroke. Avoid concomitant use of apixaban with rifampin, carbamazepine (Tegretol), phenytoin and St. John’s wort, because such drugs may lead to a ~50% reduction in apixaban exposure.

Coadministration of antiplatelet agents, fibrinolytics, heparin, aspirin, and chronic NSAID increases the risk of bleeding.[17]

Long term safety[edit]

The safety (and efficacy) of apixaban in the longer term (beyond 1,7 years) are uncertain.

Contraindications[edit]

Apixaban must not be used in patients who are hypersensitive (allergic) to apixaban or any of the other ingredients.

It must not be used in patients who are actively bleeding, or who have liver disease which leads to problems with blood clotting and an increased risk of bleeding. The medicine must also not be used in patients with conditions putting them at risk of major bleeding, such as an ulcer in the gut, or in patients being treated with other anticoagulant medicines.[20]

The use is not recommended for creatinine clearance lower than 25 ml/min.

The use is not recommended in people receiving concomitant systemic treatment with strong inhibitors of both CYP3A4 and P-gp, such as as azole-antimycotics (e.g., ketoconazole, itraconazole, voriconazole and posaconazole) and HIV protease inhibitors (e.g., ritonavir)[21]

Pharmacokinetics[edit]

The bioavailability of apixaban is 50%. After intake the maximum blood level is reached after 3 to 4 hours. Apixaban can be taken with or without food. Plasma protein binding in humans is approximately 87%. The decomposition proceeds via CYP3A4/5 to inactive metabolites. Of the administered apixaban dose in humans, approximately 25% was recovered as metabolites, with the majority recovered in faeces. Renal excretion of apixaban accounts for approximately 27% of total clearance. There were additional contributions from biliary and direct intestinal excretion. The half-life is approximately 12 hours. In individuals with mild (creatinine clearance 51-80 ml/min), moderate (creatinine clearance 30-50 ml/min) and severe (creatinine clearance 15-29 ml/min) renal impairment, apixaban plasma concentrations (AUC) were increased 16, 29, and 44% respectively, compared to individuals with normal creatinine clearance. [22]

Approval[edit]

Apixaban has been available in Europe since May 2011 and was approved for preventing venous thromboembolism after elective hip or knee replacement.[23] In November 2012 it was approved in Europe for prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation.[24] The FDA approved apixaban in December 2012 with an indication of reducing the risk of stroke and dangerous blood clots (systemic embolism) in patients with atrial fibrillation that is not caused by a heart valve problem.[25]

References[edit]

  1. ^ "Bristol-Myers Squibb News Release 26 April 2007". Archived from the original on 11 September 2007. Retrieved 2007-09-15. 
  2. ^ Nainggolan, Lisa. "Apixaban better than European enoxaparin regimen for preventing VTE". Retrieved 2011-04-01. 
  3. ^ http://packageinserts.bms.com/pi/pi_eliquis.pdf
  4. ^ Adam SS, McDuffie JR, Ortel TL, Williams JW (December 2012). "Comparative effectiveness of warfarin and new oral anticoagulants for the management of atrial fibrillation and venous thromboembolism: a systematic review". Ann. Intern. Med. 157 (11): 796–807.doi:10.7326/0003-4819-157-10-201211200-00532
  5. ^ Wann LS, Curtis AB, Ellenbogen KA, Estes NA, Ezekowitz MD, Jackman WM, January CT, Lowe JE, Page RL, Slotwiner DJ, Stevenson WG, Tracy CM, Fuster V, Rydén LE, Cannom DS, Crijns HJ, Curtis AB, Ellenbogen KA, Halperin JL, Kay GN, Le Heuzey JY, Lowe JE, Olsson SB, Prystowsky EN, Tamargo JL, Wann LS, Jacobs AK, Anderson JL, Albert N, Creager MA, Ettinger SM, Guyton RA, Halperin JL, Hochman JS, Kushner FG, Ohman EM, Stevenson WG, Yancy CW (March 2011). "2011 ACCF/AHA/HRS focused update on the management of patients with atrial fibrillation (update on Dabigatran): a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines". Circulation 123 (10): 1144–50. doi:10.1161/CIR.0b013e31820f14c0. PMID 21321155. 
  6. ^ a b Adam SS, McDuffie JR, Lachiewicz PF, Ortel TL, Williams JW (August 2013). "Comparative effectiveness of new oral anticoagulants and standard thromboprophylaxis in patients having total hip or knee replacement: a systematic review". Ann. Intern. Med. 159 (4): 275–84. doi:10.7326/0003-4819-159-4-201308200-00008. PMID 24026260. 
  7. ^ Komócsi A, Vorobcsuk A, Kehl D, Aradi D (November 2012). "Use of new-generation oral anticoagulant agents in patients receiving antiplatelet therapy after an acute coronary syndrome: systematic review and meta-analysis of randomized controlled trials". Arch. Intern. Med. 172 (20): 1537–45. doi:10.1001/archinternmed.2012.4026. PMID 23007264. 
  8. ^ Oldgren J, Wallentin L, Alexander JH, James S, Jönelid B, Steg G, Sundström J (June 2013). "New oral anticoagulants in addition to single or dual antiplatelet therapy after an acute coronary syndrome: a systematic review and meta-analysis". Eur. Heart J. 34 (22): 1670–80. doi:10.1093/eurheartj/eht049. PMC 3675388. PMID 23470494. 
  9. ^ a b Adam SS, McDuffie JR, Ortel TL, Williams JW (December 2012). "Comparative effectiveness of warfarin and new oral anticoagulants for the management of atrial fibrillation and venous thromboembolism: a systematic review". Ann. Intern. Med. 157 (11): 796–807. doi:10.7326/0003-4819-157-10-201211200-00532. PMID 22928173. 
  10. ^ Gomez-Outes A, Terleira-Fernandez AI, Calvo-Rojas G, Suarez-Gea ML, Vargas-Castrillon E. Dabigatran, rivaroxaban, or apixaban versus warfarin in patients with nonvalvular atrial fibrillation: a systematic review and meta-analysis of subgroups. Thrombosis 2013; 2013: 640723 http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0062678/
  11. ^ O'Dell KM, Igawa D, Hsin J (April 2012). "New oral anticoagulants for atrial fibrillation: a review of clinical trials". Clin Ther 34 (4): 894–901. doi:10.1016/j.clinthera.2012.01.019. PMID 22417716. 
  12. ^ Factor Xa inhibitors versus vitamin K antagonists for preventing cerebral or systemic embolism in patients with atrial fibrillation Karsten MH Bruins Slot, Eivind Berge DOI: 10.1002/14651858.CD008980.pub2
  13. ^ Gómez-Outes A, Terleira-Fernández AI, Suárez-Gea ML, Vargas-Castrillón E (2012). "Dabigatran, rivaroxaban, or apixaban versus enoxaparin for thromboprophylaxis after total hip or knee replacement: systematic review, meta-analysis, and indirect treatment comparisons". BMJ 344: e3675. doi:10.1136/bmj.e3675. PMC 3375207. PMID 22700784. 
  14. ^ EMA apixaban summary of product characteristics http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002148/WC500107728.pdf
  15. ^ Vanassche, Thomas; Connolly, Stuart J.; Eikelboom, John W. (18 February 2014). "Review: New oral anticoagulants increase GI bleeding in venous thrombosis and ACS". Annals of Internal Medicine 160 (4): JC4. doi:10.7326/0003-4819-160-4-201402180-02004. 
  16. ^ EMA apixaban summary of product characteristics http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002148/WC500107728.pdf
  17. ^ a b c IMPORTANT SAFETY INFORMATION FOR ELIQUIS -apixaban-supplemental-new-drug-application-review-
  18. ^ EMA apixaban summary of product characteristics http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002148/WC500107728.pdf
  19. ^ Gomez-Outes A, Terleira-Fernandez AI, Calvo-Rojas G, Suarez-Gea ML, Vargas-Castrillon E. Dabigatran, rivaroxaban, or apixaban versus warfarin in patients with nonvalvular atrial fibrillation: a systematic review and meta-analysis of subgroups. Thrombosis 2013; 2013: 640723 http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0062678/
  20. ^ EMA Eliquis ema.europa.eu
  21. ^ EMA apixaban summary of product characteristics http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002148/WC500107728.pdf
  22. ^ EMA apixaban summary of product characteristics http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002148/WC500107728.pdf
  23. ^ "ELIQUIS® (apixaban) Approved In Europe For Preventing Venous Thromboembolism After Elective Hip Or Knee Replacement" (Press release). Pfizer. April 20, 2012. Retrieved 2012-05-29. 
  24. ^ ELIQUIS®(apixaban) Approved in Europe for Prevention of Stroke and Systemic Embolism in Patients with Nonvalvular Atrial Fibrillation http://news.bms.com/press-release/financial-news/eliquisapixaban-approved-europe-prevention-stroke-and-systemic-embolism
  25. ^ "FDA approves Eliquis to reduce the risk of stroke, blood clots in patients with non-valvular atrial fibrillation". FDA. Retrieved 2012-12-30.