Apixaban

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Apixaban
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 namesEliquis
AHFS/Drugs.comentry
Licence dataEMA:LinkUS FDA:link
Pregnancy cat.B (US)
Legal statusPOM (UK) -only (US)
RoutesOral
Pharmacokinetic data
Bioavailabilityca. 50%
Half-life9–14 h
Excretion75% biliary, 25% renally
Identifiers
CAS number503612-47-3 YesY
ATC codeB01AF02
PubChemCID 10182969
DrugBankDB07828
ChemSpider8358471 YesY
UNII3Z9Y7UWC1J YesY
KEGGD03213 YesY
ChEBICHEBI:72296 N
ChEMBLCHEMBL231779 YesY
SynonymsBMS-562247-01
Chemical data
FormulaC25H25N5O4 
Mol. mass459.497 g/mol
 N (what is this?)  (verify)
 
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Apixaban
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 namesEliquis
AHFS/Drugs.comentry
Licence dataEMA:LinkUS FDA:link
Pregnancy cat.B (US)
Legal statusPOM (UK) -only (US)
RoutesOral
Pharmacokinetic data
Bioavailabilityca. 50%
Half-life9–14 h
Excretion75% biliary, 25% renally
Identifiers
CAS number503612-47-3 YesY
ATC codeB01AF02
PubChemCID 10182969
DrugBankDB07828
ChemSpider8358471 YesY
UNII3Z9Y7UWC1J YesY
KEGGD03213 YesY
ChEBICHEBI:72296 N
ChEMBLCHEMBL231779 YesY
SynonymsBMS-562247-01
Chemical data
FormulaC25H25N5O4 
Mol. mass459.497 g/mol
 N (what is this?)  (verify)

Apixaban (INN, trade name Eliquis) is an anticoagulant for the prevention of venous thromboembolism and venous thromboembolic events. It is a direct factor Xa inhibitor. Apixaban has been available in Europe since May 2011 and was approved for preventing venous thromboembolism after elective hip or knee replacement.[1] 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.[2] The drug was developed in a joint venture by Pfizer and Bristol-Myers Squibb.[3][4]

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. [5] 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.[6] 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.[7]

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.[8]

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).[9][10]

Systematic reviews[edit]

Prevention of stroke in 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.[11]

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.[12]

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.[13]

Prevention of deep venous thrombosis: perioperative[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.[8] 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.[14]

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.[11]

Bleeding risk[edit]

Apixaban increases the risk of bleeding and can cause serious, potentially fatal bleeding. 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.

Overdose[edit]

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. [15]

Discontinuation[edit]

There is increased risk of 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. If apixaban must be discontinued for a reason other than pathological bleeding, consider coverage with another anticoagulant.[15]

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 . Avoid them or reduce the dosis of apixaban.

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 will decrease exposure to apixaban.

Coadministration of antiplatelet agents, fibrinolytics, heparin, aspirin, and chronic NSAID increases the risk of bleeding.[15]

Long term safety[edit]

The safety (and efficacy) of apixaban in the longer term (beyond two 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.[16]

Pivotal clinical trials for authorisation[edit]

Prevention of venous thromboembolism: perioperative[edit]

In the ADVANCE trials apixaban 2.5 mg orally twice daily for deep venous thromboembolism prophylaxis following knee and hip replacement surgery was equivalent to standard enoxaparin with similar bleeding rates.[17][18][19][20]

Treatment and prevention of venous thromboembolism[edit]

The AMPLIFY trial found a non inferior effect for apixaban (10 mg twice daily for 7 days, followed by 5 mg twice daily for 6 months) in prevention of recurrences of venous thromboembolism and less major bleedings against LMWH and warfarin treatment.[21]

Prevention of stroke in atrial fibrillation[edit]

A 2011 trial, AVERROES, showed that, in patients with atrial fibrillation who have failed or are not candidates for vitamin K antagonist therapy, apixaban (5 mg twice daily), as compared with aspirin, reduced the risk of stroke or systemic embolism by 55%. Major bleeding events were similar for both groups. The trial was stopped early because the efficacy of apixaban had been shown, while the mean follow-up period was 1.1 years.[22]

A systematic review of warfarin trials against aspirin for atrial fibrillation gives a similar risk decrease of 45% in favour of warfarin for any stroke, gives a higher risk of major bleeding and a lower risk of cardiovascular events.[23]

In the ARISTOTLE study, a head-to-head study of apixaban 5 mg twice daily versus warfarin in patients with atrial fibrillation,[24][25] apixaban was superior to warfarin at preventing stroke, hemorrhagic stroke or systemic embolism and was superior in avoiding major bleeding. The rate of ischaemic stroke was not significantly lower. There was no exces risk of myocardial infarction or gastrointestinal mayor bleeding. In this study 30.5% of patients took aspirin with warfarin. Time within the therapeutic range was mean 62%. This is poorly controlled warfarin therapy considering that such a range can be achieved 76% of the time among patients receiving warfarin in Sweden.[26] Risk for stroke was low: mean CHADS2 score 2.1.[27] For more in deepth analysis see RE-LY trial with dabigatran.

In the ARISTOTLE trial, serious misconduct, including fraud, was detected at the Chinese trial sites. A senior clinical site manager, with another monitor, “altered source records to cover up evidence of good clinical practice violations.” According to FDA documents the company told the FDA that patients got the wrong medicine, records were secretly changed and “serious adverse events” went unreported.[28] This eventually led FDA investigators to question data from 24 of the 36 sites in China.[29] This led to additional questions during the FDA approval process and delayed approval of the drug by nine months.[30] Ultimately the FDA reviewers concluded that the results of the trial were not substantially altered by the problem.

Negative trials[edit]

Prevention of venous thromboembolism: medically ill patients[edit]

In the ADOPT study patients hospitalised for medical reasons and with risk of venous thromboemboli, following an extended treatment of 25 days with apixaban 2.5 mg twice per day had no significant added value above enoxaparin 40 mg daily for about seven days for the prevention of venous thromboembolic events, but more major hemorrhages occurred.[31]

Currently available evidence does not indicate that routine administration of post-discharge extended prophylaxis will be beneficial to the patients admitted for medical illness.[32]

Prevention of recurrences of heart infarction[edit]

A 2011 trial, APPRAISE-2, showed patients receiving apixaban 5 mg twice daily against placebo after acute coronary syndrome experienced an 150% increased rate of major bleeding episodes without a significant reduction in recurrent ischemic events, so the trial was terminated early. A greater number of intracranial and fatal bleeding events occurred with apixaban than with placebo. With a median follow up of 241 days, absolute risk increase for TIMI major bleeding was 0.8%, for TIMI major and minor bleeding 1.4%, for fatal bleeding 0.1%, for intracranial bleeding 0.2% and for any bleeding 10.1% against placebo. The majority of the patients (81%) were receiving aspirin plus a P2Y12-receptor antagonist, predominantly clopidogrel. The increase in bleeding events with apixaban, as compared with placebo, was seen both in patients taking combination antiplatelet therapy and in patients taking aspirin alone. More patients discontinued apixaban than the placebo drug. The most common reasons for discontinuation of the study drug were adverse events (8.5% in the apixaban group vs. 6.5% in the placebo group) and withdrawal of consent (5.3% vs. 4.2%).[33] The trial points to the possible dangers of adding new anticoagulants to combination antiplatelet therapy.(Triple therapy).

According 2 systematic reviews in patients with a recent acute coronary syndrome, the addition of a new oral anticoagulant to antiplatelet therapy results in a modest reduction in cardiovascular events but a substantial increase in bleeding, most pronounced when new oral anticoagulants are combined with dual antiplatelet therapy. The use of anti-Xa or direct thrombin inhibitors is associated with a dramatic increase in major bleeding events, which might offset all ischemic benefits in patients receiving antiplatelet therapy after an ACS.[9][10]

See also[edit]

References[edit]

  1. ^ "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. 
  2. ^ "FDA approves Eliquis to reduce the risk of stroke, blood clots in patients with non-valvular atrial fibrillation". FDA. Retrieved 2012-12-30. 
  3. ^ "Bristol-Myers Squibb News Release 26 April 2007". Archived from the original on 11 September 2007. Retrieved 2007-09-15. 
  4. ^ Nainggolan, Lisa. "Apixaban better than European enoxaparin regimen for preventing VTE". Retrieved 2011-04-01. 
  5. ^ http://packageinserts.bms.com/pi/pi_eliquis.pdf
  6. ^ 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
  7. ^ 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. 
  8. ^ 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. 
  9. ^ a b 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. 
  10. ^ a b 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. 
  11. ^ 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. 
  12. ^ 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. 
  13. ^ 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
  14. ^ 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. 
  15. ^ a b c IMPORTANT SAFETY INFORMATION FOR ELIQUIS -apixaban-supplemental-new-drug-application-review-
  16. ^ EMA Eliquis ema.europa.eu
  17. ^ Lassen MR, Raskob GE, Gallus A, Pineo G, Chen D, Hornick P (March 2010). "Apixaban versus enoxaparin for thromboprophylaxis after knee replacement (ADVANCE-2): a randomised double-blind trial". Lancet 375 (9717): 807–15. doi:10.1016/S0140-6736(09)62125-5. PMID 20206776. 
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  21. ^ Oral Apixaban for the Treatment of Acute Venous Thromboembolism Giancarlo Agnelli, M.D., Harry R. Buller, M.D., Ph.D., Alexander Cohen, M.D., Madelyn Curto, D.V.M., Alexander S. Gallus, M.D., Margot Johnson, M.D., Urszula Masiukiewicz, M.D., Raphael Pak, Ph.D., John Thompson, Ph.D., Gary E. Raskob, Ph.D., and Jeffrey I. Weitz, M.D. for the AMPLIFY Investigators N Engl J Med 2013; 369:799-808 August 29, 2013http://www.nejm.org/doi/full/10.1056/NEJMoa1302507
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  28. ^ Eliquis (apixaban) 2.5 and 5 mg Tablets Company: Bristol-Myers Squibb Application No.: 202155 Approval Date: 12/28/2012 approval data Other letters
  29. ^ "Roller Coaster Path To Approval For Eliquis Uncovered By FDA Documents". Forbes. 2013-06-21. 
  30. ^ "Chinese Trial Misconduct Delayed Bristol-Myers Medicine". Bloomberg. July 9, 2013. 
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  32. ^ Sharma A, Chatterjee S, Lichstein E, Mukherjee D (October 2012). "Extended thromboprophylaxis for medically ill patients with decreased mobility: does it improve outcomes?". J. Thromb. Haemost. 10 (10): 2053–60. doi:10.1111/j.1538-7836.2012.04874.x. PMID 22863355. 
  33. ^ Alexander JH, Lopes RD, James S, Kilaru R, He Y, Mohan P, Bhatt DL, Goodman S, Verheugt FW, Flather M, Huber K, Liaw D, Husted SE, Lopez-Sendon J, De Caterina R, Jansky P, Darius H, Vinereanu D, Cornel JH, Cools F, Atar D, Leiva-Pons JL, Keltai M, Ogawa H, Pais P, Parkhomenko A, Ruzyllo W, Diaz R, White H, Ruda M, Geraldes M, Lawrence J, Harrington RA, Wallentin L (August 2011). "Apixaban with antiplatelet therapy after acute coronary syndrome". N. Engl. J. Med. 365 (8): 699–708. doi:10.1056/NEJMoa1105819. PMID 21780946.