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doi:10.1111/j.1538-7836.2007.02764.x is a recent trial in VTE post-TKR. User:Jfdwolff/Apixaban is a dump that we can use to expand this article in the medium-to-long term. JFW | T@lk 00:44, 16 September 2007 (UTC)

Note regarding Conflict of Interest and removal of edit from 9 July 2013[edit]

Statement from Johnson & Johnson: It has come to our attention that an individual using a computer associated with a Johnson & Johnson IP address added the following content to this article, without authorization from the company. Because a Johnson & Johnson company markets a competitor product, we recognize this is a Conflict of Interest under Wikipedia’s policy. Accordingly, we have removed the edit.

"In the ARISTOTLE trial, concerns arose about serious misconduct, including fraud, at the Chinese trial sites.[1] This led to additional questions during the FDA approval process and delayed approval of the drug by nine months.[2] "

Thank you, Scott, for explaining the edit. I actually reinstated it before you commented here, because I didn't see anything here. We care more about whether or not the material is neutral and verifiable. Is there any reason to think it is not? Do you think it is undue weight? Thanks. Also, you can sign your posts with four tildes as described at H:Cheatsheet. Best. Biosthmors (talk) 19:46, 5 August 2013 (UTC)
I see nothing wrong with the edit itself - it appears constructive. If J&J wants to make it clear that the edit was from someone acting on his own behalf, rather than something authorized by J&J, I think the statement here on this talk page is sufficient. Removing the edit is not necessary (nor is it particularly helpful). -- Ed (Edgar181) 22:54, 5 August 2013 (UTC)

Secondary sources[edit]

Secondary sources need to be used. This is overly instructive and who says these trials are pivotal?

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.[3][4][5][6]

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.[7]

In a systematic review 5 studies were included about dabigatran, rivaroxaban, apixaban and edoxaban against vitamin K antagonists. NOACs have a comparable efficacy for recurrent venous thromboembolism, fatal pulmonary embolism and overall mortality and are associated with a significantly lower risk of bleeding complications, compared to warfarin although the NNT to prevent one major bleeding is relatively high at 149.[8]

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.[9]

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.[10]

In the ARISTOTLE study, a head-to-head study of apixaban 5 mg twice daily versus warfarin in patients with atrial fibrillation,[11][12] 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.[13] Risk for stroke was low: mean CHADS2 score 2.1.[14] 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.[15] This eventually led FDA investigators to question data from 24 of the 36 sites in China.[16] This led to additional questions during the FDA approval process and delayed approval of the drug by nine months.[17] 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.[18]

Currently available evidence does not indicate that routine administration of post-discharge extended prophylaxis will be beneficial to the patients admitted for medical illness.[19]

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%).[20] 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.[21][22]

Doc James (talk · contribs · email) (if I write on your page reply on mine) 00:01, 16 March 2014 (UTC)

Chinese clinical sites and effects on overall mortality[edit]

I removed the statement that "The FDA has raised concerns with misconduct at at least one of the research sites in China where the evidence upon which this recommendation is partly based", which cites the FDA's review document. This statement does not accurately reflect the FDA's position as shown in the final approved label, which states:

"ELIQUIS treatment resulted in a significantly lower rate of all-cause death (p = 0.046) than did treatment with warfarin, primarily because of a reduction in cardiovascular death, particularly stroke deaths. Non-vascular death rates were similar in the treatment arms."

While the approval summary documents some internal dissent (by a single staffer who was not an assigned reviewer of this NDA) around this issue, the approved label represents the FDA's overall position. There is probably room for debate on whether the existence of a single dissenting FDA staffer is worth mentioning in the article. My position on that would be that the POV of a single staffer is equivalent to a primary research finding, and thus at least in spirit incompatible with WP:MEDRS. Formerly 98 talk|contribs|COI statement 16:08, 6 April 2015 (UTC)

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  1. ^ "Roller Coaster Path To Approval For Eliquis Uncovered By FDA Documents". Forbes. 6/21/2013.  Check date values in: |date= (help)
  2. ^ "Chinese Trial Misconduct Delayed Bristol-Myers Medicine". Bloomberg. July 9, 2013. 
  3. ^ 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. PMID 20206776. doi:10.1016/S0140-6736(09)62125-5. 
  4. ^ Lassen MR, Raskob GE, Gallus A, Pineo G, Chen D, Portman RJ (August 2009). "Apixaban or enoxaparin for thromboprophylaxis after knee replacement". N. Engl. J. Med. 361 (6): 594–604. PMID 19657123. doi:10.1056/NEJMoa0810773. 
  5. ^ Lassen MR, Gallus A, Raskob GE, Pineo G, Chen D, Ramirez LM (December 2010). "Apixaban versus enoxaparin for thromboprophylaxis after hip replacement". N. Engl. J. Med. 363 (26): 2487–98. PMID 21175312. doi:10.1056/NEJMoa1006885. 
  6. ^ Nainggolan, Lisa. "Apixaban better than European enoxaparin regimen for preventing VTE". by WebMD. Retrieved 2011-04-01. 
  7. ^ 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, 2013
  8. ^ van der Hulle T, Kooiman J, den Exter PL, Dekkers OM, Klok FA, Huisman MV.Effectiveness and safety of novel oral anticoagulants compared with vitamin K-antagonists in the treatment of acute symptomatic venous thromboembolism- a systematic review and meta-analysis.J Thromb Haemost. 2013 Dec 13doi: 10.1111/jth.12485
  9. ^ Connolly SJ, Eikelboom J, Joyner C, Diener HC, Hart R, Golitsyn S, Flaker G, Avezum A, Hohnloser SH, Diaz R, Talajic M, Zhu J, Pais P, Budaj A, Parkhomenko A, Jansky P, Commerford P, Tan RS, Sim KH, Lewis BS, Van Mieghem W, Lip GY, Kim JH, Lanas-Zanetti F, Gonzalez-Hermosillo A, Dans AL, Munawar M, O'Donnell M, Lawrence J, Lewis G, Afzal R, Yusuf S (March 2011). "Apixaban in patients with atrial fibrillation". N. Engl. J. Med. 364 (9): 806–17. PMID 21309657. doi:10.1056/NEJMoa1007432. 
  10. ^ van Walraven C, Hart RG, Singer DE, et al. Oral anticoagulants vs aspirin in nonvalvular atrial fibrillation: an individual patient meta-analysis. JAMA 2002;288:2441-2448 oral anticoagulants versus aspirin
  11. ^ Clinical trial number NCT00412984 for "Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation (ARISTOTLE)" at
  12. ^ Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, Hanna M, Al-Khalidi HR, Ansell J, Atar D, Avezum A, Bahit MC, Diaz R, Easton JD, Ezekowitz JA, Flaker G, Garcia D, Geraldes M, Gersh BJ, Golitsyn S, Goto S, Hermosillo AG, Hohnloser SH, Horowitz J, Mohan P, Jansky P, Lewis BS, Lopez-Sendon JL, Pais P, Parkhomenko A, Verheugt FW, Zhu J, Wallentin L (September 2011). "Apixaban versus warfarin in patients with atrial fibrillation". N. Engl. J. Med. 365 (11): 981–92. PMID 21870978. doi:10.1056/NEJMoa1107039. 
  13. ^ Wieloch M, Själander A, Frykman V, Rosenqvist M, Eriksson N, Svensson PJ (September 2011). "Anticoagulation control in Sweden: reports of time in therapeutic range, major bleeding, and thrombo-embolic complications from the national quality registry AuriculA". Eur. Heart J. 32 (18): 2282–9. PMID 21616951. doi:10.1093/eurheartj/ehr134. 
  14. ^ Husten L (2011-06-22). "ELIQUIS® (apixaban) Meets Primary and Key Secondary Endpoints in Phase 3 ARISTOTLE Study". CardioBrief. Retrieved 2011-06-23.
  15. ^ Eliquis (apixaban) 2.5 and 5 mg Tablets Company: Bristol-Myers Squibb Application No.: 202155 Approval Date: 12/28/2012 approval data Other letters
  16. ^ "Roller Coaster Path To Approval For Eliquis Uncovered By FDA Documents". Forbes. 2013-06-21. 
  17. ^ "Chinese Trial Misconduct Delayed Bristol-Myers Medicine". Bloomberg. July 9, 2013. 
  18. ^ Goldhaber SZ, Leizorovicz A, Kakkar AK, Haas SK, Merli G, Knabb RM, Weitz JI (December 2011). "Apixaban versus enoxaparin for thromboprophylaxis in medically ill patients". N. Engl. J. Med. 365 (23): 2167–77. PMID 22077144. doi:10.1056/NEJMoa1110899. 
  19. ^ 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. PMID 22863355. doi:10.1111/j.1538-7836.2012.04874.x. 
  20. ^ 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. PMID 21780946. doi:10.1056/NEJMoa1105819. 
  21. ^ Cite error: The named reference archinte.jamanetwork was invoked but never defined (see the help page).
  22. ^ Cite error: The named reference pmid23470494 was invoked but never defined (see the help page).