Do Not Use the New Oral Blood Thinner Apixaban (ELIQUIS)

Apixaban (ELIQUIS) is a new oral anticoagulant (blood thinner). It was first approved by the Food and Drug Administration (FDA) in December 2012 for decreasing the risk of stroke and systemic embolism (lodging of a blood clot inside a blood vessel) in patients with non-valvular atrial fibrillation (a common type of irregular heart rhythm not caused by a heart valve problem).[1] The drug was subsequently approved to reduce the risk of deep vein thrombosis (DVT, a blood clot in a large vein, usually in the leg) and pulmonary embolism (PE, a clot lodged in a blood vessel in the lungs) in patients who have undergone hip or knee replacement surgery.[2] It also has been approved to treat DVT and PE and to reduce the risk of recurrence of these conditions.

Like other new oral anticoagulants — dabigatran (PRADAXA), edoxaban (SAVAYSA) and rivaroxaban (XARELTO) — apixaban has been marketed heavily to patients.

Public Citizen’s Health Research Group continues to classify apixaban and all other new oral anticoagulants as Do Not Use drugs. Although clinical trials show that apixaban has similar or slightly better benefits than well-studied standard anticoagulants such as warfarin (COUMADIN, JANTOVEN) and low-molecularweight heparins (LMWHs) such as enoxaparin (LOVENOX), apixaban’s long-term risk-benefit balance is still unknown. Additionally, there is no test to monitor the adequacy of apixaban’s dosing, nor is there an adequately validated antidote to reverse its effect in case of major bleeding or emergency surgery.

Limited benefit over standard therapy

The effectiveness of apixaban for its first approved use was evaluated in the ARISTOTLE trial, which involved more than 18,000 subjects with non-valvular atrial fibrillation. The trial showed that fewer subjects taking apixaban (1.3 percent per year) had a stroke or systemic embolism event than did subjects taking warfarin (1.6 percent per year). The small difference in these rates, which was mainly due to a lower number of hemorrhagic strokes (strokes associated with bleeding into the brain) in subjects receiving apixaban, reached statistical significance. Subjects receiving apixaban also experienced slightly fewer deaths than those in the warfarin group, [3] but an FDA reviewer described the difference as “fragile” because “a swing of one death” would have rendered this difference statistically insignificant.[4]

This trial also showed a small but statistically significant lower major bleeding rate in the apixaban group than in the warfarin group (2.1 versus 3.1 bleeding events per 100 patients per year, respectively).[5] Apixaban group subjects also had a slightly lower rate of intracranial (inside the skull) bleeding than did warfarin group subjects.[6] However, the rate of major gastrointestinal bleeding was similar for the two groups.[7]

Notably, the ARISTOTLE trial suffered from a number of methodological flaws that were identified by FDA reviewers. First, nearly 600 patients discontinued the trial early, and their final survival status was not known to the trial researchers.[8] Second, an estimated 10 percent or more of the subjects may have erroneously received at least one bottle of the drug intended for the other group during the trial.[9] Third, there were problems with the quality of how subjects were randomized during the trial.[10]

Three trials, called the ADVANCE trials, enrolled nearly 11,700 subjects collectively and supported approval of apixaban for use after hip or knee replacement.[11] Two of these trials showed that apixaban was more effective than enoxaparin in reducing the risk of a composite endpoint: death, DVT and nonfatal PE.[12] However, two of the ADVANCE trials also showed that apixaban did not have a lower bleeding risk than enoxaparin.[13]

The AMPLIFY trial, which enrolled more than 5,200 subjects and supported approval of apixaban for the treatment of DVT and PE, found that the drug’s effectiveness was similar to that of the standard treatment with enoxaparin (for at least five days) followed by warfarin.[14] However, the apixaban group had fewer major bleeding events than the enoxaparin/warfarin group in this trial.[15]

Other issues

Bleeding is an inevitable risk with any anticoagulant. The availability of a monitoring test of coagulation status and a validated antidote to counter adverse bleeding events are important factors to consider when choosing a suitable anticoagulant.

Although a routine lab test is readily available to monitor warfarin levels in the blood and another test can be used to monitor enoxaparin’s effect in case of bleeding, no useful monitoring tests are currently available for apixaban. Similarly, warfarin and enoxaparin have validated antidotes, but no wellstudied antidote is currently available for apixaban. Even dialysis (filtering of the blood through a machine) does not reduce levels of apixaban in the blood.[16] Moreover, there are no established treatment procedures for apixaban patients when they experience major or life-threatening bleeding or require emergency surgery.[17]

It is worth noting that the FDA has been considering an approval application for an experimental drug, andexanet (ANDEXXA), that is purported to reverse adverse bleeding events caused by apixaban and a few other new oral anticoagulants (the expected decision date at press time was May 4, 2018).[18] However, this drug application is based on interim results from a small number of patients enrolled in an ongoing trial that does not use a control group.[19] This trial is supposed to enroll 350 patients and be completed by late 2022.[20] Even if the FDA approves andexanet this year, we believe that evidence from more robust (large, double-blind, randomized) trials is needed before we can recommend this investigational antidote.

The fact that apixaban performed similarly to or slightly better than standard anticoagulants in clinical trials, particularly in terms of lower bleeding rates, must be weighed against the drug’s lack of a monitoring test and a validated antidote. Also, the long-term profile of this new drug is currently unknown. Therefore, we do not recommend its use over wellstudied standard anticoagulants.

What You Can Do

Do not start taking apixaban if you undergo hip or knee replacement surgery; have non-valvular atrial fibrillation; or develop DVT or PE, or if you are at risk of experiencing a recurrence of either condition. Instead, ask your doctor to prescribe a LMWH or warfarin, as appropriate. If you are currently taking apixaban, talk with your doctor about switching to the aforementioned standard anticoagulants. Never stop taking apixaban or any anticoagulant without consulting your doctor first because doing so increases your risk of blood clots and stroke.

Report all serious adverse effects related to anticoagulants or any drug to the FDA’s MedWatch adverse event reporting program by visiting www. fda.gov/MedWatch or by calling 800-FDA-1088.

References

[1] Food and Drug Administration. Approval letter for Bristol-Myers Squibb re. NDA 202155 – eliquis (apixaban) 2.5 and 5 mg tablets. December 28, 2012. https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2012/202155Orig1s000ltr.pdf. Accessed April 6, 2018.

[2] Bristol-Myers Squibb Company. Label: apixaban (ELIQUIS). February 2018. www.accessdata.fda.gov/drugsatfda_docs/label/2018/202155s018lbl.pdf. Accessed April 6, 2018.

[3] Ibid.

[4] Food and Drug Administration. Application number: 202155Orig1s000. Medical review(s): Apixaban. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202155Orig1s000MedR.pdf. Accessed April 6, 2018. PDF page 73.

[5] Bristol-Myers Squibb Company. Label: apixaban (ELIQUIS). February 2018. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/202155s018lbl.pdf. Accessed April 6, 2018.

[6] Ibid.

[7] Ibid.

[8] Food and Drug Administration. Application number: 202155Orig1s000. Medical review(s): Apixaban. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202155Orig1s000MedR.pdf. Accessed April 6, 2018. PDF page 243.

[9] Ibid. PDF page 118.

[10] Ibid. PDF page 144.

[11] Bristol-Myers Squibb Company. Label: apixaban (ELIQUIS). February 2018. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/202155s018lbl.pdf. Accessed April 6, 2018.

[12] Ibid.

[13] Deeks ED. Apixaban: A review of its use in the prevention of venous thromboembolism after knee or hip replacement surgery. Drugs. 2012;72(9):1271-1291.

[14] Bristol-Myers Squibb Company. Label: apixaban (ELIQUIS). February 2018. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/202155s018lbl.pdf. Accessed April 6, 2018.

[15] Ibid.

[16] Bleeding with dabigatran, rivaroxaban, apixaban. No antidote, and little clinical experience. Prescrire Int. 2013;22(139):155-159.

[17] Ansell J. New oral anticoagulants should not be used as first-line agents to prevent thromboembolism in patients with atrial fibrillation. Circulation. 2012;125(1):165-170.

[18] Portola Pharmaceuticals. News release: Portola Pharmaceuticals provides update on biologics license application (BLA) for AndexXa® (andexanet alfa). December 22, 2017. http://investors.portola.com/phoenix.zhtml?c=198136&p=irol-newsroomArticle&ID=2324012. Accessed April 6, 2018.

[19] American College of Cardiology. Drug stops dangerous bleeding in patients taking factor Xa inhibitors. March 12, 2018. http://www.acc.org/about-acc/press-releases/2018/03/10/12/18/mon-1045am-drug-stops-dangerous-bleeding-in-patients-taking-factor-xa-inhibitors. Accessed April 6, 2018.

[20] Prospective, open-label study of andexanet alfa in patients receiving a factor xa inhibitor who have acute major bleeding (ANNEXA-4). https://clinicaltrials.gov/ct2/show/study/NCT02329327. Accessed April 6, 2018.