The Blood Thinner Apixaban (ELIQUIS): An Update

Anticoagulants, or blood thinners, are a class of medications prescribed for the treatment or prevention of blood clots forming in the heart, veins or arteries to reduce a patient’s risk of having a heart attack or stroke.[1]

Several older anticoagulants, such as warfarin (JANTOVEN and generics), and injectable low-molecular-weight heparins (such as enoxaparin [LOVENOX and generics]) are well-studied and for many years have been standard treatments for patients who are at risk of blood clots, such as patients suffering from nonvalvular atrial fibrillation (a common type of irregular heart rhythm not caused by a heart valve problem).[2] A more recent class of blood thinners is direct-acting oral anticoagulants (DOACs), which includes apixaban (ELIQUIS and generics), rivaroxaban (XARELTO) and dabigatran (PRADAXA and generics). Public Citizen’s Health Research Group has previously classified all DOACs as Do Not Use drugs because the various safety concerns associated with these drugs outweighed their benefits.

In 2018, we classified apixaban as a Do Not Use drug for several reasons. Unlike warfarin, blood levels of apixaban cannot be monitored through a laboratory test and no well-studied antidote is available. In 2021, we designated apixaban’s antidote, andexanet alfa (ANDEXXA), as Do Not Use because its clinical efficacy and safety had not been adequately established.[3],[4]

Moreover, although clinical trials showed that apixaban had similar or even slightly more benefits than warfarin,[5] no long-term data on its safety were available.

Based on more recent evidence, we reassessed the risk–benefit balance of apixaban as described in more detail below and are changing our designation of this drug to Limited Use.

Recent evidence on apixaban’s safety and efficacy

Apixaban was first approved by the Food and Drug Administration (FDA) in 2012 to decrease the risk of stroke and systemic embolism (a blood clot lodged inside a blood vessel) in patients with nonvalvular atrial fibrillation.[6] It also has been approved to treat and reduce the risk of recurrence of deep vein thrombosis (a blood clot in a deep vein, usually in the leg) and pulmonary embolism (which occurs when a blood clot blocks one of the arteries in the lungs). In patients who have undergone hip- or knee-replacement surgery, apixaban also is indicated to reduce the risk of deep vein thrombosis and pulmonary embolism. Apixaban is available in 2.5- or 5-milligram doses only and is taken orally twice daily.

A 2022 meta-analysis, funded by the companies that manufacture apixaban, included over 3.9 million adults with atrial fibrillation across 38 studies. The meta-analysis compared treatment with apixaban to treatment with other anticoagulants, such as warfarin and the DOACs dabigatran and rivaroxaban.[7] The researchers found that apixaban was generally associated with a lower risk of major bleeding, stroke and systemic embolism than the other treatments. This analysis did not find a significant association of apixaban with lower mortality. However, a 2015 meta-analysis that included over 100,000 subjects either with nonvalvular atrial fibrillation or receiving treatment for venous thromboembolism across 13 trials found that treatment with DOACs, including apixaban, was associated with a significant reduction in all-cause mortality, including a significantly lower risk of death from major bleeding compared with treatment with warfarin.[8]

One of the studies included in the 2022 meta-analysis, which was itself also funded by the makers of apixaban, was a retrospective study of 20,378 adults in the United States with nonvalvular atrial fibrillation. This study, published in 2019, found that patients who were taking apixaban had a slightly lower rate of major bleeding (5.9%) and were less likely to suffer from a stroke or systemic embolism (1.2%) than patients taking warfarin (8.7% and 1.6%, respectively).[9] This study also did not find a difference in the risk of bleeding or thrombosis between the two groups among patients who were taking antiarrhythmic medications concomitantly (at the same time).

Important adverse events

Apixaban’s product labeling includes a boxed warning — the FDA’s most prominent warning — telling patients that the premature discontinuation of any anticoagulant, including this drug, increases the risk of thrombosis (blood clots) except when the anticoagulant is discontinued for bleeding complications. Moreover, apixaban-treated patients who are undergoing certain procedures, such as a spinal puncture (spinal tap), may develop epidural or spinal hematomas (a pool of mostly clotted blood that forms in an organ, tissue or body space), which may lead to long-term or permanent paralysis.[10]

The increased risk of bleeding, which can be severe and life-threatening, is the most important health risk of all anticoagulants, including apixaban. This risk is further increased if a patient is older, has prior episodes of hemorrhage or stroke, has kidney or liver damage, or has low body weight. Several drug-drug interactions also can increase a patient’s risk of bleeding, for example concomitant use of other anticoagulants or medications to prevent or treat blood clots, as well as aspirin, other antiplatelet drugs or long-term use of nonsteroidal anti-inflammatory drugs.[11],[12]

Generally, however, it is important to keep in mind that different anticoagulants have different advantages and disadvantages.[13] For example, treatment with apixaban is associated with fewer drug interactions and food restrictions than treatment with warfarin and requires less frequent monitoring and follow-ups.[14] However, apixaban’s level of anticoagulation still cannot be easily tested and monitored, and no well-studied antidote to reverse the drug’s effect is available.[15]

For some patients, such as those who are at highest risk of bleeding and for whom monitoring and adjusting the degree of anticoagulation is crucial, warfarin may continue to be a safer option[16],[17] because it can be dosed and monitored more accurately than apixaban, for which only two doses are available.[18] Moreover, an effective antidote, which is available for warfarin, continues to be unavailable for apixaban. Warfarin also remains a safer option for patients with severe valvular disease, severely impaired kidney function, mechanical heart valves, mitral stenosis or those at an increased risk of bleeding (for example, due to concomitant treatments). For other patients, apixaban appears to be a reasonable alternative, with a slightly lower risk of severe bleeding.[19],[20]

Apixaban’s blood-thinning effect also sets on more immediately and lasts for less time than warfarin’s. This means that patients need to be more careful to take apixaban regularly than warfarin. At the same time, the fact that apixaban is more rapidly cleared from the body can be an advantage if a patient requires emergency surgery or experiences bleeding.

Ultimately, however, which anticoagulant is the best choice for a patient should be an individualized decision that takes into account the patient’s specific medical condition, concomitant drug use, ability to regularly take the medication and other possible risk factors.[21]

What You Can Do

If you are at risk of blood clots or stroke and your clinician recommends anticoagulant therapy, fully discuss which medication would work best for you. Once you are taking an anticoagulant, make sure to monitor yourself for possible adverse effects and get regular check-ups.

Never discontinue any anticoagulant without talking with your clinician first, because doing so can increase your risk of developing blood clots or stroke. Make sure to discuss all planned procedures, including some dental procedures, with your clinician, as your anticoagulant dose may need to be paused. If you require emergency surgery, mention that you are taking apixaban (or any other anticoagulant). Also consider keeping a notice in your wallet or purse to alert first responders and clinicians in cases of emergencies that you are taking anticoagulants.

While taking any anticoagulant, seek immediate medical help if you injure yourself or fall, particularly if you hit your head, or if you experience any signs or symptoms of bleeding, a blood clot or a stroke.
 

References

[1] American Heart Association. What are direct-acting oral anticoagulants (DOACs)? https://www.heart.org/-/media/files/health-topics/answers-by-heart/what-are-doacs.pdf. Accessed February 6, 2024.

[2] Do not use the new oral blood thinner apixaban (ELIQUIS). Worst Pills, Best Pills News. June 2018. https://www.worstpills.org/newsletters/view/1202. Accessed February 6, 2024.

[3] Ibid.

[4] Overview of the questionable drug andexanet (ANDEXXA). Worst Pills, Best Pills News. February 2021. https://www.worstpills.org/newsletters/view/1379. Accessed February 8, 2024.

[5] Hylek EM, Held C, Alexander JH, et al. Major bleeding in patients with atrial fibrillation receiving apixaban or warfarin: The ARISTOTLE trial (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation): Predictors, characteristics, and clinical outcomes. J Am Coll Cardiol. 2014;63(20):2141-2147.

[6] Bristol-Myers Squibb. Label: apixaban (ELIQUIS). April 2021. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/202155s034lbl.pdf. Accessed February 6, 2024.

[7] Buckley BJR, Lane DA, Calvert P, et al. Effectiveness and safety of apixaban in over 3.9 million people with atrial fibrillation: A systematic review and meta-Analysis. J Clin Med. 2022;11(13):3788.

[8] Chai‐Adisaksopha C, Hillis C, Isayama T, et al. Mortality outcomes in patients receiving direct oral anticoagulants: a systematic review and meta‐analysis of randomized controlled trials. J Thromb Haemost. 2015;13(11):2012-2020.

[9] Wanat MA, Wang X, Paranjpe R, et al. Warfarin vs. apixaban in nonvalvular atrial fibrillation, and analysis by concomitant antiarrhythmic medication use: A national retrospective study. Res Pract Thromb Haemost. 2019;3(4): 674-683.

[10] Bristol-Myers Squibb. Label: apixaban (ELIQUIS). April 2021. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/202155s034lbl.pdf. Accessed February 6, 2024.

[11] Hylek EM, Held C, Alexander JH, et al. Major bleeding in patients with atrial fibrillation receiving apixaban or warfarin: The ARISTOTLE trial (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation): Predictors, characteristics, and clinical outcomes. J Am Coll Cardiol. 2014;63(20):2141-2147.

[12] Bristol-Myers Squibb. Label: apixaban (ELIQUIS). April 2021. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/202155s034lbl.pdf. Accessed February 6, 2024.

[13] Leung LLK. Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects. UpToDate. Updated July 27, 2023.

[14] Chen A, Stecker E, Warden BA. Direct oral anticoagulant use: a practical guide to common clinical challenges. J Am Heart Assoc. 2020;9(13):e017559.

[15] Leung LLK. Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects. UpToDate. Updated July 27, 2023.

[16] Apixaban, edoxaban, rivaroxaban: situations with a high risk of bleeding or thrombosis. Prescrire Int. October 2020; 29(219): 238-241.

[17] Oral anticoagulants in atrial fibrillation: Warfarin or apixaban, depending on the clinical situation. Prescrire Int. 2019;28(205):159-160

[18] Deep vein thrombosis and pulmonary embolism. Treatment with warfarin, LMWH or apixaban, depending on the situation. Prescrire Int. 2021; 30(223):49-50.

[19] Drugs for atrial fibrillation. The Medical Letter. September 2019;61(1580):137-144.

[20] The 2023 American Geriatrics Society Beers Criteria® Update Expert Panel. American Geriatrics Society 2023 updated AGS Beers Criteria® for potentially inappropriate medication use in older adults. J Am Geriatr Soc. 2023;71(7):2052-2081.

[21] Leung LLK. Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects. UpToDate. Updated July 27, 2023.