Do Not Use the New Blood Thinner Edoxaban (SAVAYSA)

Edoxaban (SAVAYSA) is one of the newest oral blood thinners. It was approved by the Food and Drug Administration (FDA) in 2015 for decreasing the risk of stroke caused by a blood clot in patients with non-valvular atrial fibrillation (a type of irregular heart beat not caused by a heart valve problem)[1] and mild-to-moderate kidney function impairment. The drug also has been approved for treating deep vein thrombosis (DVT, a blood clot in a large vein, usually in the leg) and pulmonary embolism (PE, a clot in a blood vessel in the lungs) in patients who have already been treated with injectable blood thinners, such as enoxaparin (LOVENOX), for five to 10 days.

Similar to other new blood thinners — such as dabigatran (PRADAXA), rivaroxaban (XARELTO) and apixaban (ELIQUIS) — edoxaban does not offer a better risk-benefit balance than warfarin (COUMADIN, JANTOVEN) when the latter is maintained within its recommended therapeutic range. Warfarin has been the most commonly used oral blood thinner for decades. It has a proven track record but requires careful attention to the intake of vitamin K-containing foods to avoid dangerous fluctuations in warfarin levels and also requires periodic lab tests to monitor the level of the drug.

Public Citizen’s Health Research Group has designated edoxaban as a Do Not Use drug because it is no more effective than warfarin, its effectiveness is significantly impacted by kidney function, there is no antidote to reverse its blood-thinning effect in case of severe bleeding and its long-term safety profile is unknown.

No effectiveness advantage over warfarin

Edoxaban’s effectiveness was assessed in two randomized clinical trials. The first trial, which involved more than 8,000 patients with DVT or PE, found similar rates of DVT and PE recurrence among edoxaban users and warfarin users.[2]

The second trial, which enrolled over 21,000 patients with atrial fibrillation who had a moderate-to-high risk of stroke, showed that the rate of stroke or systemic embolism (blood clots in the heart traveling to other parts of the body) was similar among edoxaban users and warfarin users.[3] However, this trial found that edoxaban’s effectiveness varied based on how well the patient’s kidneys work.[4] This is not the case for warfarin.

Because approximately half of each dose of edoxaban is eliminated by the kidneys, the blood level of this drug tends to be much lower in patients with normal kidney function than in those with impaired kidney function. Specifically, the atrial fibrillation trial showed that edoxaban blood levels were 40 percent lower — thus increasing the risk of blood-clot-related stroke — in patients with normal kidney function than in those with mild-to-moderate impairment of kidney function. Therefore, one of edoxaban’s black-box warnings, the strongest warning required by the FDA, states that edoxaban should not be used in atrial fibrillation patients with normal renal function.

On the other hand, edoxaban’s label also states that the drug is not recommended in patients with the most severe degree of kidney function impairment because the kidneys cannot eliminate the drug adequately, which raises the risk of bleeding.

Based on the above data, edoxaban’s effectiveness is limited to patients with mild or moderate kidney impairment. In fact, an FDA advisory committee member who opposed approval of the drug questioned whether edoxaban is even needed, given the availability of other blood thinners and the fact that edoxaban can leave clinicians in a bind about how to manage patients with mild renal function impairment who take this drug if their kidney function becomes normal.[5]

Adverse effects

The most common side effect leading to discontinuation of edoxaban in the two clinical trials was bleeding. Although the risk of major bleeding was slightly lower among edoxaban users than among warfarin users in these trials, edoxaban users had a higher risk of gastrointestinal bleeding than did warfarin users. Edoxaban also carries a black-box warning for significant bleeding within the spine, which can result in permanent paralysis, in patients who undergo spinal injections or anesthesia.

The risk of bleeding during edoxaban therapy is higher in patients taking certain medications that inhibit the breakdown of the blood thinner, including dronedarone (MULTAQ), quinidine (generic only) and verapamil (CALAN, VERELAN),[6] and in those taking other drugs that can cause bleeding, such as antiplatelet drugs (including aspirin).

Edoxaban can cause abnormal liver function test results; therefore, the drug is not recommended in patients with moderate-to-severe liver disease.[7] In fact, the European Medicine Agency’s review committee for edoxaban recommended conducting liver function tests before initiating edoxaban therapy and periodically thereafter in patients who take the drug for more than one year.[8]

Other issues

There is a standard blood test (known as the international normalized ratio, or INR) for monitoring warfarin’s blood-thinning effect to make sure the dose is not too high or too low. However, no such test is currently available to monitor the dosing of edoxaban.[9]

Additionally, edoxaban’s fixed-dosing scheme (60 milligrams [mg] once daily for most patients or 30 mg in patients with moderate kidney function impairment) is troublesome[10] because it was based on clinical trials involving patient populations that may not necessarily represent patients in the real world, especially older and frail people who commonly need to use blood thinners. Moreover, even patients with the same risk factors, including those with kidney function impairment and those taking drugs that interact with edoxaban, may metabolize edoxaban differently, which might put some patients at risk of inadequate or excessive blood thinning with the fixed-dose regimen. Monitoring blood levels of edoxaban would help clinicians determine whether patients are compliant with their treatment regimen and reassure clinicians and patients that the blood thinner is working properly.[11]

A major disadvantage of edoxaban is that there is no antidote to reverse its blood-thinning effect — which can persist for approximately 24 hours after the last dose[12] — in case of major bleeding. Even dialysis (filtering of the blood using a machine) cannot clear edoxaban from the blood. In contrast, warfarin’s effect can be reversed quickly with an injection of vitamin K.

Additionally, edoxaban is an expensive brand-name-only drug with a wholesale price that exceeds $3,400 per year in the U.S., whereas warfarin’s cost ranges from approximately $100 (generic) to $700 (brand-name) per year.[13] Even including the costs of lab testing and doctor’s follow-up visits associated with monitoring and dose adjustment, warfarin’s expenses remain far below those of edoxaban.[14] This has implications for patient adherence to treatment because patients tend not to fill prescriptions they regard as too expensive or they may skip or split doses to make the medication last longer, behaviors that could lead to dangerous undertreatment.

What You Can Do

If you have non-valvular atrial fibrillation or a DVT or PE, do not start taking edoxaban. Instead, you should ask your doctor to prescribe warfarin. If you are currently taking edoxaban, talk with your doctor about switching to warfarin. Never stop taking edoxaban or any blood thinner without discussing it with your doctor first, because doing so increases your risk of stroke and blood clots.

Report all serious side effects related to oral blood thinners 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. FDA news release: FDA approves anti-clotting drug Savaysa. January 8, 2015. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm429523.htm. Accessed September 6, 2017.

[2] Hokusai-VTE Investigators, Büller H, Décousus H, et al. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med. 2013;369(15):1406-1415.

[3] Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2013;369(22):2093-2104.

[4] Daiichi Sankyo, Inc. Label: Edoxaban (SAVAYSA). September 2016. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/206316s004lbl.pdf. Accessed September 6, 2017.

[5] Food and Drug Administration. Transcript of the meeting of the Cardiovascular and Renal Drugs Advisory Committee (CRDAC). October 30, 2014. Accessed September 6, 2017.

[6] Mendell J, Zahir H, Matsushima N, et al. Drug-drug interaction studies of cardiovascular drugs involving P-glycoprotein, an efflux transporter, on the pharmacokinetics of edoxaban, an oral factor Xa inhibitor. Am J Cardiovasc Drugs. 2013;13(5):331-342.

[7] Daiichi Sankyo, Inc. Label: Edoxaban (SAVAYSA). September 2016. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/206316s004lbl.pdf. Accessed September 6, 2017.

[8] Committee for Medicinal Products for Human Use. Assessment report for lixiana, international non-proprietary name: edoxaban. Procedure No. EMEA/H/C/002629/0000. April 23, 2015. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/002629/WC500189047.pdf. Accessed September 4, 2017.

[9] Daiichi Sankyo, Inc. Label: Edoxaban (SAVAYSA). September 2016. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/206316s004lbl.pdf. Accessed September 6, 2017.

[10] Patel JP, Couchman L, Chitongo PB, et al. New oral anticoagulants: Dosing and monitoring. BMJ. 2015;350(May 19):h2655.

[11] Scridon A, Serban RC. Laboratory monitoring: A turning point in the use of new oral anticoagulants. Ther Drug Monit. 2016;38(1):12-21.

[12] Daiichi Sankyo, Inc. Label: Edoxaban (SAVAYSA). September 2016. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/206316s004lbl.pdf. Accessed September 6, 2017.

[13] Which oral anticoagulant for atrial fibrillation? Med Lett Drugs Ther. 2016;58(1492):45-46.

[14] Shah SV, Gage BF. Cost-effectiveness of dabigatran for stroke prophylaxis in atrial fibrillation. Circulation. 2011;123(22):2562-2570.