Eliquis is a powerful blood thinner prescribed to prevent strokes and potentially fatal blood clots. Manufacturer Bristol-Myers Squibb markets it as the most effective drug in its class at preventing strokes while minimizing bleeding that is common with similar anticoagulants. But the U.S. Food and Drug Administration delayed the drug’s initial approval after it found errors in a clinical trial that could have skewed safety and efficacy results.
Eliquis (apixaban) is a prescription anticoagulant, or blood thinner, used to lower the risk of strokes and blood clots in people with an irregular heartbeat known as atrial fibrillation.
Doctors also prescribe the drug to people after knee or hip replacement surgery to prevent deep vein thrombosis, or DVT, which is when blood clots form in veins deep in the body. Left untreated, these blood clots can travel and become lodged in arteries that go from the heart to the lungs. This life-threatening condition is called pulmonary embolism, or PE.
The U.S. Food and Drug Administration approved apixaban to not only treat DVT and PE, but also to lower the chance of the blood clots forming again.
Bristol-Myers Squibb manufactures Eliquis. The medication works by blocking Factor Xa, which is a key enzyme in the blood clotting process.
The drug is the latest in a new class of anticoagulants that includes Pradaxa (dabigatran etexilate) and Xarelto (rivaroxaban). The FDA warns these medicines can cause serious, potentially fatal bleeding.
Eliquis’ effects last for at least 24 hours after the last dose, according to the drug’s label. In May 2018, the FDA approved the first antidote to stop rare, uncontrolled bleeding caused by the medication.
Eliquis comes in 2.5 mg and 5 mg oral tablets. The most commonly prescribed dosage for patients with atrial fibrillation is 5 mg taken twice a day. A smaller, twice daily 2.5 mg dose is recommended for atrial fibrillation patients with any two of the following characteristics:
- 80 years of age or older
- Body weight of about 132 pounds or less
- Blood levels of creatinine at 1.5 mg/dL or greater
Doctors may also prescribe twice daily 2.5 mg doses to prevent DVT after a hip or knee replacement. Patients should take the first dose 12 hours to 24 hours after the surgery, according to the drug’s label. They should continue to take the medication for about 35 days after a hip replacement and for about 12 days after a knee replacement.
The recommended dosage in patients who have suffered DVT or PE is 10 mg taken twice daily for seven days. After that, the drug label recommends doctors decrease the dose to 5 mg twice a day.
Patients who have taken apixaban for at least six months to treat DVT or PE may be instructed to continue taking 2.5 mg of the drug twice a day to reduce the risk of the blood clots forming again.
If for some reason you do not take a dose at the scheduled time, try to take the dose as soon as possible. But you should never double up on a dose if you miss one.
People should stop taking the drug 48 hours prior to any surgery that has a moderate to high risk of bleeding and at least 24 hours prior to surgeries with a low risk of bleeding, according to the drug’s label. Patients should never stop taking a prescription drug without the supervision of a doctor.
Common and Serious Side Effects
According to the drug’s label, the most common side effects of Eliquis are related to bleeding. More than 1 percent of patients who took the drug in clinical trials reported the issues. Minor side effects include bruising more easily and minor bleeding that takes longer than usual to stop.
Serious and potentially life-threatening bleeding is the most severe side effect. The drug’s label mentions two trials in which the most common reason for stopping the drug was severe bleeding, or hemorrhaging.
For about six years, apixaban users did not have an approved remedy for internal bleeding. But the FDA cleared large scale production of Portola Pharmaceuticals’ antidote, Andexxa, to begin in January 2019.
Black Box Warnings
The FDA required Bristol-Myers Squibb to add two black box warnings to the medication’s packaging.
The first cited an increased risk of spinal or epidural blood clots in patients who undergo procedures that inject certain medicines into those regions of the body. The warning states that the clots can potentially cause long-term or permanent paralysis.
The second warning advises patients that stopping Eliquis may result in an increased risk of blood clots, stroke or pulmonary embolism. The warning recommends doctors consider another anticoagulant treatment if they take a patient off apixaban before treatment is completed for any reason other than “pathological bleeding.”
Certain drugs can interact with Eliquis and cause it to be less effective. Other medicines may also put the patient at an increased risk of complications such as bleeding.
Common medicines that can increase bleeding when taken with apixaban include:
- Aspirin or other products that contain aspirin
- Long-term use of nonsteroidal anti-inflammatory drugs (NSAIDs) such as Advil, Motrin and Aleve
- Any medicine that contains heparin such as Lovenox, Innohep or Fragmin
- Selective serotonin reuptake inhibitors (SSRIs) such as Prozac, Paxil or Zoloft
- Serotonin norepinephrine reuptake inhibitors (SNRIs) such as Cymbalta or Effexor
- Other medications used to help prevent or treat blood clots, including other anticoagulants such as Coumadin or Xarelto
Taking apixaban with CYP3A4 inhibitors or inducers can also cause serious interactions. CYP3A4 is an enzyme that allows the body to remove drugs or toxins. It’s primarily found in the intestines and liver.
CYP3A4 inhibitors can increase the risk of bleeding while CYP3A4 inducers can reduce apixaban’s effectiveness and increase the patient’s risk of stroke or blood clots.
- Nizoral, Xolegel or Extina, which are antifungal medications
- Sporanox and Onmel, which are antifungal medications
- Norvir, an HIV antiviral medication
- Biaxin, an antibiotic
- Rifadin, used with other medications to treat tuberculosis (TB)
- Tegretol, Carbatrol, Epitol or Equetro, anticonvulsant medications used to treat seizures, nerve pain and bipolar disorder
- Dilantin, Dilantin-125, Phenytek or Cerebyx, anticonvulsant medications used to treat and prevent seizures
- St. John’s Wort
- a flowering plant often sold as a supplement and used for many different health purposes including the treatment of depression
Taking apixaban with a P-gp inhibitor can also increase the risk of bleeding.
Other Risks to Discuss With Your Doctor
Women who take Eliquis should speak with their doctor if they are pregnant or may become pregnant. The drug’s label recommends pregnant women do not take apixaban. The drug can potentially increase the risk of bleeding during pregnancy and delivery.
Well-controlled studies of apixaban have not looked at pregnant women, and clinical trials have not tested the safety and effectiveness of the drug during labor and delivery.
The label also recommends nursing mothers either stop nursing or stop taking the drug after first talking with their doctor.
The drug’s safety and effectiveness has also not been studied in patients with prosthetic heart valves, and the drug is not recommended for use in those patients. The label also advises against using the drug if you have certain types of abnormal bleeding conditions or severe liver impairment.
Eliquis is not approved for use in children. Very little research has assessed the safety and effectiveness of the drug in pediatric patients.
Clinical Trial Errors
A 2011 article published by the New England Journal of Medicine gave a favorable review of an Eliquis clinical trial conducted by Bristol-Myers Squibb. The trial was called Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE).
The article concluded apixaban was superior to the older blood thinner warfarin at preventing strokes or blood clots in patients with atrial fibrillation, and it caused less bleeding and had a lower mortality rate.
But the FDA discovered drugs and placebos may have been switched during the study, causing potential errors in the study’s findings.
“As you are aware, some subjects in ARISTOTLE were given the wrong study drug (e.g. active instead of placebo and vice-versa),” the FDA wrote in a letter to Bristol-Myers Squibb. “We believe the information you have submitted for us to review has not adequately characterized the frequency of errors in dispensing study drugs.”
The agency required the company to resubmit “reliable information” regarding several aspects of the trial to straighten out the errors.
“As you are aware, some subjects in ARISTOTLE were given the wrong study drug (e.g. active instead of placebo and vice-versa).”
Bristol-Myers Squibb and Pfizer responded to the ARISTOTLE controversy. They said they had carried out “significant analyses” despite the dispensing errors. They also said the rate of errors was too low to affect the trial’s eventual outcome.
The problem delayed Eliquis’ approval by nine months.
After the company had resubmitted its application, the FDA concluded the major findings of the ARISTOTLE trial remained valid, and the agency approved the drug.
However, in 2013, a news report questioned whether the study actually showed apixaban’s superiority to warfarin. Forbes reported FDA reviewers had found the drug’s superiority claim for reduced “all-cause death” (or death by any cause) was not nearly as significant as the other findings for prevention of stroke and major bleeding.
The magazine quoted a statistical reviewer for the FDA. He said if just one more person who had taken warfarin in the clinical trial had died over the course of the study, it would have erased any claim of superiority for apixaban.
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