Eliquis is a blood thinner manufactured and marketed by Bristol-Myers Squibb, which says the drug is the most effective in its class at preventing strokes and reducing bleeding common with anticoagulants. But the FDA delayed the drug’s initial approval due to findings of clinical trial errors that could have potentially skewed its study results for overall safety and efficacy.
Eliquis (apixaban) is the last in a new class of anticoagulant drugs (blood thinners) approved by the FDA in 2012. Others in the class include Pradaxa (dabigatran etexilate) and Xarelto (rivaroxaban). They are meant to take the place of the blood thinner Coumadin (warfarin).
Bristol-Myers Squibb is the manufacturer of both Eliquis and Coumadin. Prior to 2010, Coumadin was the only choice in an oral blood thinner in the U.S. market.
Eliquis is used to treat a heart condition called atrial fibrillation (an irregular heartbeat that causes poor blood flow) that affects nearly 6 million people in the U.S. Patients with this condition are at an increased risk (about five times greater) for stroke. Anticoagulants such as Eliquis help to reduce the patient’s risk of stroke by preventing blood clots from forming.
While its predecessor, Coumadin, required regular monitoring for blood-plasma levels, Eliquis does not require patients to undergo blood testing; nor does it require dosing adjustments dependent upon a person’s diet. Unlike Coumadin, though, Eliquis does require dosage adjustments in patients with abnormal kidney function.
Also unlike Coumadin, there is no antidote for internal bleeding or hemorrhage caused by Eliquis. While the drug has a relatively short half-life, meaning its effects are quick to wear off, excessive bleeding in patients taking Eliquis can be serious and in some cases, even life-threatening.
There is also some controversy surrounding alleged errors in the company’s initial clinical trials conducted on the safety and efficacy of Eliquis. FDA approval of the drug was halted for nine months while the FDA reportedly investigated the drugmaker for evidence of fraud specific to its Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) study.
An anticoagulant is a substance that deters blood clotting (coagulation). Blood clotting is essential to preventing excess bleeding when a person experiences an injury that causes damage to a blood vessel. Platelets (blood cells) and plasma proteins work together stop bleeding by forming clots over injuries.
These clots typically resolve on their own as the injury heals. In some instances though, clots do not dissolve, or they form in places they shouldn’t, such as in veins or arteries. These clots can then prevent normal blood flow to and from the heart. If a clot detaches from the vessel and travels to the heart or lungs, it can become a life-threatening situation.
Anticoagulants help to prevent clotting and potentially fatal circumstances from deep vein thrombosis (blood clots in the legs) and pulmonary embolism (blood clots in the lungs). Although they are more commonly known as blood thinners, anticoagulants do not actually thin the blood. Instead, they inhibit the body’s natural production of vitamin K in the liver, which increases the time it takes your blood to clot.
Since they impair the body’s ability to clot blood naturally, these drugs can also cause internal bleeding.
Eliquis is a prescription medication intended for use in patients with atrial fibrillation, a type of irregular heartbeat that puts patients at a greater risk of forming blood clots that can potentially lead to a stroke.
Atrial fibrillation (AF) is the most common type of arrhythmia, or irregular heartbeat. An arrhythmia can cause the heart to beat too fast, too slow or at an irregular rate. In AF, an irregularity in the heart’s electrical signals causes the heart’s upper chambers (atria) to fibrillate, or vibrate. This abnormality causes blood to pool in the atria since it cannot be completely pumped to the heart’s lower chambers (ventricles).
A diagnosis can be determined by an electrocardiogram (EKG), which examines the electrical currents of the heart.
If left untreated, AF can result in stroke, heart attack or heart failure. Approximately 15 to 20 percent of all people who have strokes also have this condition.
Eliquis has not been studied in patients with prosthetic heart valves; nor is it recommended for individuals with certain types of abnormal bleeding conditions. It is also not recommended for patients with severe liver impairment.
The safety and effectiveness of the drug in children has also not been established. It is recommended that women who are breastfeeding either discontinue breastfeeding or discontinue Eliquis after speaking with their doctor.
Taking Eliquis can potentially increase the risk of bleeding during pregnancy and delivery. There are no well-controlled studies of Eliquis in pregnant women, and the safety and effectiveness of the drug during labor and delivery has not been tested in clinical trials.
In two separate studies, the most common reason for discontinuing Eliquis was severe bleeding (hemorrhage). This side effect was the most serious reaction experienced by individuals taking the drug. The risk of bleeding can also become potentially life-threatening, and Eliquis does not have an antidote to reverse this effect.
Allergic reactions or hypersensitivity may also occur while taking Eliquis. These reactions can include skin rash and anaphylactic reactions, such as swelling, which may be life-threatening.
Patients who are taking Eliquis while having certain medications (anesthesia) injected into their spinal and epidural (space around the dura mater of the spinal cord) areas, or other spinal puncture, are at an increased risk of developing blood clots in that region.
In addition to a warning to patients about bleeding risks, Eliquis drugmaker Bristol-Myers Squibb added two black box warnings to its blood thinner drug’s packaging since its FDA-approval in 2012.
The first addition had to do with a patient’s increased risk of developing blood clots in the spinal or epidural regions if taking Eliquis while also receiving injections of certain medications or anesthesia in the spinal or epidural areas, or undergoing other spinal punctures. The warning states that the potential clots can result in long-term or permanent paralysis to the patient.
The second black box warning was added in August 2014. It advises patients that the discontinuation of Eliquis may result in an increased risk of blood clots.
Black box warnings are required by the FDA in certain instances to call attention to “serious or life-threatening risks.”
Certain drugs can interact with Eliquis causing it to be less effective. Other medicines may also put the patient at an increased risk of complications, such as bleeding.
Bleeding can be serious and in some cases lead to the death of the patient. Taking certain medications concurrently with Eliquis may increase a patient’s risk of bleeding.
The risk of bleeding can also increase when apixaban (the active ingredient in Eliquis) is taken with inhibitors of CYP3A4 (cytochrome P450 3A4 – an enzyme in the body) and P-gp (P-glycoprotein).
The effectiveness of Eliquis can be decreased with the concurrent use of certain CYP3A4 and P-gp inducers. The decreased exposure to apixaban in patients prescribed the drug for certain conditions can increase the patient’s risk of stroke or blood clots.
The most commonly prescribed dosage of Eliquis is 5 mg taken orally twice a day. For certain individuals, a dosage of 2.5 mg twice daily is recommended. This reduced dose is recommended for patients also taking CYP3A4 and P-gp inhibitors, unless their regular dosage is already set at 2.5 mg and then they should avoid taking both medications together.
For patients taking Eliquis following a hip or knee replacement surgery, the recommended dose is 2.5 mg taken orally twice a day. The first dose should be taken 12 to 24 hours after the surgery. Patients should continue taking Eliquis for approximately 35 days following a hip replacement surgery, and approximately 12 days following a knee replacement surgery.
In patients taking Eliquis for the treatment of blood clots, the recommended dosage is 10 mg taken twice a day for the first seven days, and then 5 mg twice a day after that. For the prevention of risk of recurrent blood clots, the recommended dose of Eliquis is 2.5 mg taken orally twice daily for at least six months.
Doses should never be doubled up if a patient misses a dose.
Patients should stop taking Eliquis for at 48 hours prior to elective or invasive surgeries with a moderate to high risk of bleeding, and at least 24 hours prior to surgeries with a low risk of bleeding and in non-critical locations of the body.
A 2011 article published by the New England Journal of Medicine (NEJM) gave a favorable review to a clinical trial conducted by Bristol-Myers Squibb for Eliquis. That trial was called Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE).
The article concluded that apixaban was superior to warfarin in preventing strokes or blood clots in patients with atrial fibrillation, and that it caused less bleeding and had a lower mortality rate. But controversy surrounding the ARISTOTLE trial persisted, delaying Eliquis’ approval by nine months. The FDA issued a letter to the manufacturer in June 2012, explaining the delay.
For that reason, the FDA determined that the application could not be approved because “knowledge of the study drugs actually dispensed to subjects is crucial to understanding the outcomes of the study.”
After the company resubmitted its application, the FDA concluded that the major findings of the ARISTOTLE trial remained valid. Apixaban was approved in December 2012.
However, one FDA reviewer concluded that although apixaban was found to be superior to warfarin in the prevention of stroke, major bleeding and death by any cause, “the significant findings of apixaban cannot be concluded unless various aspects of the medication errors can be addressed by the sponsor.”
In 2013, Forbes reported that FDA reviewers found that Eliquis’ 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. Forbes said the agency’s statistical reviewer noted that “one less death in the warfarin arm would negate statistical significance for apixaban’s superiority.”
Another FDA official was reported to have written that if the agency had been aware of the dispensing errors prior to the company’s submission of its initial new drug application (NDA), “we would have refused to file it.”
Bristol-Myers Squibb along with Pfizer sent their own response to the ARISTOTLE trial controversy, stating, “The companies conducted significant analyses to confirm that although there were medication dispensing errors in ARISTOTLE, the rate was very low and it did not impact the outcome measures of the trial.”
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