One of the newest blood thinners on the market, doctors prescribe Eliquis to prevent blood clots and strokes. Bristol-Myers Squibb and Pfizer tout their drug as one of the safest available, but clinical trials involved several flaws, leading some experts to believe the results are unsubstantiated.
Eliquis (apixaban) is an anticoagulant (blood thinner) used to reduce the risk of blood clots and stroke. Doctors prescribe the oral medication in one dose, unlike older anticoagulants that required patient-specific dosages and patient monitoring. Bristol-Myers Squibb and Pfizer developed the drug and market it as safer than older blood thinners.
However, Eliquis’s approval process did not go smoothly. It was one of the last blood thinners to receive U.S. Food and Drug Administration approval. It is currently approved for three uses:
- To reduce the risk of systemic embolisms (life-threatening blood clots) and strokes in patients with non-valvular atrial fibrillation (irregular heartbeats).
- To reduce the risk of deep vein thrombosis (DVT), which are blood clots that form in the legs, and pulmonary embolisms (PEs) – blood clots in the lungs – following hip or knee replacement surgery.
- To treat DVT and PEs and reduce the risk of reoccurrence.
Unlike older anticoagulants, Eliquis does not have an antidote. In December 2015, Portola Pharmaceuticals submitted an FDA application to approve an antidote for Eliquis and Xarelto. But, in August 2016, the FDA rejected it.
All blood thinners increase the risk of serious and uncontrollable bleeding, which can lead to death. With no known antidote, doctors are limited in their ability to treat the side effect if it occurs. Eliquis is not for people with artificial heart valves, and there is no information available on its safety or efficacy in children.
How Eliquis and Anticoagulants Work
Like other new anticoagulants Xarelto (rivaroxaban) and Pradaxa (dabigatran etexilate), Eliquis works by interrupting the blood-clotting (coagulation) process. Both Eliquis and Xarelto block an enzyme called Factor Xa during the blood clotting process, preventing a protein called thrombin from forming. Pradaxa directly blocks the formation of thrombin. Each of the newer anticoagulants has unique side effects that accompany it.
FDA Approval of New Anticoagulants
- 2010: Pradaxa
- 2011: Xarelto
- 2012: Eliquis
Companies developed the new anticoagulants for patients looking for an alternative to warfarin (Coumadin, Jantoven), which requires doctors to monitor patients closely. Warfarin works by blocking clotting factors that rely on Vitamin K. This allows doctors to use Vitamin K as an antidote if someone suffers uncontrollable bleeding while on warfarin. Warfarin is much cheaper and less-profitable than the patent-protected new anticoagulants.
|Annual Sales for New Anticoagulants|
|Pradaxa||$1.19 billion||$1.20 billion|
|Xarelto||$864 million||$1.5 billion|
|Eliquis||$146 million||$774 million|
Eliquis Side Effects
Eliquis can cause numerous side effects, some deadly. Like all blood-thinners, Eliquis increases the risk of uncontrollable bleeding. The risk is increased when taken at the same time as popular drugs like Aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs). Other anticoagulants, selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) also increase the likelihood of bleeding.
People who stop taking Eliquis face an increased risk of blood clotting and other thrombotic events if it is not replaced with an alternative anticoagulant.
Other possible side effects of Eliquis include:
- Bruising more easily
- Developing skin rash
- Internal bleeding
- Brain hemorrhaging
FDA Approval and Clinical Trial Cover-ups
The future of Eliquis as a blockbuster drug hung on the success of one of its clinical trials called ARISTOTLE (Apixaban for Reduction in Stroke and Other Thrombotic Events in Atrial Fibrillation). The goal was to prove that the drug was the best in its class, but the FDA delayed the drug’s approval after the trial raised a number of troubling questions.
Reasons for Delay in FDA Approval
- Alleged cover-up attempt
- Unreported serious adverse events
- Patients received incorrect medicine
The concerns led to a reanalysis of the data and disagreement within the FDA regarding the effectiveness of the drug. In a meeting with Bristol Myers and Pfizer, FDA minutes show the trial’s problems represented a “pattern of inadequate trial conduct and oversight.”
Altered, Inaccurate and Missing Data
The concerns centered on a clinical trial in China. The Eliquis trials involved more than 1,000 locations in 40 different countries, including 36 sites and 18,000 patients in Asia.
At one of the Chinese sites, a senior clinical manager (who also worked at 18 other sites) altered records to cover up violations of good clinical practice guidelines. Bristol-Myers eventually fired the manager and two other employees involved in the incident.
Good Clinical Practice Violations:
- Failed to report four adverse events
- Reported three adverse events late
- Left three medical outcomes out of data
The FDA found other problems with inaccurate data. Some patient names and dates were recorded incorrectly, and data in the English and Chinese versions of reports didn’t match.
Even more concerning, patient data sometimes vanished before FDA investigators visited. The FDA eventually questioned data from 24 different Chinese locations, before concluding the violations did not significantly change the trial results.
Receiving Wrong Medication
The data problems weren’t the only flaw in the ARISTOTLE trial. Participant safety was threatened when it was realized that a large amount of participants received the incorrect medication or incorrect dose of medication.
A flaw in the study’s design caused some patients to receive a double dose of the drug or no drug at all, putting many people who needed some form of anticoagulation at a risk for stroke. Bristol-Myers did not provide a reason for the mistake.
In the drug’s official FDA application review, an FDA official wrote that, “If the Agency had been aware of the (decencies) for ARISTOTLE prior to filing the application, we would have refused to file it.” Meaning, the agency wouldn’t have reviewed the application for drug approval based on the suspect data.
The FDA stood strong when it refused to allow an addition to Eliquis’s label that would have claimed the drug demonstrated a significant reduction in all-cause mortality when compared to warfarin. If allowed, it would mean the manufacturers could claim people who took Eliquis died less often than those on warfarin, something Pradaxa and Xarelto couldn’t claim.
The data from the trial indicated, with an extremely small amount of statistical significance, that the drug was safer than warfarin. However, one FDA reviewer said the significance was so small that if just one more person had died, the stat would be insignificant. The reviewer also criticized trial reports which indicated patients who had died were visiting doctors.
Study Publication and Drug Approval
The ARISTOTLE study was eventually published in the New England Journal of Medicine, but critics objected to its publication. Former editor of the NEJM Arnold Relman criticized the journal for publishing the study, saying financial conflicts influenced its publication. He pointed to flaws in the study’s limitations.
Relman argued the study showed Eliquis was no more effective than warfarin in 7,000 European patients and 35 percent of patients on warfarin did not take the correct therapeutic dose. If they took the correct dose, warfarin might have been as effective as Eliquis. Neither of those facts was discussed in the study.
FDA reviewers decided results from other trial sites were enough to support the drug’s approval, and the problematic data did not compromise the drug’s proof of effectiveness. The FDA approved Eliquis in December of 2012 after a nine-month delay.
An independent 2013 study found warfarin was equally as effective as the new anticoagulants (Eliquis, Xarelto and Pradaxa) at the prevention of strokes and embolic events.
Bristol-Myers Squibb and Pfizer
In 2001, Bristol-Myers participated in an illegal business practice called channel stuffing, resulting in a U.S. Securities and Exchange Commission investigation and fraud charges. Channel stuffing is a tactic in which companies inflate their sales numbers by sending businesses more products than they can sell. The company settled the claims for $839 million.
In 2002, Pfizer settled charges for illegally marketing a drug called Bextra for $2.3 billion. During the following decade, it settled separate lawsuits involving its drugs Lipitor, Nuerontin and Detrol for a combined total of more than $490 million.
In 2007, Bristol-Myers settled illegal marketing and pricing charges for $515 million after overcharging the government for drugs and illegally promoting the antipsychotic Abilifiy.
Neither company believed the ARISTOTLE trial cover up, the missing data nor the inaccurate distribution of medicine to patients affected the trial’s integrity.
According to various media reports, Bristol-Myers representatives said the mistakes made during the trials were “not exceptional issues,” and had "no impact on the integrity of the study results or conclusion of the study.” A spokesman for Pfizer was reported as saying the company was confident in the results of the clinical trials.
Legal experts expect Eliquis lawsuits to mount as the drug remains on the market amidst claims that it is not as safe as its manufacturers suggest. Deborah Herschell filed the first Eliquis lawsuit in the Southern District of New York in July of 2015 after her husband, Donald Herschell, died from gastrointestinal and brain hemorrhages while taking Eliquis. The lawsuit claims Bristol-Myers and Pfizer concealed knowledge of Eliquis’ defects from the Herschells and their doctor.
Thousands of lawsuits have already been filed against the manufacturers of Xarelto and Pradaxa. Boehringer Ingelheim settled more than 4,000 lawsuits for $650 million after studies found people taking Pradaxa suffered a high rate of heart attacks and uncontrollable bleeding. More than 500 lawsuits have been filed by people claiming Xarelto caused irreversible bleeding in them or their loved ones.