Xarelto

Studies + Science

Xarelto is meant to selectively inhibit Factor Xa, stomp out clots and keep blood flowing to the brain, lungs, heart, and kidneys. During the drug’s five years on U.S. markets, research has repeatedly linked it to life-threatening complications.

Xarelto Compared to Warfarin

Warfarin, also known as Coumadin, is a different kind of anticoagulant. Various clotting factors play a role in the formation of a blood clot. Classified as a vitamin K antagonist, Warfarin works to stop blood clots by targeting vitamin K–dependent clotting factors.

Approved in 1954, Warfarin has been the go-to blood thinner for decades. But as the competition between old and new generations of blood thinners grows fierce, Xarelto works hard to make its way to the forefront of the $10 billion blood-thinner market.

Xarelto gained popularity because it doesn’t require extensive blood monitoring or place limitations on food, whereas people taking Warfarin must be conscious of their diet. Warfarin patients have to avoid foods high in vitamin K and go for regular blood check-ups.

The Rocket AF (Rivaroxaban versus Warfarin in Nonvalvular Atrial Fibrillation) study, published in the New England Journal of Medicine in 2011, found that “Xarelto was non-inferior to Warfarin in the prevention of subsequent stroke or systemic embolism.” Additionally, Xarelto was linked to higher instances of abdominal bleeding.

Many doctors choose Warfarin because of its well-established safety profile, though patients might also experience extreme bleeding side effects. Since 2018, this has meant that both Warfarin and Xarelto have curable extreme bleeding as a side effect.

Xarelto Side Effects: Extreme Bleeding

A Phase III study tested 16,041 participants and discovered that 73 percent of people who took Xarelto experienced side effects, with higher doses leading to worsened complications. Side effects are different for each participant, but the most common complication is severe bleeding.

Excessive bleeding could put patients in the hospital. If bleeding occurs near essential organs, there is potential for the body to lose function and fail. Hemorrhaging and bleeding in the brain is also fatal. There have been 65 reported deaths linked to Xarelto bleeding to date.

Additional Xarelto Side Effects

The Food and Drug Administration (FDA) urged individuals taking Xarelto to be on the lookout for specific symptoms, which indicate internal bleeding:

• Nosebleeds that happen often
• Unusual bleeding from the gums
• Menstrual bleeding that is heavier than normal
• Vaginal bleeding
• Bleeding that is severe, or you cannot control
• Red, pink or brown urine
• Bright red or black stools (looks like tar)
• Cough up blood or blood clots
• Vomit blood or your vomit looks like “coffee grounds”
• Headaches, feeling dizzy or weak
• Pain, swelling, or new drainage at wound sites

Certain patients are at a much higher risk of developing excessive bleeding and even paralysis. Individuals who have had spinal surgery or current spinal issues, those taking other blood thinners or NSAIDS, or those with an epidural catheter should steer clear of Xarelto.

Additional complications may arise from the extensive loss of blood. In addition to or regardless of bleeding, Xarelto may cause:

• Numb or tingling muscles
• Loss of ability to control movement
• Abnormal liver function
• Reduced platelet levels
• Hemorrhaging
• Bleeding from the rectum
• Intestinal or abdominal bleeds
• Bleeding in the brain
• Difficulty breathing or swallowing
• Back pain
• Dizziness
• Headache
• Leg weakness
• Bladder or bowel dysfunction

Risk for Post-Orthopedic Surgery

Clotting, infection, complication and return-to-surgery rates are much higher for people who take Xarelto after orthopedic surgery, such as a knee or hip replacement. A study published in the National Library of Medicine concluded that Xarelto comes with a “higher wound complication rate.”

That’s because Xarelto can worsen bleeding near a wound, increasing the risk of clotting. Slow-healing wounds are more vulnerable to bacteria and infection.

In 2012, the Journal of Bone and Joint Surgery published a study that included 13,000 people who had a knee or hip replaced. The researchers compared the complication rates associated with Xarelto and an alternative anticoagulant called Heparin. The study found that Xarelto caused four times some wound infections and leakage.

Xarelto can cause leakage at the surgical site, requiring patients to have their implants removed. In 2012, the American Academy of Orthopedic Surgeons measured the likelihood that post-op patients would need additional surgeries after treatment with Xarelto. They concluded that within 30 days, there was a significant risk of further surgery.

A National Library of Medicine study summarizes the dangers as such, “Postoperative complications after total hip or knee replacement can delay recovery, prolong hospitalization, increase rates of re-admission and, in the most severe cases, lead to long-term disability or even death.”

Regulation Recap

In July 2011, Xarelto joined the list of FDA-approved anticoagulants after data from the 2006 to 2010 Rocket AF clinical trials was reviewed. The agency agreed Xarelto was an appropriate treatment for deep vein thrombosis after knee or hip replacements but required that the manufacturer conducts postmarketing studies and clinical trials to better understand the significant bleeding risk.

Since the 2011 approval, Xarelto has been the subject of some FDA letters and safety communications. Despite a lack of consensus from the FDA Cardiovascular and Renal Drugs Advisory Committee, the drug was expanded to treat blood clots and prevent stroke for people with abnormal heart rhythm in 2012.

2013 FDA Black Box Warning

In August 2013, the Food and Drug Administration added a black boxed warning to Xarelto’s labeling. The notice informed users of an increased risk of bleeding when users discontinue using Xarelto prematurely. It also cautioned patients with prosthetic heart valves against using the drug.

2013 Expanded Use Denial

That same year, the FDA issued a complete response letter to Janssen, when the company attempted to expand the use of Xarelto again. The letter indicated that the drug application “will not be approved in its present form.” The agency refused to allow Xarelto to treat patients with acute coronary syndrome.

2014 FDA Updates

In December 2014, the FDA updated the adverse reactions section. The agency added a condition called thrombocytopenia, a platelet deficiency that causes bruising, bleeding into the tissue, and slow clotting.

In March 2014, the FDA added spinal/epidural anesthesia or puncture to the warnings and precautions section. The update focused on reducing the risk of bleeding in these patients, urging doctors to “monitor frequently to detect any signs or symptoms of neurological impairment, such as midline back pain, sensory and motor deficits (numbness, tingling, or weakness in lower limbs), bowel and/or bladder dysfunction.”

The update demanded doctors “initiate urgent diagnosis and treatment including consideration for spinal cord decompression even though such treatment may not prevent or reverse neurological sequelae.”

The March 2014 update, which also updated the boxed warning with a focus on how to minimize risk for spinal hematoma, offered little, with “optimal timing between the administration of XARELTO and neuraxial procedures is not known.”

2016 FDA Safety Communication

The FDA updated Xarelto’s safety information again, this time focusing on bleeding and special populations. People with acute renal failure and end-stage renal disease (ESRD), also noting that Xarelto can cause bleeding when taken with:

• selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs)
• other medicines to treat blood clots

In 2017, Xarelto was approved in a 10mg daily dosage format by the FDA.

In 2018, the FDA released a new label for Xarelto featuring warnings that “ XARELTO can cause serious and fatal bleeding” and that physicians should “Promptly evaluate signs and symptoms of blood loss. An agent to reverse the anti-factor Xa activity of rivaroxaban is available”

In 2019, Xarelto was approved by the FDA to treat acutely ill hospitalized patients.

A Questionable Approval

In February 2016, the FDA launched an investigation to see if a malfunctioning blood monitor compromised the results during the safety trial that lead to support. The inaccurate readings could have altered the agency’s likelihood to approve the drug and given it an unfair advantage over competitors.

According to the New York Times, this isn’t the first time critics questioned the results of the Rocket-AF trial. The FDA originally approved the drug despite reservations from the committee.

“In 2011, the FDA’s medical reviewers recommended against approval of Xarelto, citing concerns that the patients receiving Warfarin during the trial were being poorly managed, which could give an unfair advantage to Xarelto,” the New York Times reports.

An analysis titled “Research Misconduct Identified by the US Food and Drug Administration: Out of Sight, Out of Mind, Out of the Peer-Reviewed Literature” found that eight of 16 Xarelto testing sites had been rated as “official action indicated” (OAI), the most severe inspection classification.

“These inspections had uncovered evidence of various transgressions, such as ‘systemic discarding of medical records,’171(p3) unauthorized unblinding, falsification, and ‘concerns regarding improprieties in randomization,'” according to the analysis.

Xarelto Advertising

Johnson & Johnson spends a significant amount of money on advertising, though it sometimes gets them into trouble. In 2013, the FDA sent a warning letter to Johnson & Johnson, indicating a “minimization of risk information” and “misleading claims” published in WebMD magazine.

“Promotional materials are false or misleading if they fail to present risks associated with a drug with a prominence and readability reasonably comparable with the presentation of information relating to the benefits of the drug,” according to the letter.

“[The] claim misleadingly suggests that dosage adjustments are not necessary with Xarelto,” however, according to the FDA,” patients with renal impairment may need to have their dosage adjusted.”

Johnson & Johnson also recruits a battalion of superstars to gush about the drug. Xarelto’s website boasts advertisements from “Hall-of-Fame golfer Arnold Palmer,” “NBA All-Star Chris Bosh,” “Champion NASCAR driver Brian Vickers” and “NBA Legend and two-time Hall of Famer, Jerry West.”

But while the company has spent more than $20 million on promotion, there’s still no antidote.

Driven By Profits

A detailed analysis of drug company spending showed that the most heavily promoted drugs, like Xarelto, have serious side effects that come to light after they’ve entered the market. But that doesn’t stop manufacturers from spending millions on promotion.

The 2013 analysis showed that the most heavily promoted drugs were not cures or even breakthroughs, but new pharmaceuticals that manufacturers hoped would be able to claim a significant share of the market.

“They may have some unique niche in the market, but they are fairly redundant with other therapies that are already available,” said Dr. Joseph Ross, associate professor of medicine and public health at Yale University School of Medicine in a New York Times article. “Many of these, you could call me-too drugs.”

The anticoagulant market is booming, with Warfarin, Pradaxa and Eliquis competing to sit at the top of the million-dollar pedestal. For nearly five years, Xarelto has made big bucks for Bayer. It brought in $494 million in the United States in 2015, according to Shareholder.

And now, with an expected 31.5 percent rise in sales, Xarelto is set to bring in billions for Johnson & Johnson and Bayer worldwide.

The Next Steps

There are more than 21 million Xarelto prescriptions in the U.S. alone. As the number of Xarelto-related injuries climbs, Bayer and Janssen continue to push the drug.

Now, the FDA has launched an investigation into the drug’s approval, focusing on the defective blood-testing device. We’re here to keep you informed as the story unfolds.