Pradaxa, Xarelto makers dispute purported Eliquis safety edge

Is Pfizer ($PFE) and Bristol-Myers Squibb's ($BMY) Eliquis really safer than its competitors? A recent analysis of FDA adverse events reports suggested that it is. Clinical trials certainly found it safer than warfarin, the old anticoagulant these new-generation clot-fighters seek to replace. And before Eliquis (apixaban) won FDA approval, analysts figured it would snap up market share precisely because clinical trials hinted that it might work better.

That market-share coup hasn't happened. The anticoagulant market is led by Johnson & Johnson ($JNJ) and Bayer's Xarelto, followed by Boehringer Ingelheim's Pradaxa. And Eliquis' rivals figure that it's too early, really, to compare adverse-event reports on the newest drug in the class with those that have been on the market years longer--and have been used by millions more patients.

Plus, both Xarelto (rivaroxiban) and Pradaxa (dabigatran) have multiple approved indications under their belts, each with its own particular patient populations and patient vulnerabilities. "Apixaban was approved recently for one clinical use," Janssen pointed out in an emailed statement to FiercePharma. "In just over one year, it has been prescribed to far fewer patients and may not yet have an established pattern in reported adverse events."

In the U.S., Xarelto is approved for 6 different uses and boasts 5.4 million prescriptions. Pradaxa is approved to prevent blood clots and strokes in patients with atrial fibrillation in the U.S.; in Europe it's also approved to prevent clots in certain surgery patients. It has racked up about 8 million U.S. prescriptions since its 2010 approval, the company said. By contrast, Janssen says, there have been approximately 435,000 prescriptions for apixaban since its approval in December 2012.

As Boehringer points out, the FDA explicitly states that its adverse-events database is spotty, because the reports are voluntary, and far from comprehensive. The reported side effects aren't necessarily caused by the product in question. "For that reason, comparison of adverse event rates across products is not methodologically supported due to biases which cannot be adequately controlled," the FDA says on its website. The agency launched its Sentinel initiative, which relies on insurance data, to get a more comprehensive look at post-marketing safety.

AdverseEvents, the data provider that analyzed FDA adverse event reports to compare clot-fighting drugs, says its methodology is designed to counteract the limitations of the agency's database and account for an individual product's time on the market. "We differentially weigh each of the cases reported ... based on 9 factors," President Brian Overstreet said in an email. Each case report then gets an individual score that's used in turn to arrive at an overall assessment. "This method removes issues such as sales or prescription differences, time on market, or approved indication," Overstreet said.

While not as controlled as a clinical trial, the analyses can give payers and providers a broader, real-world and more timely indication of safety risks, Overstreet said, which allows them to make informed decisions sooner. "Previously, all of these groups have had to rely solely on the pharma companies themselves for safety data or wait around for the FDA to take some declaratory action," he said.

However the FDA adverse events database is analyzed, there's no question that safety concerns have affected the new group of warfarin alternative drugs. Some doctors have said they're wary of the drugs, which, unlike warfarin, have no ready antidote should bleeding occur. Their makers are working to develop those antidotes, but in the meantime, reports of serious bleeding continue to mount. The Institute for Safe Medicine Practices flagged hundreds of such reports last fall, and German regulators counted almost 1,000 side-effect reports on Xarelto last year, including 72 deaths.

The German agency said that those numbers aren't out of the realm of expectations, given the large number of patients using Xarelto, and the inherent risks of bleeding with any clot-fighting medication. The FDA and its European counterparts have said the same. After slicing and dicing the data on Pradaxa more than once, the agency has backed the drug's safety when used as directed.

The FDA recently said it's planning another dive into Pradaxa data, drawn from the Sentinel database of insurance records rather than AE reports from its own database. Before that announcement, the agency commented in the New England Journal of Medicine about AE reports on Pradaxa in its database. "[T]he large number of reported cases of bleeding associated with dabigatran ... provided a distorted estimate of the comparative bleeding rates associated with dabigatran and warfarin in clinical practice," the FDA said.

Since Pradaxa's approval, Boehringer has added cautionary language to its label, warning against its use patients with prosthetic heart valves and advising doctors to check kidney function before prescribing it. The German drugmaker has continued to rack up data on on the drug, partly as a safety demonstration, partly to support its bid for broader use in preventing deep vein thrombosis and pulmonary embolism. Boehringer asked FDA for that new indication last year.

Meanwhile, Boehringer is fighting 2,000 liability lawsuits filed by patients claiming the company didn't adequately warn about the drug's bleeding risks. The plaintiffs' lawyers have accused Boehringer of withholding information from the FDA about those risks, but the company maintains that it has been open and honest about Pradaxa's safety. "We are confident the facts will show that Boehringer Ingelheim and its employees acted appropriately and responsibly," the company said in a statement yesterday.

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Editor's note: The correct name of AdverseEvents' president is Brian Overstreet. A previous version identified him as Brian Cox. Also, Xarelto is the market leader, not Pradaxa as previously stated.

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