For more than half a century, patients with Non-Valvular Atrial Fibrillation (NVAF) have been using vitamin K antagonist (Warfarin) to prevent stroke and thromboembolism. Warfarin has proved to be effective, however, it comes with its own baggage of side effects. The use of warfarin is limited due to risk of bleeding, regular INR monitoring and possible food-drug interactions; resulting in poor patient compliance.
In recent years, a number of New Oral Anticoagulants (or Non-Vitamin K Oral Anticoagulants) have entered the market such as Pradaxa® (dabigatran), Xarelto® (rivaroxaban), Eliquis® (apixaban) and Lixiana® (edoxaban). These “new generation” blood thinners have an advantage over warfarin as they do not require regular monitoring, they have a rapid onset-offset of action, are relatively free of dietary restrictions and have noticeably fewer drug interactions. NOACs have shown similar efficacy to warfarin, with a slightly superior safety. However, both warfarin and these new age anticoagulants come with a risk of internal bleeding (GI bleeds, Intracranial hemorrhages etc.). While the effects of warfarin and Pradaxa® can be reversed, the Factor Xa inhibitors (Xarelto®, Eliquis® and Lixiana®) have no antidote as of yet.
Stories of bleeding and death in patients began appearing soon after the launch of the very first NOAC, Pradaxa®. Let’s have a quick look at the battles of each NOAC
Pradaxa® – Paying the Price of Being a Pioneer?
Dabigatran was launched in 2010, as a superior alternative to traditional warfarin for the prophylaxis of Deep Vein Thrombosis (DVT) and Pulmonary Embolism(PE) in patients undergoing hip/knee replacement. It was later approved for prevention of stroke and systemic embolism in NVAF. Shortly after launch, deaths were reported in >500 patients, driving the FDA to issue a safety alert against dabigatran. According to published articles, approx. 3,781 serious adverse events associated with dabigatran, were reported in 2011. The reports of side effects attributed to dabigatran surpassed all other monitored drugs for that year. In early December 2011, the FDA decided to evaluate reports of bleeding in patients on dabigatran that were submitted to the agency’s Adverse Events Reporting System (AERS) database to determine if serious side effects were occurring at a higher rate than expected.
The rapidly increasing number of lawsuits filed against Boehringer Ingelheim (manufacturer) were consolidated on August 2012 into a Multidistrict Litigation (MDL) in the U.S. In December 2013 the FDA posted, for a public comment, a proposed protocol of a new study, intended to be a one-time “real world” assessment of selected safety outcomes in adults with NVAF taking Pradaxa® compared to those patients taking warfarin (will be touched upon below). Finally, in May 2014, Boehringer agreed to settle most of the dabigatran lawsuits (~4000) against an amount of $650M. One year later in May 2015, an order was issued which disbanded and ended the dabigatran MDL litigation.
Before moving on to Xarelto’s story, we would like to briefly highlight the outcomes of FDA´s “real world” study using Medicare patient data. The Medicare study of 134,000 patients of ages 65 years and above, compared dabigatran to warfarin, for risk of ischemic or clot related stroke, intracranial bleeding and death. The independent FDA analysis showed that dabigatran was associated with lower risk of ischemic clot related strokes, intracranial bleeding and death compared to warfarin. FDA concluded that dabigatran has a favorable benefit-to-risk profile and have made no changes to the current label or recommendations to use.
Xarelto® – Convenient or Dangerous?
Rivaroxaban was approved in 2011 by the US FDA for secondary prevention of DVT and PE in patients undergoing hip/knee replacement, followed by stroke prevention in NVAF and primary prevention of DVT and PE. Rivaroxaban´s biggest selling points were its once daily dosage convenience and the freedom from dietary restrictions and regular monitoring. Since 2013, several TV commercials have hyped the medicine´s superiority over warfarin.
Rivaroxaban´s troubles started soon after. In January and March of 2014, the FDA issued two “black box” warnings for the product. Starting from 2015-16, legal proceedings began to be filed against the drug makers Bayer and Janssen, cumulating to the current total of ~18000 (as of April 2017) lawsuits. Bayer and Janssen have been accused of misleading patients about the bleeding risks and providing insufficient information. The lawsuits claim that the Pharmaceutical companies have focused on rivaroxaban´s safety and benefits without thoroughly explaining its potential hazards, including a lack of reversal agent.
In early May 2017, Bayer and Janssen won the first bellwether trial over rivaroxaban. The verdict confirmed the safety and efficacy of the drug and that its FDA approved label contains accurate, evidence based information. However, this is only a temporary victory, as there are several pending cases.
Eliquis® – Still Too Early?
The third NOAC – apixaban was approved by the US FDA in 2012, for the prevention of stroke in NVAF and treatment of Venous Thromboembolism. In July 2015, the first federal lawsuits against BMS and Pfizer (the Pharmaceutical companies holding the marketing authorization for apixaban) was filed. Similar to other NOACs, the plaintiffs accuse Pfizer and BMS of the failure to warn patients against potentially serious life threatening risks. They also claim that the label is flawed because the dosage recommendations aren’t individually tailored for patients. Currently, there are ~80 lawsuits filed against apixaban and more are expected.
FDA Also Faces Criticism!
Perhaps due to the novelty factor or due to the paradigm shift promised by the NOACs, even the clinical trials and regulatory decisions have come under greater than normal public scrutiny.
Boehringer was accused of failing to share with the regulators, information from the RE-LY trial about the potential benefits of INR monitoring and adjusting dabigatran´s dose to maximize the effectiveness of the drug. At the same time, FDA came under criticism for approving dabigatran based on an un-blinded study (however, the two dabigatran doses were blinded in RE-LY) knowing that lack of blinding might have affected the data.
A similar story played out for rivaroxaban´s ROCKET-AF trial where faulty INR devices being used and poor warfarin control in the trial were highlighted. Publicly available reports suggest that these issues may have skewed the results in favor of rivaroxaban. As a result, the US FDA re-examined the analysis from ROCKET-AF trial and concluded that the trial results were not substantially affected by the faulty blood monitoring device used during the study.
Apixaban´s ARISTOTLE trial has also been nit-picked, with claims of clinical trial misconduct. The US FDA delayed the drug approval for nine months over unreported SAEs, incorrect medication administration and an alleged cover-up at one of the investigator sites in China. The US FDA approved apixaban after deciding that the trial results were enough to support approval, despite the several issues.
Some lessons learnt?
The NOAC market is expanding rapidly – the 2022 market for the NOACs is estimated at north of $15 billion (across all cardiovascular indications, including taking over warfarin patients). At the same time, the competitive dynamics and public scrutiny are very stringent. Any Pharmaceutical company developing an anticoagulant, here are some key GCP points to keep in mind:
Read More Disclaimer: All data and information provided on this site is for informational purposes only. This blog is an attempt to summarize publicly available data as objectively as possible!
Disclaimer: All data and information provided on this site is for informational purposes only. This blog is an attempt to summarize publicly available data as objectively as possible!