Is Xarelto alleged superior effectiveness over its counterparts worth its harmful side effects in senior populations? Just like many other elderly citizens, the 88-year-old Gloria Glatz died in 2012 because of a serious complication caused by a lethal internal bleeding. Gloria Glatz was an atrial fibrillation patient, a medical risk factor for stroke. In December 2011, her physician prescribed her a new blood thinner medication: Xarelto (rivaroxaban).
Xarelto is a Novel Oral Anticoagulant (NOAC), a group of four new anticoagulants, and was approved in 2010. The NOACs were widely advertised as more convenient and easier to use than the older alternatives, and became a staple of the modern treatments. The main difference between Warfarin (the old blood thinner) and NOACs, is that the first one antagonizes the effects of Vitamin K, so if a patient suffers from a bleeding emergency or needs to be operated, its effects can be reverted with the administration of this vitamin. There is no antidote available instead for the Xarelto side effects, so a fresh platelet infusion can just lend a minor help to reduce its blood thinning action.
On March 23, 2012, a gastrointestinal bleeding accident killed Gloria. Doctors at the Kenosha hospital had no means to save her life. In a famous Journal Sentinel/MedPage Today investigation, evidence showed that more than 58,000 subjects have reported a potentially fatal NOACs adverse reaction since 2010, including severe bleedings and at least 8,000 death cases. Comparing these numbers to the previous anticoagulants, Warfarin only accounted for a total of 700 deaths: not even one tenth of the fatalities caused by the newer drugs.
NOACs just accounted for 10 percent of all blood thinner prescriptions since 2010. However an astounding 90 percent of deaths reported to the Food and Drugs Administration (FDA) are associated with these medications. The newer blood thinners are also significantly more expensive than those already on the market. According to an analysis of Medicare data, the number of Warfarin prescriptions in 2013 were 6 times higher than Pradaxa (dabigatran) and Xarelto ones together, but while taxpayers paid the old blood thinner just $240 million, the newer ones costed more than $1 billion.
The risks associated with the use of the dangerous NOACs
One of the main improvements of NOACs over their counterparts, is that they do not require dietary restrictions, so alcohol and foods with high contents of Vitamin K are not forbidden. Patients also do not require to continuously check their INR values in specialized blood clinics. The investigators of the Journal Sentinel found that the British doctor who invented a new system for determining stroke risk that significantly increased NOACs sales, Dr. Gregory Lip, had extensive economic ties to the Big Pharma that manufacture these medications. The new evaluation method was quickly included in the standard treatment guideline used by leading European and American medical societies that also received important monetary incentives by the same pharmaceutical companies. The new risk scale invented by Dr. Gregory Lip to decide if a patient should take blood thinners, is called the CHA2DS2-VASc.
In 2013, a study published in The American Journal of Cardiology indicated that U.S. patients affected by atrial fibrillation, increased their number to 5.2 million from just 3 million. According to the new guidelines, the number of subjects for which blood thinning therapy was recommended increased to 4.7 million from 3.7 million. A a whole one million, according to data included in a JAMA Internal Medicine paper. This impressively higher number is caused by the fact that, according to the guidelines’ changes, almost all women affected by afib as well as virtually all elderly patients now require this kind of treatment. Nonetheless, due to the risk of a potentially lethal bleeding accident caused by a NOAC, in low-risk for stroke patients, this treatment may be more harmful than beneficial. Many raised numerous concerns about the harmful NOACs-related bleedings, however. A 2012 letter in the Journal of Neurosurgery, a 2014 paper in a journal Haematology, and a 2011 letter to the New England Journal of Medicine, all described cases of subjects whose internal bleedings killed or brought them to the brink of death. All these patients took NOACs to treat their conditions, and the bleeding accidents were caused by simple domestic accidents.
In May of 2014, American citizens who allegedly suffered serious harm after taking Pradaxa, filed a lawsuit against the German pharmaceutical company Boehringer Ingelheim. Eventually, the drugmaker settled more than 4,000 litigations by paying $650 million. To date, an even higher number of Xarelto lawsuits have been filed against Bayer AG and Janssen Pharmaceuticals.
Another important selling point of the newer anticoagulants, was the reduction of the risk of brain bleeding accidents, coupled with a small benefit in the reduction of strokes. In the pivotal study of Eliquis (apixaban), the ARISTOTLE-AF trial, more than 18,000 subjects were involved. The number of patients taking the newer drug who suffered a brain bleeding accident was just 0.3 percent of total cases, while in those who took Warfarin that percentage was higher with a total of 0.8 percent of cases. The number of blood vessel clots or stroke among patients treated with apixaban was just 1.3 percent, a little less than the 1.6 percent in patients treated with Warfarin. In the Xarelto’s clinical trial, the ROCKET-AF study, just 0.5 percent of the 14,000 patients treated suffered from an intracranial hemorrhage (ICH), compared to a 0.8 percent in those treated with Warfarin. However, if we look at the rates of the life-threatening major bleeding accidents such as the gastrointestinal hemorrhages, the numbers are swapped. Xarelto accounted for a 5.6 percent, while Warfarin for just 5.4 percent. In the RE-LY Pradaxa’s clinical trial 1.5 percent of patients had a heart attack, compared to just 1.1 percent of those under Warfarin treatment.
The FDA also raised many doubts on whether Warfarin was appropriately used during both the ROCKET-AF and RE-LY clinical trials. The blood levels of the old anticoagulant must be continuously monitored to maintain the coagulation levels within a safe range. However, during these trials, the scientists checked the effectiveness of NOACs in a population of patients whose Warfarin’s blood levels weren’t adequately monitored. When the FDA reviewed the Pradaxa trial, and confronted it to data coming from patients whose levels of Warfarin were appropriately controlled, the alleged benefit of the NOAC disappeared. Similarly, during the Xarelto trial many studies were conducted in many countries around the globe such as India that weren’t able to adequately use Warfarin. The effectiveness of NOACs was, at best, strongly biased. A later FDA panel even recommended against the approval of Xarelto in patients affected by afib, since they determined that the new drug was too dangerous. Curiously enough, many of the physicians who worked as co-authors during these trials also wrote the newer guidelines. Many of them even worked as consultants or speakers for the Big Pharma that manufacture these drugs.
Article written by Dr. Claudio Butticè, Pharm.D.
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