Is Xarelto effectiveness worth its side effects in Seniors?

Is NOACs’ effectiveness worth their dangerous safety issues?

Just like many other senior Americans, Gloria Glatz, age 88, died in 2012 because of a severe complication caused by Xarelto side effects.

Gloria Glatz was an 88-years-old patient from atrial fibrillation, a medical risk factor for stroke, so in December 2011, her doctor prescribed her a new anticoagulant drug: Xarelto (rivaroxaban).

Together with other four new oral anticoagulants known as (NOACs), Xarelto was approved in 2010. NOACs were amply marketed as easier and more convenient than warfarin, and became a staple of the newer therapeutic approaches.

The main difference between NOACs and warfarin, is that the latter is a vitamin K antagonist, so its effects can be reverted in a bleeding emergency or prior to a surgical intervention by administering vitamin K. There’s no know antidote to NOACs instead, although packed red blood cells can somewhat help reducing their anticoagulation action.

Gloria died March 23, 2012 at a Kenosha hospital because of a gastrointestinal bleeding that doctors had no means to stop.

A vast MedPage Today/Journal Sentinel investigation showed that since 2010, more than 58,000 people have reported a life-threatening NOACs side effect, such as a major bleeding episode. Since 2010, warfarin-related bleeding accidents accounted for just 700 deaths: a much small number compared to the 8,000 victims caused by the NOACs side effects.

Although newer NOACs represent just the 10% of all anticoagulant prescriptions since 2010, up to 90% of deaths reported to the FDA voluntary adverse events reporting system are linked to them. The newer anticoagulant drugs are also way more expensive than the old ones. According to an analysis of Medicare data, in 2013 warfarin was dispensed about 6 times more than Xarelto and Pradaxa (dabigatran) together, but while the first costed taxpayers only $240 million, the other two were paid more than $1 billion.

One of the main advantages of NOACs is that they don’t require continuous INR testing like Coumadin (warfarin) does. To avoid reducing warfarin’s effectiveness by eating Vitamin K-rich foods, patients need also to undergo some dietary restrictions and avoid alcohol consumption.

The MedPage Today/Journal Sentinel investigation cited above, discovered that Gregory Lip, the British doctor who ideated a new system for determining

stroke risk that vastly increased NOACs sales, had extensive monetary ties to the pharmaceutical companies that produce these drugs. This new system was included into standard treatment guidelines written by U.S. and European leading medical societies that were also significantly financed by the same Big Pharma lobbies.

A 2013 paper published in The American Journal of Cardiology showed that American patients that suffer from afib, increased their number from 3 million to over 5.2 million. Following the new guidelines, the number of patients that qualify for anticoagulant therapy jumped by one full million: from 3.7 million to 4.7 million, according to a paper published in May in the journal JAMA Internal Medicine.

This incredibly larger number is due to the fact that following the new guidelines, virtually all women suffering from atrial fibrillation and almost all patients aged 65+ require this kind of therapy. The newer risk scale ideated by Gregory Lip, MD to determine whether a patient should undergo anticoagulation therapy, is called theCHA2DS2-VASc. However treating a patient with a low risk for a stroke may be more harmful than more beneficial because of the increased risk of a life-threatening bleeding side effect of NOACs.

Many concerns about dangerous bleeding caused by NOACs side effects have been raised though. A 2011 letter to the New England Journal of Medicine, a 2012 letter in the Journal of Neurosurgery, and a 2014 paper in a hematology journal, all described cases of patients who died or were rescued from the brink of death caused by internal bleeding provoked by NOACs side effects after small domestic accidents.

In May of 2014, people in the U.S. who allegedly were harmed after using Pradaxa (dabigatran), filed a lawsuit against German drug maker Boehringer Ingelheim, and the company agreed to pay $650 million to settle about 4,000 lawsuits. Newer Xarelto cases keep being filed daily.

One of the main selling point of NOACs is that these drugs showed a reduced risk in terms of brain bleeding accidents, and a small percentage increase in terms of stroke reduction.

In the ARISTOTLE-AF study of Eliquis, which involved 18,000 people, for example, brain bleeding accidents in patients under Eliquis treatment were just 0.3% of total cases, compared to 0.8% in patients who took warfarin. The number of strokes or blood vessel clots among Eliquis patients was just 1.3%, compared to a slightly higher 1.6% in warfarin patients.

In the famous ROCKET-AF trial, that included 14,000 patients, only 0.5% of those taking Xarelto suffered intracranial hemorrhage (ICH), against 0.8% of those under warfarin treatment.

That’s for bleeding accidents. But what about major bleeding accidents – i.e. the life-threatening ones including gastrointestinal hemorrhages? Here the numbers seem to swap: warfarin only accounts for 5.4% cases, compared to Xarelto’s 5.6%. Although both Pradaxa and Xarelto seemed to show some benefits compared to warfarin in terms of stroke reduction, some numbers still raised several concerns. For example in the RE-LY, the Pradaxa pivotal trial, 1.5% of patients under treatment with Pradaxa had an heart attack: a larger percentage than the 1.1% of those who took warfarin.

Also, it should be noted how in both Xarelto and Pradaxa trials, the FDA raised some question on whether warfarin was used in an appropriate way. As warfarin levels need to be constantly monitored to keep coagulation levels within the appropriate range, it was discovered that during these trials, researchers compared the newer drugs with patients with uncontrolled levels of warfarin. As soon as their values were appropriately monitored, a later FDA review showed how all the benefits showed in the Pradaxa trial actually disappeared. The same happened in similar FDA reviews about Xarelto, as the trial was conducted in several countries around the world, including ones like India that didn’t use warfarin well enough, leading to a bias in favor of the NOACs. An FDA review, even recommended against approving Xarelto for atrial fibrillation as it was considered too dangerous. Also, many of the doctors who wrote the newer guidelines on NOACs or worked as co-authors during these trials, worked in their past as speakers or consultants for these same companies that produce them.

 

REFERENCES

1. http://www.imshealth.com/portal/site/imshealth
2. http://www.medpagetoday.com/special-reports/slipperyslope/52875
3. Estimates of Current and Future Incidence and Prevalence of Atrial Fibrillation in the U.S. Adult Population
Colilla, Susan et al. American Journal of Cardiology , Volume 112 , Issue 8 , 1142 – 1147
4. O’Brien EC, Kim S, Hess PL, et al. Effect of the 2014 Atrial Fibrillation Guideline Revisions on the Proportion of Patients Recommended for Oral Anticoagulation.JAMA Intern Med. 2015;175(5):848-850. doi:10.1001/jamainternmed.2015.13.

5. https://www.cms.gov/Research-Statistics-Data-and-Systems/Statistics-Trends-and-Reports/Medicare-Provider-Charge-Data/Part-D-Prescriber.html

6. Acutely Injured Patients on Dabigatran
N Engl J Med 2011; 365:2039-2040November 24, 2011DOI: 10.1056/NEJMc1111095

7. Journal of Neurosurgery May 2012 / Vol. 116 / No. 5 / Pages 1093-1096. “Neurosurgical complications of direct thrombin inhibitors—catastrophic hemorrhage after mild traumatic brain injury in a patient receiving dabigatran
Case report” Sarah T. Garber, M.D., Walavan Sivakumar, M.D., and Richard H. Schmidt, M.D., Ph.D. Published online March 6, 2012; DOI: 10.3171/2012.2.JNS112132.

8. Nannapaneni N, Singh R, Mckay P, Al-Hajeili M. Managing a Rivaroxaban Bleed: Understanding the Difficulties in Acute Reversal of the New Oral Anticoagulants through a Case Report. Case Reports in Hematology. 2014;2014:548272. doi:10.1155/2014/548272.

9. Frank Siebelt, Jonathan Gould, William Hardy: “Bayer faces law suits in United States over Xarelto: paper”  http://www.reuters.com/article/2014/06/14/us-bayer-suit-idUSKBN0EP0HW20140614 Reuters website, June 14, 2014. (Accessed June 2015)

10. http://www.medpagetoday.com/Cardiology/Strokes/28367

11. http://www.medpagetoday.com/Cardiology/Arrhythmias/44986

12. Manesh R. Patel et al, “Rivaroxaban versus Warfarin in Nonvalvular Atrial Fibrillation” N Engl J Med 2011; 365:883-891September 8, 2011DOI: 10.1056/NEJMoa1009638

13. http://www.medpagetoday.com/MeetingCoverage/AHA/23346

14. http://www.medpagetoday.com/MeetingCoverage/ESCCongress/28237