News on Newer Oral Anticoagulants (NOAC)

For most of my adult medical career, warfarin or Coumadin has been the gold standard for achieving anticoagulation to prevent deep vein thrombosis, pulmonary embolism, embolic strokes and other hypercoaguable conditions. Taking warfarin required monitoring your INR or Prothrombin Time by taking blood from a vein or puncturing your finger and using the finger stick blood on a strip to calculate the INR. Our goal was to keep the INR level therapeutic between 2 and 3. The safe dose of warfarin (Coumadin) is affected by dietary intake of foods containing Vitamin K (green leafy vegetables and fruits) and medications that either makes the warfarin more or less potent. These dietary and medication interferences either made your blood more coaguable increasing your risk of an embolic event, or made the blood less coaguable and contributed to bleeding events. These could include intracranial bleeds leading to permanent neurological damage and or death or gastrointestinal or retroperitoneal bleeding which could be life threatening. Warfarin or Coumadin’s anticoagulant effect could be reversed quickly by administering an antidote, fresh frozen plasma (FFP) and or replacing Vitamin K.

Within the last decade, pharmaceutical manufacturers developed and released newer oral anticoagulants such as Pradaxa (dabigatran), Xarelto (rivaroxaban) and Eliquis (apixaban). These medications were advertised as safe and did not require blood tests to monitor their effectiveness while eliminating interactions with healthy foods and most medicines. They were embraced by cardiologists trying to prevent embolic strokes in patients with the arrhythmia atrial fibrillation. The major drawback was that if you started to bleed, there was no antidote to stop the bleeding available. In the introductory period the drug could only be reversed by removing the drug via hemodialysis. There were additional questions about whether the drug was actually as or more effective than warfarin when the warfarin dosage was monitored and regulated at reputable and established medical centers in the United States.

At the European Society of Cardiology meetings in Rome, Italy, Stuart J Connelly, MD, from McMaster University in Hamilton, Ontario Canada reported this week on the results of the ANNEXA – 4 Study. They reported being able to reverse the effects of Xarelto and Eliquis using a newly created chemical. According to their report they had achieved a safe and effective antidote for these two drugs which would complement another product already approved by the FDA and in use to reverse the anticoagulant effects of Pradaxa. Their presentation of the data was accompanied by the simultaneous publication of the results in the New England Journal of Medicine. Despite the papers presentation and warm reception and publication in a respected peer review journal, the FDA has yet to approve this medication for use in the United States.

At the same meeting, Dutch researchers presented data showing that the NOAC’s (Pradaxa, Xarelto, Eliquis) provide at least the same degree of embolic stroke prevention as warfarin with less chance of intracranial bleeding. Clearly if this study is reproducible and if the antidote for bleeding with Xarelto and Eliquis receives FDA approval, it will be far easier for patients and clinicians to work with these NOAC’s then to continue treatment with Coumadin. The NOAC’s are far more expensive than warfarin (Coumadin) but their ease of use and reversibility with the newly approved agents, will make them the drugs of choice when an oral anticoagulant is required.

High Disability and Death Rates in Bleeds Associated with New Oral Anticoagulants

In the trailer for the movie Jaws 2 they show a swimmer in the ocean with a deep voice saying, “Just when you thought it was safe to go back into the water…” followed by the classic music associated with a shark attack and a big fin approaching the unsuspecting swimmer. I feel much the same way upon reading a Medpage Today online journal review of an article in JAMA Neurology published on December 14, 2015. Jan C. Purrucker, MD and colleagues looked at 61 consecutive patients with non-trauma related cerebral hemorrhages due to the newer oral anticoagulants Pradaxa, Xarelto and Eliquis. Overall there was a death rate of 28% at three months and “two out of 3 survivors had an unfavorable outcome.”

In October of 2015 the FDA approved the use of the antibody fragment idarucizumab (Praxbind) to reverse anticoagulation in patients bleeding from the administration of the oral anticoagulant Pradaxa. There are currently no medications to reverse the bleeding from the drugs Xarelto or Eliquis but we are promised that new products are in development. The article goes on to discuss how physicians have been forced to improvise when patients on these medications show up bleeding. They have tried fresh frozen plasma, 3-factor, 4-factor and activated prothrombin complex concentrates prothrombin complex concentrates, recombinant factor VIIa and cryoprecipitate alone or in combination with marginal success at best.

Despite there being no antidote to these blood thinners, the massive direct to consumer advertising continues on television prime time and magazines as if the products are no more dangerous than an antacid for heartburn. Coumadin or warfarin is the prototype anticoagulant working by inhibiting vitamin K dependent clotting factors. Its effects are reversible with administration of Vitamin K and clotting factors if bleeding occurs. Coumadin requires periodic blood tests (INR) to check on its efficacy and there is a long list of medications and foods that need to be avoided or adjusted while taking it. It is less convenient but safer in the sense that its effects can be reversed with medication.

The newer oral anticoagulants were championed by several studies that suggested that they were more effective in preventing embolic strokes in patients with the heart rhythm atrial fibrillation. Many experts in the field felt that those conclusions were flawed because the Coumadin group was not tightly regulated to keep their INR in a therapeutic non-clotting range thus unfairly biasing the results in favor of the newer agents.

There is no question that the newer agents are more convenient than warfarin treatment, but until there are readily available antidotes, complications seem to be more difficult to limit and control.