The New Anticoagulants (NOACs)
by Steve S. Ryan, PhD
After the excitement of last year’s Boston A-Fib Symposium where three new anticoagulants were introduced, this year’s presentations on anticoagulants and stroke prevention were somewhat anticlimactic. After nearly 40 years of warfarin as virtually the only anticoagulant choice, it’s a wonderful thing to have three new anticoagulants to choose from. But it’s also a challenge. (The new anticoagulants are now collectively referred to as “NOACs” Novel Oral Anticoagulants.) The new anticoagulants (NOACs) are:
- Dabigatran (brand name Pradaxa by Boehringer Ingelheim); a direct thrombin inhibitor
- Rivaroxaban (brand name Xarelto by Bayer); a direct factor Xa inhibitor
- Apixaban (brand name Eliquis by Bristol-Meyers Squibb & Pfizer); a direct factor Xa inhibitor
(Plus, in the near future Edoxaban by Daiichi Sankyo; a direct factor Xa inhibitor)
Note: Warfarin is a vitamin K antagonist, and is still one of the most widely prescribed medicines in the world.
Which New Anticoagulant is the Best?
The most important question for both doctors and A-Fib patients is: which of the three new anticoagulants is the best, or which is better for particular patients? None of the presenters addressed this question directly or unequivocally. But I’ll put my neck on the line and try to draw conclusions from the data presented. Here’s the short version of my conclusions (in case you don’t want to read through all the data below).
Stay away from dabigatran (Pradaxa) until ‘the smoke clears’.
The clear winner of the clinical trials sweepstakes was Apixaban (Eliquis). But this anticoagulant was only recently approved by the FDA (December, 2012); there’s little real-world data on it yet.
The new anticoagulants’ cost is approximately $250.00/month. Compared to the cost of warfarin use at around $4.00/month plus about $55.00/month for monitoring INR levels, at about $60/month, warfarin is still more economical.
History of Warfarin
Dr. Daniel Singer began his presentation by recalling how warfarin was something of a wonder drug when it was first introduced. It reduced the risk of an A-Fib stroke by 70% which is all the more remarkable since many of the people in the early studies weren’t maintaining warfarin at proper INR levels (or sometimes weren’t taking it at all). According to Dr. Singer, “This corresponded to a complete prevention of additional risk of A-Fib for stroke.” Since A-Fib produces a 4-5 times increased risk of stroke, “a relative reduction of this magnitude is effectively removing it.” Warfarin’s risk of producing a hemorrhagic stroke is around 0.3%/year. The rate of strokes prevented by warfarin versus intracranial bleeding (hemorrhagic stroke) was around 15-1.
Should Everyone with A-Fib Be Taking Anticoagulants?
In his discussion of the diagnostic guidelines for when to prescribe anticoagulants (CHADS2 & CHA2DS2-VASc), Dr. Singer pointed out that according to the CHA2DS2-VASc risk stratification guidelines for estimating the risk of stroke in patients with A-Fib, 90%-95% of all A-Fib patients should be taking anticoagulants. “We should think about whether that is right or wrong.” (In other words, are we possibly doing more harm than good requiring or diagnosing that so many A-Fib patients take anticoagulants? How many actually have a real risk of stroke? Anticoagulants are not benign medications. They carry their own risk of bleeding, hemorrhagic stroke, stomach (GI) bleeding, etc.)
(The Cha2DS2-VASc diagnostic system has been adopted by the European Society of Cardiology. But the provision that simply being female is a risk factor for stroke isn’t confirmed by all scientific data. See “Women in A-Fib Not at Greater Risk of Stroke.)
Dabigatran (Pradaxa) was the first new anticoagulant approved by the FDA in 2010 after the RE-LY clinical trial with 18,000 patients at 951 centers. Like all the new anticoagulants, dabigatran has a rapid onset (two hours) compared to warfarin which is slow on and slow off. Like the others, dabigatran has a “single key activated factor” (direct thrombin inhibitor) compared to warfarin which affects many different steps in the anticoagulant process. There’s no need to adjust the dosage, but also there’s currently no good way to monitor how much of an anticoagulant effect dabigatran is having. Whereas with warfarin one can measure the INR. Dabigatran has a half-life of 12-17 hours and is 80% excreted by the kidneys. (Anyone with weak kidneys probably shouldn’t be taking dabigatran.)
At the 150 mg dose taken twice a day (the only dosage approved by the FDA), dabigatran was statistically better at reducing ischemic stroke. (The 110 mg dose approved in Canada was non-inferior to warfarin.) But dabigatran also reduced hemorrhagic stroke compared to warfarin by 60-70%. However, there were more stomach (GI) bleeds and indigestion (dyspepsia). The Pradaxa fact sheet states “In addition to bleeding, Pradaxa can cause stomach upset or burning, and stomach pain.” Nearly two out of five people (35%) could not tolerate Pradaxa, which is a high rate of adverse reactions. Patients on Pradaxa 150mg had an increased incidence of gastrointestinal adverse reactions (35%/yr) compared to warfarin (24%/yr).
If you’re taking dabigatran (Pradaxa), watch out for indigestion, burning, stomach pain and weight loss. Based on the clinical trial data, there is a danger that dabigatran over time may cause long-term damage to the gastrointestinal system.
Currently there’s no antidote to dabigatran or to the other new anticoagulants. After a fall or serious injury, one could bleed to death before the anticoagulant effect wears off. There is an antidote for warfarin.
(Update October 26, 2015: FDA Approves Reversal Agent for Pradaxa (dabigatran)
In a new study of 90 patients who had uncontrolled bleeding with Pradaxa, Praxbind (idarucizumad) stopped this bleeding within minutes. No serious side effects were reported.
We have previously reported on the reversal agent Andexanet Alfa which is on FDA fast track approval as an antidote to the Factor Xa inhibitors Xarelto and Eliquis. FDA approval is pending.
In the studies which compared warfarin to dabigatran, only 64% of warfarin A-Fib patients maintained their INR levels in the 2-3 recommended range. 36% of warfarin patients didn’t have proper INR levels. At first glance that might seem to skew the results in favor of the new anticoagulants. But that’s pretty close to real world experience with warfarin. It’s very hard for doctors and patients to maintain proper INR levels which is one of the advantages of the new anticoagulants.
Pradaxa: 6.0 Adverse Reactions Pradaxa Label Information. DailyMed.nih.nih.gov Last accessed April 10, 2013. URL: http://tinyurl.com/praxada-dailymed
Add Aspirin to the new Anticoagulants?
Dr. Singer pointed out that adding aspirin to all the new anticoagulants increased the risk of bleeding by 40%-50% without any added benefit for patients.
Rivaroxaban is a once-a-day, fast acting anticoagulant 20 mg (15 mg for younger patients) that is less dependent on the kidneys for excretion (33% versus 80% for dabigatran). Rivaroxaban is also a “single key activated factor” anticoagulant, but unlike dabigatran it is a direct factor Xa inhibitor. In case of serious injury, there’s currently no antidote. The FDA also approved it for DVT (Deep Vein Thrombosis) and PE (Pulmonary Embolism).
The Rocket-AF clinical trial of rivaroxaban studied 14,000 A-Fib patients at increased risk of stroke. The CHADS2 overall score was around 3 ½, while the other trials were around 2. 55% had a prior stroke or TIA, 60% had heart failure, 90% had hypertension.
Note: The patients in this trial were sicker than those in the other trials. One problem with this trial is that, of the patients taking warfarin, only 55% were in the therapeutic range. (45% were not taking warfarin properly, which could have skewed the results in favor of rivaroxaban.)
Rivaroxaban was non-inferior to warfarin with regards to preventing ischemic stroke, but it reduced hemorrhagic stroke by 40%. It was safer than warfarin for intracranial hemorrhage.
Like the other new anticoagulants, Apixaban is fast acting with no need for dosage monitoring. It has a short half-life and is the least dependent on the kidneys for excretion (25%). It is a direct factor Xa inhibitor. Like the other NOACs, there is no antidote in case of a fall or serious accident. In the Aristotle clinical trial 18,000 A-Fib patients took 5 mg daily and were followed for nearly two years. The mean CHADS2 score was 2.1. Apixaban was superior to warfarin in preventing ischemic stroke and hemorrhagic stroke. There was a 31% reduction in bleeding, 58% reduction in intracranial hemorrhaging, and no increase in GI problems.
Dr. Singer’s Conclusions
The new anticoagulants (NOACs) are clearly as good as or better than moderately controlled warfarin. The improvement in intracranial hemorrhaging is an unexpected but crucial benefit. But for people doing well on warfarin, there isn’t much to gain except convenience.
However, today 40%-50% of patients in A-Fib aren’t adequately anticoagulated. Maybe the added convenience of NOACs will enlarge the percentage of people protected from stroke. NOACs may be more attractive to the warfarin-reluctant patient. NOACs may be better for older people more prone to hemorrhagic stroke.
Dr. Singer (and Dr. Peter Kowey in the next presentation) said that there hasn’t been a major revolution or switch to NOACs. The percentage of people on anticoagulants hasn’t increased much. A small percentage of people starting out on anticoagulants have chosen NOACs over warfarin. But we only have data on dabigatran, while the other NOACs are very new with little data.
The three clinical trials used somewhat different inclusion criteria, different definitions, had somewhat different populations, and reported data differently. But despite these differences, we can still draw conclusions that are very important to patients.
- Anyone over 70 with A-Fib should talk to your doctor about switching to the new anticoagulants. They reduce the risk of a hemorrhagic stroke. If you’re on warfarin, the risk of a hemorrhagic stroke increases as one gets older. But the new anticoagulants reduce the risk of a hemorrhagic stroke.
- If you’re doing OK on warfarin, all things considered, it’s probably better to stay on it (with the exception of the elderly).
- Dabigatran (Pradaxa) produced more stomach (GI) bleeds and indigestion (dyspepsia). Nearly two out of five people (35%) could not tolerate it which is a high rate of adverse reactions. Even in the case of people who don’t experience obvious symptoms, dabigatran over time may be causing long-term damage to one’s gastrointestinal system. And real-world data about dabigatran has raised red flags. For example, in a multi-center study of patients having a Pulmonary Vein Isolation procedure, those taking dabigatran had significantly higher major bleeding and clots than those taking warfarin. Doctors are now weaning patients off of dabigatran and on to warfarin before an ablation. See Steve’s report: Dabigatran (Pradaxa) Danger During Ablation—Switch to Warfarin.
- Apixaban (Eliquis) produced the best results. It was superior to warfarin in preventing both ischemic stroke and hemorrhagic stroke. Rivaroxaban, however, was “non-inferior” to warfarin which isn’t as good as being significantly better than or superior to warfarin. And, unlike dabigatran, apixaban didn’t produce any increase in GI problems. But apixaban (Eliquis) is a brand new anticoagulant only recently approved by the FDA (December, 2012); there’s little real-world data on it yet.
Last updated: Monday, February 6, 2017