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Warfarin vs. Pradaxa and the Other New Anticoagulants

by Steve S. Ryan, PhD, Last Updated June 2018
CT scan - Ischemic Stroke - NOAC and Warfarin at A-Fib.com

Most would agree that the worst thing that can happen to a patient with A-Fib is a life-altering stroke. A stroke often causes death or permanent disability. Thus the importance of anticoagulation therapy for A-Fib patients.

Low-Risk Patients: For patients at low or intermediate risk of stroke (including younger patients without any additional stroke risk factors), aspirin may be prescribed, or no anticoagulation therapy at all.

Stroke Prevention With warfarin

For many years, there was only one proven therapy for stroke prevention in A-Fib patients at high or intermediate risk for stroke: the anticoagulant warfarin (Coumadin). It’s readily available and inexpensive.

But maintaining correct warfarin levels is difficult especially over the long haul (studies indicate around 30% of people will stop taking warfarin).

But maintaining correct warfarin levels is difficult especially over the long haul (studies indicate around 30% of people will stop taking it).

Frequent blood tests are required to regulate the dose.

Higher Risk of Bleeding Gene? About a third of the people who take warfarin are at a higher risk of bleeding because their genes make them more sensitive to warfarin. If a family member experienced side effects, talk to your doctor about taking a genetic warfarin sensitivity test.

Drug Interactions: Warfarin also has many interactions with other drugs, herbs, and food sources. If taken incorrectly, warfarin can increase your risk of dangerous bleeding.

Warfarin: Notable Concerns

Taking warfarin over several years may lead to microbleeds in the brain and dementia.

Read about the post-ablation patient on anticoagulation therapy for 10 years who developed cerebral microbleeds and early dementia: The New CHA2DS2-VASc Guidelines and the Risks of Life-Long Anticoagulation Therapy 

“Oral anticoagulants…increase the risk of intracerebral hemorrhages (ICH), a less common but more deadly and disabling type of stroke. Over 50% of patients sustaining a  warfarin-related ICH die within the first three months.” (NOAC-related intracerebral hemorrhages outcomes are similar to warfarin.)

GI intestinal bleeding is another potential risk of Warfarin. “The risk of warfarin related GI bleeds can range from between 0.8% and 1.5% in patients on long term anti-coagulation.”

Stroke Prevention: NOACs

Novel Oral AntiCoagulants (NOACs) are alternatives for vitamin K antagonists (e.g., Warfarin) for stroke prevention.

For over 20 years there have been extensive efforts to replace warfarin with other drugs. In the US, we have four new anticoagulants to consider: Pradaxa (dabigatran), Xarelto (rivaroxaban), Eliquis (apixaban) and Savaysa (edoxaban)).

The data on the new anticoagulants comes from three randomized controlled trials involving more than 50,000 A-Fib patients:

RE-LY (dabigatran)
• ROCKET-AF (rivaroxaban)
• ARISTOTLE (apixaban)

Each study compared one drug against warfarin (not against each other). Taken together, these studies consistently revealed that A-Fib patients who took the non-warfarin blood thinners suffered fewer strokes, intracranial bleeds, and serious bleeds than those who took warfarin.

All of these drugs are at least as good as warfarin for preventing stroke and all are better than warfarin in reducing your risk of serious bleeding in the brain.

Questionable Trials Bias: Each of these NOAC trials had a questionable bias toward the new drug when compared against warfarin.

Warfarin users are notoriously non-compliant: Up to 50% are inconsistent in managing their diet, monitoring their INR levels and taking the correct dosage. Each of the three trials compared a group of compliant patients against a group of inconsistent warfarin patients. So results should be viewed with a critical eye.

For a more in-depth look at the clinical trials of the new NOACs, see 2013 BAFS: The New Anticoagulants (NOACs).

But NOACs are not like taking vitamins. They work by causing or increasing bleeding and are considered high risk meds. “For patients with atrial fibrillation, NOACs still pose a major bleeding risk,” according to Dr. Shang-Hung Chang and his colleagues at Chang Gung Memorial Hospital in Taiwan.

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NOACs: Three Notable Concerns

The new anticoagulants offer several advantages over warfarin. They are fast acting. And when stopped (i.e., for surgery), they just as quickly clear your body (a short “half-life). There’s a broad therapeutic window (wide range of safe use), and they have minimal drug or dietary interactions. They can be administered in fixed doses without monitoring, making them potentially more convenient to use than warfarin.

Remember: The goal of anticoagulation therapy is to reduce your risk of life-altering stroke.

Enthusiasm for the new anticoagulants (NOACs), however, must be tempered by three notable concerns in patients taking these drugs:

1. No readily available means for assessing the degree of anticoagulation
2. Life-threatening bleeding complications can occur after an injury
3. Stomach problems and gastrointestinal bleeding

According to Dr. Stephen Kimmel of the Un. of Pennsylvania: “If you have a history of stomach problems or gastrointestinal bleeding, you may want to avoid Pradaxa and Xarelto—both medications have the highest risk for those complications.”

NOACs: No Way to Measure Effectiveness

One of the problems with the newer anticoagulants (NOACs) is we don’t have a good way to measure how effective they are or how much of an anti-clotting effect there is at a given point in time. (For example, in treating trauma patients, ER doctors can only use the elapsed time from the last dose to estimate the clotting effect.)

With warfarin (Coumadin), on the other hand, we can measure how effective it is by its level in the blood stream measured in INR (International Normalized Ratio). A person not on anticoagulants will have an INR slightly above 1 (the author’s INR is 1.1). Someone with A-Fib on Warfarin should have an INR between 2.0 and 3.0. At this INR level a person will bleed more than someone with an INR of 1.0, but the blood will still clot.

With an INR below 2.0 you are more in danger of having an ischemic (clotting) stroke, the kind that most often occurs in A-Fib. With an INR of 4.0 and above, there is much more risk of blood not clotting and of developing a hemorrhagic stroke.

But the INR blood test doesn’t work with the new anticoagulants which affect only one particular stage in the anticoagulation process. Pradaxa, for example, is a direct thrombin inhibitor, whereas warfarin affects nearly every stage in the anticoagulation process. (Thrombin is an enzyme that converts soluble fibrinogen into insoluble fibrin. Fibrin is a fibrous protein involved in the clotting of blood. It forms a mesh or clot over a wound.)

The lack of a readily available method to determine the degree or current level of anticoagulation is a major challenge for ER physicians and staff treating trauma patients.

Medical ID: If you’re on any blood thinner, it’s a good idea to carry some kind of medical ID. If you have an accident involving bleeding, EMTs can call ahead to the ER and get the staff ready to help you. To print your own I.D. see: Print a free Medical Alert I.D. Wallet Card

Pradaxa: Too Effective?

Pradaxa, in particular seems to work almost too well.

Pradaxa won the FDA sweepstakes by being the first new anticoagulant to get FDA approval and thus captured a significant market share. 

In some patients there is excessive bleeding that is catastrophic (usually in older or weaker patients). Pradaxa has been associated with deaths in the ER before doctors had Praxbind, the Pradaxa reversal agent, to stop people from bleeding to death. (Warfarin on the other hand has several proven, time-tested reversal or antidote strategies.)

Pradaxa (dabigatran) won the FDA sweepstakes by being the first new anticoagulant to get FDA approval and consequently captured a significant share of the anticoagulant market.

Pradaxa comes in two doses in the United States, 150 mg twice daily or 75 mg twice daily. It’s large and harder to swallow, comes in a bottle with a 30-day shelf life once opened (or in blister packs which eliminates the shelf-life problem.) And it’s expensive.

Questionable Trials Bias: Each of these NOAC trials had a questionable bias toward the new drug when compared against warfarin.

In the RELY trial, Pradaxa was not only equal to warfarin, but it proved to be superior to it in preventing stroke. Bleeding rates in the head were lower than with Warfarin. However, bleeding from the stomach or bowels was higher. The most common side effect was stomach pain.

In addition to the bleeding deaths in the ER mentioned above, Pradaxa’s own fact sheet states common side effects of Pradaxa include:

• Indigestion, Upset Stomach, or Burning
• Stomach Pain

[These statements don’t capture the actual human toll—burning throat, roiling intestines, diarrhea, burning anus, lasting intestinal damage, etc. that Pradaxa can produce in some people.]

Xarelto and Eliquis

Xarelto (rivaroxaban) was the second drug available in the United States. Xarelto comes in two doses, 20 mg daily or 15 mg daily. In contrast to Pradaxa, it is a small pill taken once-a-day that doesn’t seem to cause a lot of intestinal problems. In the Rocket AF trial, Xarelto also significantly lowered the risk of bleeding in the brain and head compared to warfarin. Anecdotally we don’t seem to see a lot of deaths in the ER from Xarelto.

Eliquis (apixaban) was third to be approved, comes in two doses, 5 mg twice daily or 2.5 mg twice daily (the lower for A-Fib patients with kidney dysfunction). Similar to Xarelto, the risk of bleeding in the brain and head was lower versus warfarin.

However, this drug was unique in that bleeding from other sites including the stomach, bowels, and bladder was less. In the Aristotle trial, Eliquis was at least as good and tended to be better than warfarin at preventing stroke. Eliquis is the only drug that can claim that survival improved with its use compared to warfarin.

Xarelto and Eliquis, just like Pradaxa, are also very expensive.

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NOAC Reversal Agents and Bleeding Complications

As of May 2018, there are now FDA-approved NOAC reversal agents: Praxbind for Pradaxa (dabigatran) and Andexxa for the NOACs Xarelto (rivaroxaban) and Eliquis (apixaban). See FDA Approves Antidote for Xeralto and Eliquis).

The reported bleeding events tend to occur mainly in elderly patients (median age of 80) which raises a question regarding safe dosing and monitoring in older patients. Elderly patients often have mild to moderate renal impairment, which can cause plasma levels of the NOAC to increase to up to three times those with normal renal function.

“One-size-fits-all” dosage of these new anticoagulants may need to be re-examined for elderly patients. (The FDA rejected the lower 110-mg twice-daily dose of Pradaxa (dabigatran) tested in the RE-LY trial, instead approving a 75-mg twice-daily dose just for patients with severe renal impairment.)

 Eliquis Earns Best Safety Score

Through an analysis of data from the FDA Adverse Event Reporting System by AdverseEvents, Inc., Eliquis has received an “RxScore” safety score of 39.45 on a 100 point scale, with 100 representing the highest risk. In comparison, warfarin had a score of 67.57. Pradaxa (dabigatran) had a score of 67.15, Xarelto (rivaroxaban) 67.08.

The FDA’s database comprises all the reports made by doctors, patients and other healthcare providers, which means it’s not a “scientific” finding with the authority of a clinical trial. AdverseEvents applies logic, math and software to the database to sift out the important data.

For Eliquis, “the rate of suspect cases was lower in every type of adverse-event report, from hospitalization to death.” For example, among Eliquis patients reporting side effects, only 21% cited hospitalization, while Pradaxa had 39%, Xarelto 43% and warfarin 50%.

The results all point to the same general conclusion: Eliquis may be a safer choice among the new NOACs.

Choosing Your anticoagulant

If you’re conscientious and are pretty good at staying in the proper INR range, stick with warfarin (Coumadin) if you can. It may not be as convenient and easy to use as the newer anticoagulants, but we know warfarin works if you stay within the proper INR range. And there are proven reversal agents for warfarin. The cost of warfarin is significantly lower when compared to the new anticoagulants. (Your insurance provider may have a direct say about which drug you take.)

Note: There’s no guaranteed way to avoid a stroke altogether.

If you have trouble staying within the proper INR range, can’t juggle the diet restrictions or monthly monitoring, I suggest you talk with your doctor about switching from warfarin (Coumadin) to the NOAC Eliquis (apixaban). Eliquis doesn’t block Vitamin K like warfarin, has no interactions with food (not even spinach), and requires NO monitoring (no more finger stick checks).

Compared the other NOACs, Eliquis tested better and has the best RxScore safety score. Like all the NOACs, be aware of Eliquis’ much higher monthly price. (For those in the US and on Medicare with Part D coverage, the monthly cost may range from $30 to $50.) You will need to judge if the benefits outweigh the costs.

When choosing an anticoagulant, along with costs, you need to consider which is worse: the risk of uncontrolled bleeding or the risk of a debilitating stroke.

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Resources for this article
• Gurol, M Edip. Brain MRI scans can inform the choice between OACs and LAA closure for non-valvular AF. Cardiac Rhythm News. March 18, 2018, Issue 40. p. 9

• Lakkireddy, Dhanunjaya. Octreotide enables left atrial appendage closure in AF patients with GI bleeding. Cardiac Rhythm News, May 31, 2018, Issue 40. P.1.

• Chang SH et al. Association Between Use of Non–Vitamin K Oral Anticoagulants With and Without Concurrent Medications and Risk of Major Bleeding in Nonvalvular Atrial Fibrillation. JAMA. 2017; doi:10.1001/jama.2017.13883.

• Piccini, JP. Interaction between newer anticoagulants, certain drugs increases major bleeding in AF. Perspective. Arrhythmia Disorders. Healio/Cardiology Today. Oct 2017. https://www.healio.com/cardiology/arrhythmia-disorders/news/online/%7B48813250-e3e1-4a0b-81bc-b2471691e666%7D/interaction-between-newer-anticoagulants-certain-drugs-increases-major-bleeding-in-af

• Connolly SJ, et al. RE-LY Steering Committee and Investigators.  Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361(12):1139-51. Last accessed July 10, 2014 URL: http://www.ncbi.nlm.nih.gov/pubmed/19717844

• Patel MR, et al. ROCKET AF Investigators.  Rivaroxaban versus warfarin in nonvalvular atrial fibrillation.  N Engl J Med. 2011;365(10):883-91. Last accessed July 10, 2014, http://www.ncbi.nlm.nih.gov/pubmed/2183095

• Granger CB, et al. ARISTOTLE Committees and Investigators.  Apixaban versus warfarin in patients with atrial fibrillation.  N Engl J Med. 2011; 365(11):981-92 Last accessed July 10, 2014

• Ansell J, et al. Descriptive analysis of the process and quality of oral anticoagulation management in real-life practice in patients with chronic non-valvular atrial fibrillation: the interactional study of anticoagulation management (ISAM) J Thromb Thrombolysis 2007; 23: 83—91. Last accessed July 10, 2014

• Kimmel, Stephen. The Truth About Blood Thinners, Bottom Line/Health, May 2015, p. 11

• Pradaxa: Highlights of Prescribing Information. Boehringer-Ingelheim website. Last accessed March 13, 2014 URL: http://tinyurl.com/PraxadaInfo

• Examining the Comparative Safety of Blood Thinners: An Analysis Utilizing AdverseEvents Explorer, February 2014, Special Report Download. http://info.adverseevents.com/special-report-blood-thinner Last accessed July 10, 2014

• Staton, Tracy. Eliquis earns best safety score in its class in analysis of FDA adverse event reports. FiercePharma, February 26, 2014. Last accessed July 10, 2014, http://www.fiercepharma.com/story/eliquis-earns-best-safety-score-its-class-analysis-fda-adverse-event-report/2014-02-26

If you find any errors on this page, email us. Y Last updated: Tuesday, July 24, 2018

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