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Stroke Risk

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) (also called DOACs Direct Oral Anticoagulants) 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 five new anticoagulants to consider: Pradaxa (dabigatran), Xarelto (rivaroxaban), Eliquis (apixaban), Savaysa (edoxaban). and Bevyxxa (betrixaban) (FDA approved 2017).

The current 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 (e.g. 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 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 eventually 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. (You’re probably wondering why they don’t simply take a blood sample and analyze how much of the anticoagulant is in the blood stream [plazma level monitoring]. This is “discouraged for the vast majority of patients due to the lack of outcome data to support such an approach,” according to the 2018 European Heart Rhythm Association Practical Guide on NOACs in AF [p. 1339.) “Routine monitoring of plasma levels and subsequent dose adaptation is generally discouraged.” [p. 1353)

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. 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 Xarelto 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 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 generally 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 to 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, https://pubmed.ncbi.nlm.nih.gov/20211293/

• 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

• Steffel, J et al. The 2018 European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation. European Heart Journal (2018) April 21, 39(16), 1330-1393 (p. 1339). https://www.ncbi.nlm.nih.gov/pubmed/29562325. doi: 10.1093/eurheartj/ehy136 .

• 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: Friday, April 16, 2021

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2013 BAFS: The New Anticoagulants (NOACs)

2013 BOSTON ATRIAL FIBRILLATION SYMPOSIUM

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:

  1. Dabigatran (brand name Pradaxa by Boehringer Ingelheim); a direct thrombin inhibitor
  2. Rivaroxaban (brand name Xarelto by Bayer); a direct factor Xa inhibitor
  3. 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.

CostS

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)

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 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 (Xarelto)

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.

Apixaban (Eliquis)

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.

Editor’s Comments
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.

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Last updated: Saturday, March 24, 2018

Women in A-Fib Not at Greater Risk of Stroke!

Research icon Master-wider border REV 125 pix at 96 resby Steve S. Ryan, PhD, Last updated: March 24, 2018
April 2016 related article: The Controversy Continues: Women, Anticoagulants, CHA2DS2-VASc and Risk of Bleeding

Denmark Study—Being a woman not a risk factor for stroke

The new guidelines for stroke prevention in A-Fib (CHA2DS2-VASc) state that simply being a woman is a risk factor for stroke. But a recent comprehensive study from Denmark indicates this may not be true. (The guidelines were first adopted in Europe in 2012 and in the US in May 2014).

The Danes seem to have an effective health care system for everyone which includes, among other benefits, data on anyone with A-Fib. They looked at 44,744 women with A-Fib. Female gender did not increase the risk of stroke in patients aged less than 75 years. (According to most guidelines, being over 75 years old is a risk factor for stroke irrespective of whether one is female or male.) 

According to the study’s Dr. Anders Mikkelsen, “This suggests that female sex should not be included as an independent stroke/TE risk factor in guidelines or in risk stratification schemes used in treatment of patients with atrial fibrillation.”

Dr. Peter Nielsen added, that women with no additional risk factors had a 1-year stroke risk below 0.5%, “which is likely too low to warrant lifelong antithrombotic treatment.”

Israeli Study 2015

An Israeli observational study of 100,000 people came to the same conclusions as the above Denmark study. See Israeli Study—Being Female Not a Risk Factor for Stroke.

Dr. Day—Risks of Life-Long Anticoagulant Therapy

Dr. John Day, in a May 2014 editorial in The Journal of Innovations in Cardiac Rhythm Management, discusses the new CHA2DS2-VASc guidelines for anticoagulation therapy that call for many more people to be on anticoagulant therapy, particularly women. Dr. Day does not go so far as to say the new guidelines are in error (as I do), but he does ask,” What about the 35 year old woman with borderline hypertension and only one A-Fib recurrence each year? Should she now take anticoagulants for the rest of her life even if she has had a successful ablation?”

This editorial was very personal for Dr. Day. One of his patients, after a successful catheter ablation, was on anticoagulant therapy for 10 years and developed early onset dementia. A cranial MRI revealed many cerebral microbleeds. Both antiplatelet and anticoagulant therapy significantly increase the risk of cerebral microbleeds which are associated with dementia. Microbleeds are considered permanent and irreversible.

Dr. Day concludes, “Somehow I think we have lost sight of the total picture with the new A-Fib management guidelines. In my mind, I am not convinced that the long-term stroke risk of a CHA2DS2-VASc score of 1 or 2 (depending on which risk factors are present) justifies all of the risks of life-long anticoagulation therapy, particularly if the patient has had a successful ablation procedure.” For more of Dr. Day’s comments, see The New CHA2DS2-VASc Guidelines and the Risks of Life-Long Anticoagulation Therapy.

Dr. John Mandrola echoes Dr. Day, “And if there is no A-Fib, there is no benefit from anticoagulation.”

Editor’s Comments: 

For additional insights, also see: Women with A-Fib: Mother Nature and Gender Bias—Or—Get Thee to an EP ASAP

Intuitively it doesn’t make sense that simply being a woman makes you more at risk of having an A-Fib stroke. This study seems to confirm what common sense would indicate and is most welcome news for women.

Anticoagulants Not Like Taking Vitamins

Women (and men) should be aware that anticoagulants increase the risk of bleeding disorders and should be given only to patients at a real risk of stroke. “In addition to bleeding, Pradaxa can cause stomach upset or burning, and stomach pain.” (Pradaxa Fact Sheet PX81802) (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.) According to Dr. David Graham of the FDA, the anticoagulant “Coumadin provides a benefit, but it is also responsible for probably more deaths than any single drug currently marketed.”
Many people have problems when taking anticoagulants and would prefer not to have to take them. One bruises easily, cuts take a long time to stop bleeding, one can’t participate in any contact sports or any activities like mountain climbing, bike riding, etc. If in an accident, one risks bleeding to death, because there is currently no practical way to reverse the anticlotting effect of the newer anticoagulants. When taking anticoagulants, there is an increased risk of developing an hemorrhagic stroke and gastrointestinal bleeding. And anticoagulants often have other bad side effects, make one feel sick, and diminish one’s quality of life.

Update October 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.

TV Ads for Anticoagulants

Recent advertising campaigns give the impression that you must take anticoagulants if you have A-Fib, that anticoagulants are the be-all and end-all for treating A-Fib, that if you take anticoagulants, then you will live happily ever after. (Actually anticoagulants are not a treatment for A-Fib, but for the risk of an A-Fib stroke). However, no matter how altruistic these national campaigns sound in trying to increase people’s awareness and knowledge of A-Fib, be advised that their primary purpose is to sell pharmaceuticals.

Gender Bias to Sell More Anticoagulants

If someone tells you that you must take anticoagulants because you are a woman, it may be time to get a second opinion. Don’t let a form of gender bias intimidate you into taking anticoagulants.
Realize also that adding a point to a person’s risk score translates into a huge increase in sales for pharmaceutical companies. The guidelines were written by doctors with major conflicts of interest.
However, if you know the risks and bad side effects of taking anticoagulants but still want to take them, that is certainly an option to discuss with your doctor.
(Thanks to David C. Holzman for calling our attention to this important study for women.)
References for this Article
• Day, John. Letter from the Editor in Chief. The Journal of Innovations in Cardiac Rhythm Management, 5 (2014), A6-A7. Last accessed May 15, 2014, URL: http://www.innovationsincrm.com/cardiac-rhythm-management/2014/may/586-letter-from-the-editor-in-chief

• Female gender increases stroke risk in AF patients aged >75 years by 20%, What about women? European Society of Cardiology press release. August 26 2012. Note: Press release accompanies both a presentation and an ESC press conference at the ESC Congress 2012. Last accessed March 22, 2013. URL: http://www.escardio.org/about/press/press-releases/esc12-munich/Pages/female-risk-stroke-atrial-fibrillation.aspx

• Loudon, Manette The FDA Exposed: An Interview With Dr. David Graham, the Vioxx Whistleblower. Natural News, Tuesday, August 30, 2005. http://www.naturalnews.com/011401_Dr_David_Graham_the_FDA.html• Mikkelsen, A. ESC Congress 2012 presentation materials (.PDF). Last accessed March 22, 2013. URL: http://www.escardio.org/The-ESC/Press-Office/Press-releases/Last-5-years/Female-gender-increases-stroke-risk-in-AF-patients-aged-75-years-by-20

• Pradaxa Fact Sheet PX81802. Last accessed March 22, 2013. URL: http://tinyurl.com/PradaxaFactSheetPX81802

• Mandrola, John. Atrial Flutter–15 facts you may want to know. In AF Ablation, Atrial fibrillation. August 5, 2013. http://www.drjohnm.org/2013/08/atrial-flutter-15-facts-you-may-want-to-know↵

• Nielsen PB et al. Female sex is a risk modifier rather than a risk factor for stroke in atrial fibrillation: should we use a CHA2DS2-VA score rather than CHA2DS2-VASc? Circulation. 2018;137:832-840. http://circ.ahajournals.org/content/137/8/832

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Last updated: Saturday, March 24, 2018

 

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