Next-Gen Blood Thinners: What’s Right for You?

Blood thinners have saved countless lives. If you have atrial fibrillation — an abnormal heart rhythm, suffered by more than 2 million Americans — or if you were otherwise at risk of forming dangerous blood clots, it’s likely you’ve been prescribed a blood-thinning drug, chiefly warfarin (Coumadin).

Starting in 2010, a new generation of blood thinners has come on the market.

Blood thinners, more accurately called anticoagulants, are drugs that inhibit the production of various proteins made by the liver that cause clotting. “Clotting is a very important thing,” says Ronald Wharton, MD, assistant professor of medicine at Albert Einstein College of Medicine and attending cardiologist at Montefiore Medical Center in New York City. “The problem is, sometimes we have to stop it or reduce the blood’s ability to clot,” in order to lessen the risk of stroke or pulmonary embolism (a blood clot that makes its way to the lungs), among other issues. In atrial fibrillation, which Dr. Wharton says is the most common reason blood thinners are prescribed, irregular heart rhythm can allow blood to pool in tiny crevices of the heart. It’s when that pooled blood forms clots and they travel to the brain that a stroke can occur.

According to the Centers for Disease Control and Prevention, approximately 795,000 people in the U.S. have a stroke each year — and almost 130,000 of them prove fatal.  Warfarin has been very effective in reducing strokes, but those who take it have to get frequent blood tests to monitor the drug’s effect on clotting factors made in the liver, which need vitamin K to be synthesized. (These tests, which can be scheduled anywhere from once a week to once a month, allow doctors to adjust dosages as needed). Warfarin also interacts poorly with a host of drugs: some antibiotics; anti-fungal drugs such as Monistat; aspirin and other non-steroidal anti-inflammatories such as Advil; digestive-disorder drugs such as Pepcid and Zantac; and birth-control pills.

No broccoli or leafy greensAccording to the University of Maryland Medical Center, coenzyme Q10 (CoQ10) may decrease the effectiveness of warfarin and lead to the need for increased doses. Since warfarin must be monitored very closely to maintain appropriate levels and steady blood thinning, CoQ10 should be used with warfarin only under careful supervision by a healthcare provider. Some foods, too, may be problematic when taking warfarin, specifically green leafy vegetables (such as kale, collard greens, spinach, Brussels sprouts and broccoli).

New Blood Thinners

pradaxa-logo200In 2010, a new class of drugs came onto the market that, like warfarin, aim to help prevent strokes and blood clots in people with atrial fibrillation. In October of that year, the FDA approved Pradaxa (dabigatran etexilate). That was followed by the FDA approval of Xarelto (rivaroxaban) in 2011. A year later, Xarelto was also approved to treat deep vein thrombosis (blood clots that occur in the lower leg and thigh) and pulmonary embolism. Eliquis (apixaban) was approved in December 2012, and Savaysa (edoxaban) in January 2015, also to decrease the risk of strokes and blood clots in individuals with atrial fibrillation.

xarelto-logo200While all 4 of the new drugs were compared to warfarin in different clinical trials, they were not compared to each other, explains Dr. Wharton, so which of them is chosen often comes down to physician preference. And a big part of the drugs’ attractiveness to doctors, as well as patients, is that unlike with warfarin, regular blood monitoring isn’t considered to be as necessary. The new drugs target other specific clotting factors that are not vitamin K-dependent, so their effectiveness isn’t thrown off by foods that contain significant amounts of vitamin K, such as green vegetables.

That said, while the newer drugs have far fewer drug and food interactions, says Dr. Wharton, they do have to be carefully dosed based on the patient’s weight, age and kidney function.

eliquis-logo200The new drugs are not yet approved for use in patients who have mechanical heart valves, or who have kidney failure or an allergy to the drugs, says Joseph Christiana, MD, a cardiologist and former chief medical officer of Health Quest Medical Practice in New York’s Hudson Valley. Women who may become pregnant need to work with their doctors, and those having surgery or dental work should discuss any precautions that need to be taken.

The purported positives of the new drugs, says Dr. Christiana, make them seem like a good choice for patients who dislike the dietary restrictions of warfarin, who are sensitive to vitamin K, or who aren’t great at complying with the necessary blood tests.

Savaysa-logo200But there’s a downside, and it’s significant. Any blood thinner can put patients at risk for spontaneous bleeding — when the drugs cause too much anticoagulation effect. When warfarin causes uncontrolled bleeding, the situation can be immediately reversed by giving the patient vitamin K or a drug called Kcentra.

The newer drugs on the market do not yet have a reliable antidote. Studies are underway to evaluate potential antidotes for all of  these drugs. In the meantime, patients using them can run into trouble when they experience excessive bleeding. Thousands of patients have filed lawsuits against the manufacturers of some of the new drugs when they ran into problems with excessive bleeding. In addition, there’s been evidence to suggest that, in fact, patients on the newer drugs can benefit from regular blood monitoring.

Certainly, an antidote similar to the vitamin K that works with warfarin would give doctors more confidence about prescribing the new drugs, says John Eikelboom, MD, associate professor in the department of medicine at McMaster University in Hamilton, Ontario, and a steering committee member for Pradaxa’s Phase III trial.

Lawsuits and Antidote Development

According to DrugWatch.com, more than 4,000 people who suffered damaging side effects linked to Pradaxa, including gastrointestinal, rectal and brain bleeding, filed lawsuits against the drug’s manufacturer, the German company Boehringer Ingelheim Pharmaceuticals (BI). Most of those suits were compiled into a multidistrict litigation that was set to go to trial in the U.S. District Court for the Southern District of Illinois, but in May 2014, BI agreed to a $650 million settlement that involved no admittance of wrongdoing.

Pradaxa is not alone: In July 2014, a Texas woman sued Bayer and the Janssen Pharmaceuticals (a division of Johnson & Johnson) — the manufacturer and marketer, respectively, of Xarelto — claiming there were inadequate warnings about bleeding risk associated with the drug. After 4 months on Xarelto, the woman suffered a life-threatening bleed that left her with severe and permanent injuries and pain. Several Xarelto product liability lawsuits have been filed in other states, too.

Reasearch is underway to find options to reverse the new drugs’ anticoagulating properties

In an email, BI spokeswoman Mary Lewis says the company stands by Pradaxa: “We are confident in Pradaxa’s benefits and safety, which were established in 5 pivotal trials that collectively included more than 27,000 patients and were conducted without the use of an antidote.”

At the time of the settlement, Lewis said the company was investigating the use of idarucizumab (CQ) as an option to reverse Pradaxa’s anticoagulating properties in the same way vitamin K reverses bleeds triggered by warfarin. Recently, the FDA granted idarucizumab Breakthrough Therapy Designation, which is designed to “accelerate the development and review of drugs for serious or life-threatening conditions.” Lewis says that studies of idarucizumab are underway in Europe. The FDA’s breakthrough therapy designation has also been awarded to Portola Pharmaceuticals for andexant, the company’s investigational antidote for bleeds from Xarelto, Eliquis and Savaysa.

Controlling Uncontrolled Bleeding

Getting a handle on uncontrolled bleeding used to be pretty straightforward when trauma surgeons were dealing only with warfarin. “Many trauma surgeons hate the new anticoagulants, because they don’t know how much is left in the system,” says Neil Zakai, MD, associate professor of medicine and pathology at the University of Vermont, and one of the authors of the American Society of Hematology’s 2011 Clinical Practice Guide on Anticoagulant Dosing and Management of Anticoagulant-Associated Bleeding Complications in Adults. It’s difficult, he says, to determine if the new drugs are contributing to the bleeding.

‘You have to balance the risk of bleeding with the risk of clotting,’ says Dr. Neil Zakai

When confronted with uncontrolled bleeding, it’s the physician’s first task to find the source of the bleeding and stop it with surgery or topical agents. Then it’s best to determine when the last dose of the anticoagulant was taken. If it has been about 24 hours — with the newer blood-thinners — he said there won’t be much in the system. Wounds will clot, though he said it might take longer.

Overall, the newer anticoagulants tend to cause less bleeding than warfarin, Dr. Zakai noted. “You have to balance the risk of bleeding with the risk of clotting,” he said, as well as factoring in whether the drug will be used in the long term — for atrial fibrillation — or the short term — for something like a knee replacement.

Which Blood Thinner is Best for You?

Side effects and safety are major factors when doctors and patients choose a drug, but of course cost factors in as well, says Dr. Christiana. The 4 new drugs have no generic versions, while warfarin can be purchased at discount store or warehouse club pharmacies for $4 for 30 5mg tablets. Xarelto, which has a once-a-day dose, can cost upward of $300 per month, far pricier than warfarin at its lowest cost. That said, it may turn out that co-pays for the new drugs will come down when insurance companies see that warfarin-related hospital admissions decrease, and that patients require fewer blood tests, he adds. “All four of the drug companies [that make the new drugs] have excellent programs to help make the new drugs more affordable.”

When 85-year-old Mildred Essig switched from warfarin to Xarelto she was thrilled to tuck into a big serving of her old favorite, creamed spinach

In addition to cost, there’s the question of patients wanting to make a switch to a different drug. Those who live in rural areas may find that one advantage of the newer drugs, says Dr. Christiana, is not having to travel to hard-to-access clinics for blood testing. Some patients are also convinced when they learn they can go back to eating foods they once enjoyed. Take Mildred Essig, an 85-year-old New York City native who’d been on warfarin for years. “I couldn’t eat anything green,” she says, though even the promise of being able to do so again wasn’t enough to convince her to make the switch. When she did  — swapping the warfarin for Xarelto  — she was thrilled to tuck into a big serving of her old favorite, creamed spinach.

Finally, it should be noted, says Dr. Christiana, that while warfarin and the new anticoagulants have their places in the blood-thinner world, patients with atrial fibrillation who don’t have other risk factors can benefit from taking a daily aspirin to prevent blood clots. This is recommended for patients who are younger and don’t also have uncontrolled high blood pressure or a previous history of stroke. Aspirin does come with side effects: Long-term use can lead to gastrointestinal bleeding, as well as nausea, vomiting, stomach pain and heartburn in some users. But if a patient has 2 or more of the criteria for determining prescription blood thinner use — congestive heart failure, hypertension, age greater than 75, diabetes or stroke — aspirin shouldn’t be used, he says.

So how do you choose? In a very real sense, the amount of choice patients and doctors have regarding anticoagulants is breeding a lot more confusion than necessary, in large part because direct comparisons (between warfarin and the newer drugs) are not always possible. The issue about the lack of antidote for the newer drugs may be a moot point before long. In the United States, there are more than 2 million people with atrial fibrillation, says Dr. Eikelboom, and stroke is the most common cause of permanent disability, with one-third to one-half of stroke victims dying or becoming permanently disabled. Everyone would agree that reducing stroke risk is important, but patients and doctors have to weigh whether the risk of bleeding is greater than the risk of stroke.

Side Effects Comparison

All drugs have the potential for side effects and warfarin and the new anticoagulants are no different. The major side effect — common to all anticoagulants —  is unwanted bleeding. Here’s what you need to know about warfarin and the newer drugs:

Warfarin (Coumadin)

Warfarin’s side effects include gas, abdominal pain, bleeding, bloating, bruising, change in the way things taste, loss of hair and feeling cold or having chills. According to the National Institutes of Health, warfarin patients who get hives; rash; itching; difficulty breathing or swallowing; swelling of the face, throat, tongue, lips or eyes; swelling of extremities; fever; diarrhea, loss of appetite or pain in the upper right part of the stomach should call their doctor immediately. The NIH also suggests that, given the risk of bleeding, patients should avoid activities that might lead to an injury such as contact sports, and advises calling your doctor if you see dark red or black bruises. A rare side effect of warfarin therapy called “purple toes syndrome,” in which painful, purple lesions suddenly appear on the toes and sides of the feet wherever pressure is usually applied, may begin 3 to 8 weeks after beginning warfarin therapy.

Pradaxa, Eliquis, Xarelto and Savaysa

All 4 of the new blood thinners have similar side effects, including indigestion, upset stomach or stomach pain, as well as the chance of an allergic reaction which could include hives, a rash, itching or swelling of the tongue. Patients should call their doctors or seek immediate medical care if they experience: unexpected, severe or uncontrollable bleeding, or bleeding that lasts a long time; nosebleeds that happen often; unusual bleeding from gums; menstrual or vaginal bleeding that is heavier than normal; unusual or unexpected bruising; coughing up or vomiting blood, or vomit that looks like coffee grounds; pink or brown urine; red or black stools that look like tar; unexpected pain, swelling or joint pain or headaches and feeling dizzy or weak.

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Additional Reading

Michael Woyton is a freelance writer and journalist living in New York. His articles have appeared in Opera News, the Poughkeepsie Journal and AOL/Patch. He is currently teaching a journalism class at Iona College.


Michael Wilcox

Michael Wilcox

Michael Wilcox is a health and medical journalist who writes frequently about clinical research, health policy, and technology in medicine. He has written previously for a number of medical and health trade magazines with a focus on obesity, cardiovascular health, surgery and cancer, as well as covered ground-breaking medical science for academic research institutions.


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