Many patients and doctors choose between Xarelto and warfarin to prevent or treat blood clots. Each drug has advantages and disadvantages, from ease of use and cost to patients to potential risk of bleeding events.
More people take the anticoagulants (blood thinners) warfarin and Xarelto than any other anti-blood clotting drug in the U.S. Warfarin is the most widely used blood thinner in the world, and American doctors write about 30 million prescriptions a year. In 2014, doctors wrote about 4 million prescriptions for Xarelto in the U.S., and the number increases each year.
A person with a high risk for blood clots and their doctor has to choose which blood thinner is right for them.
- Xarelto is new, and warfarin is old.
- Xarelto lacks an antidote, and warfarin has one.
- Xarelto comes in a criticized once-a-day standard dose.
- Warfarin requires patient-specific dosing and monitoring.
- Both come with a high risk of adverse events.
Blood thinners work by interrupting the blood clotting process. In order to avoid bleeding to death, the body forms blood clots. The process in which blood clots form is complex and involves a variety of elements, called clotting factors. Warfarin and Xarelto (rivaroxaban) prevent blood from clotting by inhibiting different clotting factors.
Doctors prescribe blood thinners to prevent blood clots from blocking blood flow, which can cause damage to the heart and brain. There a variety of conditions that put someone at a high risk for damaging blood clots, including:
- Atrial fibrillation (abnormal heartbeat).
- Prior surgery on a heart valve.
- A heart birth defect.
- Deep vein thrombosis (a clot formed deep in the body).
- Pulmonary embolism (a DVT that blocks blood flow in the lungs).
- Pulmonary hypertension (high blood pressure affecting the heart and lungs).
Endo Laboratories introduced warfarin as brand name Coumadin in 1954. It’s been the most popular blood thinner ever since, but doctors and patients alike yearned for a safer drug that didn’t require intense monitoring.
Seeing an opportunity in the multi-billion dollar anticoagulant market, Johnson & Johnson’s subsidiary Janssen Pharmaceuticals partnered with Bayer to develop Xarelto. The new drug was one of a handful of blood thinners introduced more than 50 years after warfarin. The group is collectively referred to as new oral anticoagulants (NOACs).
Now patients and doctors have more options for treating patients at risk for blood clots, but choosing which treatment is best isn’t easy.
What is Warfarin?
Discovered in the 1940s and developed for use in humans in the 1950s, warfarin is the most widely used blood thinner in the U.S. Its brand names include Coumadin and Jantoven.
Warfarin works by blocking the blood clotting factors that rely on Vitamin K from forming. Vitamin K is used by multiple factors to help the blood clot.
Doctors prescribing warfarin do not want to completely prevent the blood from being able to clot. Doing so could result in deadly consequences.
The drawback to warfarin is the amount of monitoring it requires. Patients taking warfarin must be monitored every two to four weeks.
Doctors regularly test the amount of time it takes for a patient’s blood to clot using the prothrombin time test. The test measures the International Normalized Ratio (INR). A high INR indicates a high risk of uncontrollable bleeding, and a low INR indicates a high risk for blood clots.
Doctors adjust the dosage of warfarin based on the patient’s INR. In an attempt help avoid accidents from patients taking an incorrect dose, drug manufacturers assigned specific colors to each pill. Manufacturers of Coumadin, Jantoven and generic warfarin use similar colors to indicate the amount in each dose.
If a patient takes the incorrect dose, they increase their risk of uncontrollable bleeding or decrease their chance of preventing a stroke or heart attack. Patients who miss a dose should contact their healthcare provider, and they should never take an extra dose to make up for the missed dose.
Warfarin and Pregnancy
Because warfarin can pass from the mother to her baby in the womb, the drug may interfere with normal clotting in the baby. This affects the developing embryo’s bone and cartilage formation. Warfarin may also cause birth defects, and a woman who is pregnant or plans to have a baby should speak to her doctor before starting or continuing warfarin therapy. An alternative blood thinner, heparin, does not pass from mother to baby and may be used instead of warfarin during pregnancy.
|Warfarin Dos and Dont’s|
|Watch for bleeding signs and symptoms.||Take a double dose if you miss a dose.|
|Tell other healthcare providers, including dentists, you take warfarin.||Take new drugs or supplements without talking to your healthcare provider.|
|Contact a healthcare provider if sick or injured.||Change your warfarin dosage without talking to your healthcare provider.|
|Take warfarin as prescribed.|
|Attend blood monitoring appointments.|
Market for New Blood Thinners
The patent for Coumadin expired in 1962, but DuPont Pharmaceuticals (which bought Endo in 1970) controlled a monopoly on the blood thinner market until the 1990s when the U.S. Food and Drug Administration approved generic versions of warfarin. Bristol-Myers Squibb purchased DuPont for $7.8 billion in 2001. Today, several companies manufacture generic warfarin.
With more competition in the market, prices for warfarin dropped substantially.
Companies saw two voids in the market that could be taken advantage of to introduce a new product. The first was the need for a drug that could prevent blood clots but was safer than warfarin. The second was the need for a drug that was as effective as warfarin but easier to use. Companies began a race to develop a drug that was easier to use.
Boehringer Ingelheim won the race when the FDA approved twice-a-day Pradaxa in 2010. Bayer and Johnson & Johnson came in second, receiving approval for their co-developed blood thinner Xarelto in 2011.
The NOACs began to take some of the market away from warfarin in 2010, but Pradaxa users suffered high rates of serious side effects. The market shifted back to warfarin. At the end of 2014, doctors wrote the most warfarin prescriptions since 2008. Xarelto was by far the next-highest prescribed blood thinner, but it wasn’t close to warfarin.
Cost Differences between Xarelto and Warfarin
Xarelto is a newer drug and one of its drawbacks is its cost. The medication costs thousands more on average than warfarin which has been available in generic form for years. Warfarin costs about $3,000 a year. Generic warfarin costs about $200. Xarelto is a big moneymaker for Bayer and J&J. The companies sold more than $2 billion of their blood thinner in the first three years after its approval.
|Annual Xarelto Sales|
Xarelto’s Development and Approval
Xarelto is a Factor Xa inhibitor. Factor Xa is an integral part of the process that forms the protein thrombin, and thrombin is required for blood to clot. By inhibiting Factor Xa, Xarelto prevents thrombin from forming which prevents the blood from clotting.
Xarelto was the first once-a-day, standard dose blood thinner approved by the FDA. The agency expanded the approved uses of Xarelto several times:
- Approved to reduce the risk of blood clots after hip or knee replacement surgery in July 2011.
- Expanded use to reduce the risk of stroke in people with atrial fibrillation in November 2011.
- Expanded use to treat DVT, PE and reduce the risk of DVT and PE in November 2012.
The effect of Xarelto declines rapidly if it isn’t taken regularly, and no antidotes are available. But it does not require intense monitoring like warfarin.
Clinical trials showed taking Xarelto once a day was not inferior (or superior) to warfarin in each of the approved uses. It was the first blood thinner approved to treat and reduce the risk of blood clots since warfarin’s approval in 1954.
However, some critics of the drug claimed it should be taken twice a day, because its half-life was five to nine hours. This meant people taking Xarelto would have extremely different amounts of the drug in their system throughout a single day.
One study showed the amount of Xarelto in the blood was 16.9 times higher at its peak than its trough. The peak represents the time of day the most Xarelto is in the blood, and the trough represents the time of day the least amount of Xarelto is in the blood in a person taking the drug regularly.
But a once-a-day drug has a marketing advantage over a twice-a-day drug. The FDA recognized the problem during the approval process but approved Xarelto anyway because taking it once-a-day was not inferior to warfarin in clinical trials.
No blood thinner is completely safe, and many studies on newer blood thinners compare them to warfarin. One of the side effects of warfarin is bleeding in the brain called intracranial hemorrhage. People who take warfarin have a higher risk of brain bleeds than those who take Xarelto. But, aspirin increases Xarelto brain bleed risk.
An annual review for 2014 showed Xarelto led all therapeutic drugs with 525 direct reports of serious injuries to the FDA. Overall reports of serious injury to the FDA averaged 6.6 reports per 1,000 person-years. Xarelto also had the most cases (1,129) of treatment failure and failed more often than warfarin.
The 2014 review came one year after researchers released the results of the largest study ever to compare the four most popular anticoagulants to each other. The 2013 study analyzed three major clinical trials sponsored by pharmaceutical companies involving more than 50,000 patients.
The results indicated the NOACs were similarly efficient at preventing blood clots and strokes in South America, Asia and Africa. Interestingly, warfarin was superior to the NOACs, including Xarelto, in European patients which made up the largest proportion of participants studied.
Bleeding Antidotes for Warfarin
Unlike Xarelto, warfarin has several antidotes that reverse bleeding. Without an antidote, a bleed can quickly become a life-threatening situation. Anything from a small bruise to a severe car accident can endanger a Xarelto patient. ER doctors are limited in treatment options for these patients because of the lack of antidote. In the case of warfarin, doctors can choose from a variety of remedies. Each type of antidote varies in how quickly it begins working.
|Speed of Anticoagulation Reversal||Method|
|Complete reversal within 15 minutes||Prothrombin complex concentrate plus intravenous vitamin K|
|Partial||Fresh frozen plasma partially reverses anticoagulation|
|Within 4–6 hours||Intravenous vitamin K|
|Slow reversal within 24 hours||Oral vitamin K|
|Very slow reversal within 3–5 days||No therapy|
Source: CSL Behring
Side Effects and Interactions
The main side effects associated with all blood thinners – including Xarelto and warfarin – involve either overdosing or underdosing, leading to excessive bleeding or clotting. People taking warfarin must undergo monitoring to ensure they receive the correct dosage, but people taking Xarelto have to hope the standard dose will work for them.
Overdosing or underdosing can cause a range of symptoms ranging from dizziness and headaches to coughing up blood and nosebleeds. Each symptom could be a warning sign for a more severe complication. Severe side effects of warfarin and Xarelto include:
- Excessive or irreversible bleeding.
- Internal hemorrhaging.
- A high risk for stroke after discontinuation.
Both drugs interact with a number of substances. Patients taking Xarelto or warfarin should contact their healthcare provider before taking any new prescription or over-the-counter medication, supplement or making drastic dietary changes.
In studies, antiplatelet drugs (like Aspirin) were shown to have an effect on both blood thinners. Other popular drugs like Advil (ibuprofen), Aleve (naproxen) and antibiotics may interact with warfarin and Xarelto. A more complete list of drug interactions can be found on each drug’s label.
Foods that are high in Vitamin K can negate the effects of warfarin. Many green, leafy vegetables like broccoli, spinach and lettuce contain high amounts of Vitamin K. Alcohol can also affect the ability of the blood to clot, so it should be avoided or always taken in moderation by people taking Xarelto or warfarin.
Other Blood Thinners
In addition to warfarin, there are a few other blood thinners on the market. Some work similarly to Xarelto, while others work on different chemicals in the body to stop bleeding. Some also have antidotes to stop bleeding, while others do not. If you have certain health conditions, some of these drugs may not be safe to take.
The FDA approved Boehringer-Ingelheim’s Pradaxa (dabigatran etexilate) in 2010. It hit the market before Xarelto and enjoyed robust sales. Pradaxa directly inhibits thrombin, an enzyme used to clot blood, from forming. Like Xarelto, Pradaxa does not have an antidote for bleeding. As a result, its maker faced thousands of lawsuits. The company eventually settled them for $650 million. People with stomach pains or heartburn should not take Pradaxa. In studies, it was the only drug that was as good or a little better than warfarin in preventing stroke.
Eliquis (apixaban) is a Factor Xa inhibitor like Xarelto and is manufactured by Bristol-Myers Squibb. Like Xarelto, this drug has no antidote and it hit the market a year after. But, in clinical trials, researchers discovered it had less major bleeding and hemorrhagic stroke than Xarelto. If you have kidney problems, Eliquis has a reduced dose that may be better tolerated.
Savaysa (edoxaban) is another Factor Xa inhibitor similar to Xarelto. The FDA approved it after Pradaxa, Xarelto and Eliquis in 2015. Savaysa has the same indications as Xarelto, but it is typically used after an injectable blood thinner. Daiichi Sankyo manufactures this drug. Higher doses of Savaysa may cause more stomach bleeding than warfarin.
Heparin is an injectable blood thinner and like warfarin has been on the market for decades. It also requires periodic blood tests. In case of bleeds, this medication has antidotes like warfarin. Patients can get injections in the hospital or inject themselves at home.
Lawsuits and Settlements
Courts have handled numerous warfarin and Xarelto lawsuits throughout the years. However, the drugs were taken to court for different reasons.
Most warfarin lawsuits involved medical malpractice because a healthcare provider failed to properly monitor a patient’s INR. Healthcare providers across the country settled numerous cases, usually confidentially.
Monitoring warfarin is difficult in nursing homes which are usually understaffed. More than 165 nursing home patients were hospitalized or died between 2011 and 2014 because of monitoring errors involving warfarin.
DuPont also settled a class-action lawsuit for $44.5 million in 2002 for illegally maintaining exclusive rights for warfarin after the patent expired. The class-action claimed DuPont forced consumers to spend millions of dollars more than they would have spent on generics.
As Xarelto became popular, more patients began experiencing negative side effects like uncontrollable bleeding. Patients filed lawsuits claiming they were unaware of the drug’s risk and the drug’s lack of an antidote.
Bayer and J&J face more than 1,600 lawsuits claiming they were negligent and failed to warn. Those lawsuits are consolidated in multidistrict litigation and mass tort courts.
Another kind of lawsuit, the first to claim Xarelto failed to prevent a stroke, was filed in 2015. Some experts believe a smaller, twice-a-day dose would be more effective at preventing a stroke than Xarelto once-a-day dose.