More than half a century after the blood thinner warfarin was first sold in the United States, a major challenger arrived. Pradaxa (dabigatran), which was approved in October 2010, helps to prevent strokes, requires less maintenance than warfarin and is designed to have fewer side effects. After a year on the market, 16 percent of patients with atrial fibrillation (irregular heartbeat) were taking Pradaxa, compared with 44 percent who were taking warfarin. The remaining patients did not take medication. In late 2011, Xarelto (rivaroxaban) joined the anticoagulant market.
By August 2012, more than 3.7 million U.S. patients had filled prescriptions for Pradaxa. In 2011, Boehringer Ingelheim, the German manufacturer of Pradaxa, spent $464 million to promote the drug, and it paid off. In the first quarter of 2012, worldwide sales reached $209 million. The anticoagulant therapy market is estimated to bring in $10 billion a year in the United States alone.
Just two years after its arrival, however, Pradaxa was blamed for more than 500 deaths. Patients and their families report instances of hemorrhaging and uncontrollable bleeding. Some took action against Boehringer Ingelheim by filing personal-injury and product-liability lawsuits.
The drug maker settled more than 4,000 of these claims in May 2014, agreeing to pay $650 million to get rid of all existing multi-district litigations that were created. The company admitted no fault as part of the agreement and in fact pointed out that the benefits of Pradaxa far outweigh the negative side effects. It cited an FDA study of Medicare patients as proof.
The prescription blood-thinner Pradaxa was considered an upgrade from warfarin because it limited strokes. However, in May 2014 the manufacturer settled more than 4,000 lawsuits for $650 million.
For many years, warfarin — and its brand-name versions Coumadin and Jantoven — was the standard anticoagulant treatment for patients at risk for strokes and other conditions caused by blood clots. Heparin is another anticoagulant with a longer history, available since 1936, but it is not popular as it must be taken intravenously. Warfarin treatment can be difficult, as it requires regular doctor visits, blood tests and diet restrictions. In addition, side effects of warfarin can be debilitating, causing brain hemorrhages and other types of internal bleeding. A Duke University cardiologist noted that warfarin is one of the leading causes of emergency room fatalities in the United States.
Pradaxa and warfarin both treat patients with atrial fibrillation (AF) who do not have heart disease but are at risk for stroke and blood clots. In clinical trials, Pradaxa outperformed warfarin, reducing the risk of stroke more effectively than warfarin. Pradaxa is also easier to administer, as it does not have the strict requirements that come with warfarin. However, Pradaxa sells at a higher price and still causes some of the same side effects. Warfarin costs about $200 a year, while Pradaxa runs about $3,000 a year.
Warfarin and Pradaxa both prevent blood clots, but they function in different ways. Warfarin thins blood by decreasing the activity of vitamin K, which is essential to the chemical reaction that forms blood clots. Pradaxa inhibits the action of thrombin (a clotting protein) and is part of a drug class called direct thrombin inhibitors. The European Medicines Agency advises doctors to check a patient's kidney function before prescribing Pradaxa.
Pradaxa is administered in 75 and 150 mg capsules, with most people taking 150 mg capsules twice a day. People with kidney problems may take lower doses. Suddenly discontinuing Pradaxa or missing doses may increase the risk of stroke. Pradaxa is used to treat atrial fibrillation and venous thromboembolism.
Atrial fibrillation (AF) affects more than 2 million Americans and occurs when the heartbeat becomes irregular, which can cause blood to pool in the upper chamber of the heart. It can cause chest pain, heart failure or stroke, which occurs when blood clots travel to the brain. People with AF are around five times more likely to have a stroke than those who do not. For some, AF only occurs occasionally and is not disruptive; for others, it can be a long-term heart problem with serious consequences.
Venous Thromboembolism (VTE)
In Europe and other countries, Pradaxa is used to prevent venous thromboembolism (VTE) following knee or hip replacement surgery. VTE is a lethal disorder that includes deep vein thrombosis (where blood clots form in a deep vein) and pulmonary embolism (where a blood clot in the veins travels to the lungs). The orthopedic procedure of knee or hip surgery puts patients at the highest risk category for developing VTE. Patients begin treatment one to four hours after surgery. Treatment usually lasts for 10 days for knee replacement and around a month for hip replacement.
VTE affects 1.5 million people and causes 500,000 deaths annually. In the 2012 American Heart Association Scientific Sessions, evidence was presented showing that Pradaxa was both safe and effective for VTE. The FDA has not approved this indication for Pradaxa, but Boehringer Ingelheim is in the process of conducting clinical trials to show the efficacy of Pradaxa for VTE. If this indication is approved in the United States , the number of Pradaxa users is expected to drastically increase.
Common Side Effects
Similar to other anticoagulants, Pradaxa may cause bruising or bleeding from minor cuts. Taking blood thinners requires users to alert doctors and dentists before undergoing surgeries or medical procedures in order to prevent bleeding complications. The medication guide that comes with the prescription informs users that the drug can cause bleeding that can be serious and lead to death, therefore users must be aware of side effects and bleeding risks.
Side effects for most people taking Pradaxa will be minimal, which can deceive people into thinking this is a safe drug.
The risk of bleeding is highest in people:
|These common side effects include:
To prevent drug interactions, patients need to inform their doctor if they are taking other medications such as anticoagulants, aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs).
- Age 75 and over
- With kidney problems
- With stomach or intestine bleeding that is recent or recurring due to a stomach ulcer
Serious Side Effects
In addition to common side effects, Pradaxa can have serious side effects, including uncontrolled bleeding, heart attack, liver failure and even death. The most frequently reported serious side effect was bleeding. Bleeding can cause death, and hemorrhages in the brain and central nervous system can be just as harmful as a stroke, which is what Pradaxa is taken to prevent.
Pradaxa was one of the most frequently mentioned drugs in the FDA's database of adverse event reports for 2011, according to QuarterWatch, a publication for the nonprofit Institute of Safe Medication Practices. The FDA received 817 reports of adverse events involving Pradaxa in 2011. QuarterWatch gathered additional reports from manufacturers, databases and health professionals, documenting 3,781 serious adverse events from Pradaxa in 2011; 542 of these events were fatal.
|Patients should speak to a physician immediately or seek medical treatment if they experience:
|Coughing up blood
||Vomit that looks like coffee grounds
|Pink or brown urine
||Swelling or joint pain
|Headaches, dizziness or weakness
A March 2012 study, published in the Journal of the American College of Cardiology, analyzed five trials of 30,470 patients, using information from the U.S. National Institute of Health MEDLINE database. Researchers found that patients taking Pradaxa were more likely to have heart attacks than those taking warfarin.
That same month, a Cleveland Clinic study published in the Archives of Internal Medicine found similar results, revealing that Pradaxa causes a 33 percent increased risk of heart attack or severe symptoms of heart disease — which can include chest pain, dizziness, shortness of breath and loss of consciousness — compared with warfarin.
QuarterWatch reported 500 adverse events related to bleeding in 2011, all of which were disabling or deadly. Patients taking Pradaxa and seeking medical attention for falls or minor injuries may find that a hospital visit is not enough. As of 2012, at least eight people had died in U.S. hospitals from irreversible bleeding problems associated with Pradaxa.
The FDA released a report in November 2012, concluding that Pradaxa does not present a higher bleeding risk than warfarin. However, the report did not comment on the fact that there is no antidote if a Pradaxa patient starts bleeding. If patients taking warfarin experience bleeding, vitamin K can often stop the bleeding. Boehringer Ingelheim reports that it is working on an antidote.
Japan and Australia have issued a safety warning for Pradaxa regarding bleeding risk. The Japanese Ministry of Health, Labour and Welfare (MHLW) has received 81 reports of serious side effects from Pradaxa, including gastrointestinal bleeding, and responded by sending a safety advisory to physicians. The advisory recommended that physicians monitor patients for signs of bleeding, anemia or renal impairment. The Therapeutic Goods Administration (TGA), Australia's regulatory authority, has received 203 adverse event reports from Pradaxa use, including 47 serious bleeding events. The TGA encouraged doctors to consider the clinical need and suitability of patients, before subjecting them to unnecessary risk.
Lawsuits and Settlements
After experiencing side effects like hemorrhaging, Pradaxa patients and their families filed thousands of product-liability claims against the drug maker. Claims spanned more than three years, from 2010 to beyond 2013.
In May 2014, Boehringer Ingelheim reached an overarching settlement for all outstanding U.S. lawsuits and claims relating to Pradaxa. In announced the settlement terms, the drug maker pointed to a recent FDA study of more than 130,000 patients in which the “positive benefit-risk profile” of Pradaxa was cited.
“We continue to stand resolutely behind Pradaxa and believed from the outset that the plaintiffs’ claims lacked any mere,” said Andreas Neumann, who heads the worldwide legal department for Boehringer Ingelheim. An apparent contributing factor to the settlement was the company’s hesitance at allowing a jury of non-scientists to decide a potential billion-dollar litigation. “All this does not allow reliable predictions for the outcome of a high number of individual trials,” he said.