Anti Blood Clotting Medication
Pradaxa (dabigatran): Drug Safety Communication - Lower Risk for Stroke and Death, but Higher Risk for GI Bleeding Compared to Warfarin
ISSUE: The FDA recently completed a new study in Medicare patients comparing Pradaxa to warfarin, for risk of ischemic or clot-related stroke, bleeding in the brain, major gastrointestinal (GI) bleeding, myocardial infarction (MI), and death. The new study included information from more than 134,000 Medicare patients, 65 years or older, and found that among new users of blood-thinning drugs, Pradaxa was associated with a lower risk of clot-related strokes, bleeding in the brain, and death, than warfarin. The study also found an increased risk of major gastrointestinal bleeding with use of Pradaxa as compared to warfarin. The MI risk was similar for the two drugs.
Importantly, the new study is based on a much larger and older patient population than those used in FDA’s earlier review of post-market data, and employed a more sophisticated analytical method to capture and analyze the events of concern. This study’s findings, except with regard to MI, are consistent with the clinical trial results that provided the basis for Pradaxa’s approval. As a result of these latest findings, the FDA still considers Pradaxa to have a favorable benefit to risk profile and have made no changes to the current label or recommendations for use.
BACKGROUND: Pradaxa and warfarin are used to reduce the risk of stroke and blood clots in patients with a common type of abnormal heart rhythm called non-valvular atrial fibrillation (AF).
RECOMMENDATION: Patients should not stop taking Pradaxa (or warfarin) without first talking with their health care professionals. Stopping the use of blood-thinning medications such as Pradaxa and warfarin can increase the risk of stroke and lead to permanent disability and death. Health care professionals who prescribe Pradaxa should continue to follow the dosing recommendations in the drug label.
Source : FDA (May 2014)
Pradaxa Linked to More MIs in Certain Patients
In various patient populations, the anticoagulant dabigatran (Pradaxa) was associated with greater odds of myocardial infarction (MI) or acute coronary syndrome than control treatments, a meta-analysis showed.
Among randomized controlled trials for multiple indications, MI or acute coronary syndrome occurred at a significantly higher rate with dabigatran than with control treatment (1.19% versus 0.79%; OR 1.33, 95% CI 1.03 to 1.71), according to Ken Uchino, MD, and Adrian Hernandez, MD, PhD, of the Cleveland Clinic.
"Clinicians should consider the potential of these serious harmful cardiovascular effects with use of dabigatran," they wrote online in Archives of Internal Medicine.
In the trials, dabigatran was used for stroke prevention in atrial fibrillation (versus warfarin), prophylaxis for acute venous thromboembolism (versus warfarin) and deep venous thrombosis (versus enoxaparin), and prevention of events in acute coronary syndrome (versus placebo).
"The overall benefit and risk balance of dabigatran use appears to be favorable in patients with atrial fibrillation because of reduction in ischemic stroke," Uchino and Hernandez wrote. "However, the cardiac risk of dabigatran should be investigated further, especially if it is used in populations at high risk of MI or acute coronary syndrome."
In an accompanying editorial, Jeremy Jacobs, MBBS, and Jochanan Stessman, MD, of Hadassah-Hebrew University Medical Center in Jerusalem, wrote, "Uchino and Hernandez suggest that physicians step back for a moment, take their own pulse, and retain a critical view as a powerful new drug enters clinical use on a potentially massive scale."
"The robust finding that dabigatran is associated with increased rates of MI is alarming and emphasizes the need for continued critical appraisal of new drugs after phase III trials," they wrote.
In the largest study of dabigatran -- the 18,000-patient RE-LY trial -- the higher 150-mg dose of the anticoagulant was superior to warfarin for preventing stroke and systemic embolism in patients with atrial fibrillation. But there was also a 38% relative increase in the risk of MI (P=0.048).
After an additional search for events, however, the increase was no longer significant (RR 1.27, 95% CI 0.94 to 1.71).
Along the same lines, a recently published post-hoc analysis of the RE-LY trial showed that the risk of MI was not significantly greater with dabigatran than with warfarin, and that the rate of overall major adverse events was significantly lower with the higher dose of dabigatran.
Uchino and Hernandez performed their meta-analysis to further explore the risk of MI or acute coronary syndrome across the patient populations in which dabigatran has been tested. For the purposes of the analysis, patients receiving any dose of dabigatran were grouped together.
The researchers identified seven randomized controlled trials that included 30,514 patients -- two on preventing stroke in atrial fibrillation, one on acute venous thromboembolism prophylaxis, one on preventing events in acute coronary syndrome, and three on short-term prophylaxis of deep venous thrombosis.
The control arms included warfarin, enoxaparin, or placebo.
Although dabigatran use was associated with a significantly higher rate of MI or acute coronary syndrome, the absolute risk increase was small -- 0.27% (95% CI 0.04% to 0.50%).
Using the revised RE-LY results instead of the originally reported results weakened the association, although it maintained borderline statistical significance (OR 1.27, 95% CI 1.00 to 1.61, P=0.05).
Excluding the three short-term trials of dabigatran for prophylaxis of deep venous thrombosis after joint replacement, the higher rate of MI and acute coronary syndrome with the anticoagulant was significant (OR 1.33, 95% CI 1.03 to 1.72).
Uchino and Hernandez noted that they did not know of a pharmacologic mechanism to explain the higher rate of MI or acute coronary syndrome with dabigatran. They said that it could be a factor with dabigatran itself or it could be that the comparator drugs are better at preventing MI.
An important limitation of the meta-analysis is the dominant effect of the RE-LY trial, which included more than 18,000 patients, the researchers said. The largest of the other trials included about 3,500 patients.
In addition, patients were followed for a median of two years in RE-LY, and for six months or less in the other trials.
Source : MedPage Today
Link to Source
FDA Drug Safety Communication: Safety review of post-market reports of serious bleeding events with the anticoagulant Pradaxa (dabigatran etexilate mesylate)
[12-7-2011] The U.S. Food and Drug Administration (FDA) is evaluating post-marketing reports of serious bleeding events in patients taking Pradaxa (dabigatran etexilate mesylate). Pradaxa is a blood thinning (anticoagulant) medication used to reduce the risk of stroke in patients with non-valvular atrial fibrillation (AF), the most common type of heart rhythm abnormality.
At this time, FDA continues to believe that Pradaxa provides an important health benefit when used as directed and recommends that healthcare professionals who prescribe Pradaxa follow the recommendations in the approved drug label (See Additional Information for Healthcare Professionals).
Patients with AF should not stop taking Pradaxa without talking to their healthcare professional. Stopping use of blood thinning medications can increase their risk of stroke. Strokes can lead to permanent disability and death.
Bleeding that may lead to serious or even fatal outcomes is a well-recognized complication of all anticoagulant therapies. The Pradaxa drug label contains a warning about significant and sometimes fatal bleeds. In a large clinical trial (18,000 patients) comparing Pradaxa and warfarin, major bleeding events occurred at similar rates with the two drugs.
FDA is working to determine whether the reports of bleeding in patients taking Pradaxa are occurring more commonly than would be expected, based on observations in the large clinical trial that supported the approval of Pradaxa. (See Data Summary). FDA is working closely with the manufacturer of Pradaxa (Boehringer Ingelheim) to evaluate the post-market reports of bleeding.
FDA will communicate any new information on the risk of bleeding and Pradaxa when it becomes available.
Additional Information for Patients
- Pradaxa is an anticoagulant medicine that reduces the risk of blood clots forming in your body and causing a stroke. Having a stroke can cause permanent disability and death.
- Do not stop taking Pradaxa without talking to your healthcare professional. Stopping use of your blood thinner suddenly can put you at risk of a stroke.
- Be aware that while taking Pradaxa you may bruise more easily and it may take longer for any bleeding to stop.
- Call your healthcare professional and seek immediate care if you develop any signs or symptoms of bleeding such a
- unusual bleeding from the gums
- nose bleeding that happens often
- menstrual or vaginal bleeding that is heavier than normal
- bleeding that is severe or you cannot control
- pink or brown urine
- red or black stools (looks like tar)
- bruises that happen without a known cause or that get larger
- coughing up blood or blood clots
- vomiting blood or vomit that looks like coffee grounds.
- unusual bleeding from the gums
- Discuss any questions or concerns about Pradaxa with your healthcare professional.
- Report any side effects you experience to your healthcare professional and the FDA MedWatch program using the information in the “Contact Us” box at the bottom of the page.
- If you prescribe Pradaxa, carefully follow the approved indication and other recommendations, such as dosage and administration, in the professional drug label.
- Make sure your patients know the signs and symptoms of bleeding and when to seek care.
- Pradaxa is eliminated by the kidneys, therefore:
- Renal function should be assessed prior to treatment with Pradaxa to determine the appropriate dose.
- Renal function should be reassessed during treatment with Pradaxa if clinically indicated (fluctuating renal function, diuretic use, hypovolemia), and the dose should be adjusted following recommendations in the label.
- There is no need for dosage adjustment in patients with mild to moderate renal impairment (creatinine clearance [CrCl] > 30 mL/min). These patients should be given a dose of Pradaxa 150 mg orally twice daily.
- For patients with severe renal impairment, follow the recommended doses:
- For patients with CrCl 15-30 mL/min, the recommended dose is 75 mg orally twice daily.
- Dosing recommendations for patients with a CrCl <15 mL/min or on dialysis cannot be provided.
- Report adverse events involving Pradaxa to the FDA MedWatch program, using the information in the “Contact Us” box at the bottom of the page.
Bleeding that may lead to serious or even fatal outcomes is a well-recognized complication of all anticoagulant therapies. In a large clinical trial (18,000 patients) comparing Pradaxa (dabigatran etexilate mesylate) and warfarin, major bleeding events occurred at similar rates with the two drugs. At present, the FDA is evaluating the post-marketing reports of serious bleeding in patients taking Pradaxa submitted to the Adverse Events Reporting System (AERS) database. While serious, even fatal events have been reported, the FDA is analyzing the events to determine whether the reports of bleeding in patients taking Pradaxa are occurring more commonly than would be expected, based on observations in the large clinical trial that supported the approval of Pradaxa. Complicating this analysis, many factors can influence whether or not adverse effects are reported, particularly the length of time a drug has been marketed, whether or not the adverse effect is described in the drug label, and the amount of publicity about an event or safety concern.
For patients with non-valvular AF, the main alternative to Pradaxa is warfarin. Because warfarin has been marketed for over 50 years and is well-known to cause bleeding, patients and healthcare professionals are not likely to report bleeding in association with warfarin. Thus, a simple comparison between Pradaxa and warfarin with respect to the numbers of post-marketing reports of bleeding is of limited value.
FDA is working with the manufacturer, Boehringer Ingelheim, to analyze the post-market reports for evidence of inappropriate dosing, use of interacting drugs, or other clinical factors that might lead to a bleeding event.
FDA is also using its Mini-Sentinel active surveillance system to compare new users of Pradaxa and warfarin with respect to the likelihood of being hospitalized for bleeding.
At this time, FDA believes the benefits of Pradaxa continue to exceed the potential risks when the drug is used appropriately following the approved drug label. FDA recommends that healthcare professionals continue to prescribe Pradaxa following the recommendations in the drug label.
1. Source: SDI, Vector One: National (VONA) and Total Patient Tracker (TPT). October 2010 to August 2011. Extracted October 2011.
Facts about Pradaxa
(dabigatran etexilate mesylate)
- A blood thinner (anticoagulant) known as a direct thrombin inhibitor.
- Approved to reduce the risk of stroke and blood clots (systemic embolism) in patients with non-valvular atrial fibrillation.
- Available as 75 mg and 150 mg oral capsules.
- From approval in October 2010 through August 2011, a total of approximately 1.1 million Pradaxa prescriptions were dispensed and approximately 371,000 patients received Pradaxa prescriptions from U.S. outpatient retail pharmacies.1
Source : FDA
Link to Source
FDA Drug Safety Communication: Reduced effectiveness of Plavix (clopidogrel) in patients who are poor metabolizers of the drug
[03-12-2010] The U.S. Food and Drug Administration (FDA) has added a Boxed Warning to the label for Plavix, the anti-blood clotting medication. The Boxed Warning is about patients who do not effectively metabolize the drug (i.e. "poor metabolizers") and therefore may not receive the full benefits of the drug.
The Boxed Warning in the drug label will include information to:
- Warn about reduced effectiveness in patients who are poor metabolizers of Plavix. Poor metabolizers do not effectively convert Plavix to its active form in the body.
- Inform healthcare professionals that tests are available to identify genetic differences in CYP2C19 function.
- Advise healthcare professionals to consider use of other anti-platelet medications or alternative dosing strategies for Plavix in patients identified as poor metabolizers.
LINK TO FULL ARTICLE
MORE ON PLAVIX TAKEN WITH ASPIRIN AND PRESCRIPTION HEARTBURN MEDICATION
Plavix is a prescription medication marketed by Sanofi-Aventis and Bristol-Myers Squibb. Plavix was launched in 1998. It is currently marketed in over 80 countries. Plavix is the world's second biggest-selling medicine, with worldwide sales of around $9 billion, while Nexium revenues totalled $5.2 billion in 2008.
Cardiologists are re-evaluating how they prescribe Plavix, a popular heart medication used to prevent blood clots, after a major clinical study found the drug may cause dangerous bleeding in patients who take it along with aspirin to ward off a first heart attack. Some people taking the blood thinner Plavix on top of aspirin to try to prevent heart attacks, as many doctors recommend, now have good reason to stop. The Plavix and aspirin combination not only didn’t help most people, but it unexpectedly almost doubled the risk of death, heart attack or stroke for those with no clogged arteries but with worrisome conditions like high blood pressure and high cholesterol.
LINK TO RAY SAHELIAN MD