More Questions Raised About Boehringer Ingelheim’s Pradaxa 1

Once again dabigatran (Pradaxa) has raised the wrath of the critics. Several articles and an editorial published today in The BMJ raise more questions and concerns about the drug, which is the first of the new oral anticoagulants. Relying on new evidence along with previously disclosed data, Deborah Cohen, the  investigations editor for The BMJ, casts doubt on the reliability of the data supporting the drug as well as the behavior and decisions of regulatory authorities, trial investigators, and employees  of Boehringer Ingelheim, the drug’s manufacturer.

Click here to read the full post on Forbes.

 

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Boehringer Ingelheim Settles US Pradaxa Litigation For $650 Million Reply

Boehringer Ingelheim said today that it will pay $650 million in a “comprehensive settlement” of lawsuits over Pradaxa (dabigatran), the company’s novel anticoagulant. The company said that it expects the settlement will resolve about 4,000 current cases against the company in the US.

Click here to read the full post on Forbes.

 

FDA Study Provides Some Reassurance About Boehringer Ingelheim’s Pradaxa Reply

In the latest development in its ongoing review of the new oral anticoagulant dabigatran (Pradaxa, Boehringer Ingelheim), the FDA today offered largely reassuring news about the sometimes controversial drug. The FDA study of 134,000 Medicare patients found that dabigatran was associated with a reduced risk for ischemic stroke, bleeding in the brain, and death, compared to warfarin. But the study also found that, dabigatran was associated with an increased risk for major gastrointestinal bleeding. There was no difference between the drugs in the risk of MI.

Click here to read the full post on Forbes.

 

Boehringer Ingelheim’s Pradaxa Gains New Indication 1

The new oral anticoagulants continue to gain additional indications from the FDA. Earlier today Boehringer Ingelheim announced that the FDA had approved Pradaxa (dabigatran) for the treatment of venous thromboembolism (VTE), which includes both deep venous thrombosis (DVT) and pulmonary embolism (PE).

 Click here to read the full post on Forbes.

 

 

Registry Study Offers Reassurance About Safety And Efficacy Of Dabigatran Reply

As the first new oral anticoagulant since warfarin, dabigatran (Pradaxa, Boehringer-Ingelheim) has been subject to intense concerns over its safety and efficacy in a real-world population. Last November an FDA investigation found no indication that bleeding rates for dabigatran were any higher than bleeding rates for warfarin. A new study from Scandinavia, published in the Journal of the American College of Cardiology (see note at bottom of story), provides more real-world information that helps to confirm the safety and efficacy of the new drug.

Using data from the Danish Registry of Medicinal Product Statistics, researchers compared 4978 patients treated with dabigatran to 8936 matched patients who received warfarin. They found similar rates of stroke or systemic embolism and major bleeding with dabigatran and warfarin. In addition, mortality, intracranial bleeding, pulmonary embolism,and myocardial infarction were significantly lower in the dabigatran-treated group.

Here are the adjusted hazard ratios (and 95% confidence intervals) for dabigatran 110 mg and 150 mg, respectively, compared with warfarin:

  • Stroke: 0.73 (0.53 -1.00), 1.18 (0.85 – 1.64)
  • Systemic embolism: 0.60 (0.19 – 1.60), 1.00 (0.26 – 3.35)
  • Death: 0.79 (0.65 – 0.95), 0.57 (0.40 – 0.80)
  • MI: 0.30 (0.18 – 0.49), 0.40 (0.21 – 0.70)
  • Pulmonary embolism: 0.33 (0.12 – 0.74), 0.24 (0.06 – 0.72)
  • Intracranial bleeding: 0.24 (0.08 – 0.56), 0.08 (0.01 – 0.40)
  • Major bleeding: 0.82 (0.59 -1.12), 0.77 (0.51 – 1.13)

The authors concluded that ”previous concerns about an excess of bleeding events or myocardial infarction amongst dabigatran treated patients were not evident in this propensity-matched comparison against warfarin in a large post-approval registry study.” However, they noted one limitation of their study: The Danish AF patients included in the study were at lower risk and had a lower event rate than the patients studied in the pivotal RE-LY randomized trial of dabigatran.

Note to readers: This study is now available on Science Direct and the manuscript has been posted on CardioSource. Due to technical problems the article will be published online in the Journal of the American College of Cardiology website on Wednesday, April 10.

 

FDA Officials Calm Concerns Over Excessive Bleeding With Dabigatran 1

Concerns over excessive bleeding complications with dabigatran (Pradaxa, Boehringer Ingelheim) as compared with warfarin are most likely due to the heightened sensitivity and vigilance that can accompany a new drug, according to FDA officials in a perspective published online in the New England Journal of Medicine.

“We believe that the large number of reported cases of bleeding associated with dabigatran provides a salient example of stimulated reporting,” write Mary Ross Southworth, Marsha Reichman, and Ellis Unger. “In this case, such reporting provided a distorted estimate of the comparative bleeding rates associated with dabigatran and warfarin in clinical practice.”

Click here to read the full story on Forbes.

 

Two Experts Help Sort Out The New Generation Of Anticoagulants Reply

Don’t miss this very practical discussion about the new generation of anticoagulants and the short term loan costs to cover them over on CardioExchange. Here are a few excerpts.

Christian Thomas Ruff:

I believe the addition of the 3 currently approved novel anticoagulants (dabigatran, rivaroxaban, and apixaban) will eventually translate into a greater proportion of eligible patients being treated; it certainly has in my practice…

Although I think it is important to continue to develop reversal agents for the novel anticoagulants, I don’t think the lack of such an agent is sufficient reason to avoid using a novel anticoagulant.

I think that price is one of the most important factors that has hindered uptake of the novel agents. Although these drugs may well be “cost-effective” in complicated analyses that focused on the costs and benefits to society at large, it is the out of pocket expense for the drugs that really matters to patients…

Andrew E. Epstein:

 It is highly unlikely that a direct comparison of the new anticoagulants will ever be done. Thus, we will have to choose between one or another based on pharmacokinetics, convenience, and perhaps formulary availability. Substudy analyses are also important…

I am concerned that although the elderly often have the most to gain from the new anticoagulants, they are also the patients at greatest risk for bleeding, especially if renal function is labile with drugs cleared by the kidneys. For such patients, warfarin should be considered.

Pradaxa To Be Contraindicated In Patients With Mechanical Heart Valves 1

Boehringer Ingelheim is starting to inform physicians about a new contraindication for its oral anticoagulant drug Pradaxa (dabigatran). The company has told investigators in trials utilizing dabigatran that it will shortly be sending a “Dear Doctor Letter,” also known as a Direct Healthcare Professional Communication (DHPC), to healthcare professionals. The letter will inform physicians that Pradaxa is now contraindicated in patients with mechanical heart valves. The change was based on a recent decision of the FDA, BI told its investigators.

The FDA action follows a similar decision by the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency, which announced last week that it had recommended that Pradaxa be contraindicated in patients with prosthetic heart valves.

Both the FDA and the CHMP actions appear to be based on findings from the RE-ALIGN trial in patients with mechanical heart valves, which Boehringer Ingelheim announced last week had been stopped prematurely. (Click here for the CardioBrief story.As reported here in October, the company had previously terminated one arm of the study after an interim review of the data by the trial’s Data Safety Monitoring Board

One cardiologist who is a dabigatran investigator told CardioBrief that the label change

is consistent with the findings in Re-Align, although I wish it were presented and published in a peer reviewed journal. I do understand the urgency on behalf of the FDA to ensure that the use does not stray beyond its labeling for A-fib given both the prospective, randomized data from Re-Align and case reports of strokes on Pradaxa with mechanical valves. I don’t think this is the final word on Pradaxa (or other new generation anticoagulants), but if we are to use them, the doses will undoubtedly be different, and presumably higher, than the doses used for A-fib. The question is whether one can find a dose that prevents thromboembolic strokes with the new generation anticoagulants at an acceptable level of bleeding. It’s also worth noting that they did not recommend Pradaxa in patients with bioprosthetic valves, but didn’t absolutely contraindicate it. Yet.

Boehringer Ends Phase 2 Trial Of Dabigatran In Mechanical Valve Patients 2

Boehringer Ingelheim today announced that it had discontinued a phase 2 trial of its anticoagulant drug dabigatran (Pradaxa) in patients with mechanical heart valves. As reported here in October, the company had previously terminated one arm of the study after an interim review of the data by the trial’s Data Safety Monitoring Board

The RE-ALIGN trial was an open-label, 12-week randomized comparison of warfarin and dabigatran in 400 patients who received a mechanical valve. The first arm randomized patients during their initial hospital stay. The second arm randomized patients more than 3 months after their surgery.

Despite the recent advent of novel oral anticoagulants, the much-maligned warfarin remains the only current option available for patients who have received a mechanical valve. Now the first trial to explore this indication for one of the newer oral anticoagulants has been stopped.

In October Boehringer told members of its speakers bureau that the post-surgery arm of the trial had been terminated due to “lower than projected plasma levels of dabigatran in this population, and an imbalance in reports of thromboembolic events (primarily strokes).” At that time the company said the second arm of the trial would continue.

Dabigatran has been approved in Europe, but not in the United States, for venous thromboemoblism (VTE) prevention after knee and hip replacement surgery. Rivaroxaban (Xarelto) has been approved for both VTE prevention in the United States and Europe. To date there have been no head-to-head comparisons of the newer anticoagulants.

According to a recent study in Circulation: Cardiovascular Quality and Outcomes dabigatran now has about 19% of the oral anticoagulant market, mostly for the approved treatment of AF “but increasingly for off-label indications” as well. A recent letter in the Journal of the American College of Cardiology provided information about the off-label use of dabigatran in two mechanical valve patients. Both patients developed thrombosis after switching to dabigatran from warfarin. The authors noted that “while there is a wealth of data and clinical experience on dosing and therapeutic response to warfarin in this context, these data are unavailable for dabigatran.” Although newer anticoagulants “hold tremendous promise for mechanical valve anticoagulation… there is a need for dose-finding studies and clinical trials to demonstrate safety and efficacy in this setting.”
Click here to read the press release from Boehringer…

FDA Investigation Finds No Excess Bleeding Risk For Dabigatran 1

In its latest assessment of a highly controversial issue, the FDA has found no indication that bleeding rates for dabigatran (Pradaxa, Boehringer-Ingelheim) are any higher than the bleeding rates for warfarin. The FDA investigation was in response to the large number of post-marketing reports of bleeding in people taking dabigatran. Click here to for the full FDA statement. Here is the first paragraph of the statement:

The U.S. Food and Drug Administration (FDA) has evaluated new information about the risk of serious bleeding associated with use of the anticoagulants (blood thinners) dabigatran (Pradaxa) and warfarin (Coumadin, Jantoven, and generics). Following the approval of Pradaxa, FDA received a large number of post-marketing reports of bleeding among Pradaxa users.  As a result, FDA investigated the actual rates of gastrointestinal bleeding (occurring in the stomach and intestines) and intracranial hemorrhage (a type of bleeding in the brain) for new users of Pradaxa compared to new users of warfarin.  This assessment was done using insurance claims and administrative data from FDA’s Mini-Sentinel pilot of the Sentinel Initiative. The results of this Mini-Sentinel assessment indicate that bleeding rates associated with new use of Pradaxa do not appear to be higher than bleeding rates associated with new use of warfarin, which is consistent with observations from the large clinical trial used to approve Pradaxa (the RE-LY trial).1 (see Data Summary). FDA is continuing to evaluate multiple sources of data in the ongoing safety review of this issue.

Setback For Trial Studying Dabigatran After Mechanical Valve Surgery 2

Despite the recent advent of novel oral anticoagulants, the much-maligned warfarin remains the only current option available for patients who have received a mechanical valve. Now the first trial to explore this indication for a newer oral anticoagulant has suffered a setback.

Last year Boehringer Ingelheim announced the launch of the RE-ALIGN trial, a phase 2, open-label, 12-week randomized comparison of warfarin and dabigatran (Pradaxa) in 400 patients who received a mechanical valve. There were two arms in the trial. The first arm randomized patients during their initial hospital stay. The second arm randomized patients more than 3 months after their surgery.

Now, following the advice of the trial’s Data Safety Monitoring Board, Boehringer Ingelheim said it had discontinued the first arm of the trial, the post-surgery arm, due to “lower than projected plasma levels of dabigatran in this population, and an imbalance in reports of thromboembolic events (primarily strokes).” The trial’s second arm with patients who received a valve more than 3 months before enrollment in the trial is unaffected by this decision and will continue as planned.

Boehringer-Ingelheim said that the  news about RE-ALIGN does “not affect the positive benefit/risk profile of Pradaxa 150 mg for the current labeled indication” of stroke prevention in patients with non-valvular atrial fibrillation. “RE-ALIGN is evaluating a different patient population and different doses than were studied in the RE-LY trial.”

Dabigatran has been approved in Europe, but not in the United States, for venous thromboemoblism (VTE) prevention after knee and hip replacement surgery. Rivaroxaban (Xarelto) has been approved for both VTE prevention in the United States and Europe. To date there have been no head-to-head comparisons of the newer anticoagulants.

According to a recent study in Circulation: Cardiovascular Quality and Outcomesdabigatran now has about 19% of the oral anticoagulant market, mostly for the approved treatment of AF “but increasingly for off-label indications” as well. A recent letter in the Journal of the American College of Cardiology provided information about the off-label use of dabigatran in two mechanical valve patients. Both patients developed thrombosis after switching to dabigatran from warfarin. The authors noted that “while there is a wealth of data and clinical experience on dosing and therapeutic response to warfarin in this context, these data are unavailable for dabigatran.” Although newer anticoagulants “hold tremendous promise for mechanical valve anticoagulation… there is a need for dose-finding studies and clinical trials to demonstrate safety and efficacy in this setting.”

One clinical cardiologist who did not wish to be identified offered the following perspective:

This is similar to the case reports (with all the usual caveats) where we have seen this signal with the novel anticoagulants…. it’s not intuitively clear why this is the case.  It may be that the dose is not optimized for mechanical valves.  It is worth noting that the drug levels in patients with mechanical valves were lower than anticipated based on pharmacokinetic calculations.  Maybe patients with mechanical valves have a different metabolism of the drug versus those that don’t have mechanical valves?  There may be an interaction with von Willebrand factor in the pharmacokinetics of dabigatran. Or maybe the dose is just too low and patients with mechanical valves need higher doses, just as we use a higher INR in patients with mechanical valves?  The science keeps evolving!

Sanjay Kaul made a similar point:

The anticoagulant dose requirement for mechanical valves is higher even for warfarin (INR targeted for 2.5 to 3.5) compared with atrial fibrillation or VTE indication (Target INR of 2 to 3). It is likely that the dabigatran dose tested in RE-ALIGN was not sufficiently effective early post surgery when the thrombotic risk is the highest.

Click here to read a letter sent by Boehringer Ingelheim to members of its speakers bureau…

Growing Popularity Of Dabigatran Leads To Increased Complications 1

Since its approval in the United States in October 2010 dabigatran (Pradaxa) has been prescribed 3.2 million times to more than 600,000 patients with nonvalvular atrial fibrillation (AF), according to its manufacturer, Boehringer Ingelheim. The company also announced that, based on the pivotal RE-LY trial, the “Clinical Studies” section of the drug’s prescribing information now includes the statement that 150 mg twice daily of dabigatran “was superior in reducing ischemic and hemorrhagic strokes relative to warfarin.”

But the news about dabigatran is not entirely upbeat. According to new data compiled by QuarterWatch (PDF), in 2011 the FDA received more safety reports about dabigatran than any other drug. The data are not entirely unexpected, since the bleeding complications of dabigatran are well known and physicians are more likely to report adverse events associated with new drugs. The drug that dabigatran was designed to replace, warfarin (Coumadin), was the second most reported drug, and has been high on the FDA list for many years.

Dabigatran was the subject of  3,781 serious adverse events reported to the FDA in 2011. This included 542 patient deaths and 2,367 hemorrhages. Warfarin  was the subject of  1,106 serious adverse events, including 72 deaths.

QuarterWatch noted that the difference between the two anticoagulants “could be at least partly explained by differences in the reporting rate for an older generic drug with many manufacturers, and a newly launched brand name drug being promoted by a large sales force.” But, according to QuarterWatch:

“What is clear, however, is that the FDA’s system is receiving a strong signal about this safety issue. A large share of dabigatran reports (79%) come from health professionals, suggesting that despite this well-known drug risk the bleeding was unexpected or unusually severe.”

QuarterWatch notes that the rapid uptake of dabigatran is probably due to its ease of use– no frequent INR tests are required– and the lack of drug interactions. One likely source of complications is the use of the standard 150 mg dose in older patients or those with renal dysfunction. The label now recommends that physicians “assess renal function during therapy as clinically indicated” but QuarterWatch wonders “whether this modest language will lead to safer use.”
Click here to read the Boehringer press release…

Study Explores Role of Periprocedural Dabigatran in AF Ablation 1

Updated with a comment from John Mandrola– As dabigatran becomes more widely used in atrial fibrillation (AF) patients, electrophysiologists are now trying to figure out how to handle anticoagulation in patients taking dabigatran (Pradaxa) for whom AF ablation is planned. In a new study published in the Journal of the American College of Cardiology, Dhanunjaya Lakkireddy and colleagues report on a multicenter, observational study of 290 patients who underwent an AF ablation procedure. Half the patients were taking periprocedural dabigatran and half were matched controls taking warfarin.

There were significantly more thromboembolic  and bleeding complications in the dabigatran group than in the warfarin group:
Click to continue reading…