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Pradaxa vs. Warfarin: Rehospitalizations For Serious Bleeding Events

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Thomas J. Moore, of the Institute for Safe Medication Practices, recently wrote a “Perspective” piece about new Pradaxa-versus-warfarin study, which is described below.

Medical researchers reviewed population-wide electronic medical records from the Clinical Data Analysis and Reporting System of the Hong Kong Hospital Authority to identify the 30-day readmission rates for patients with nonvalvular atrial fibrillation treated with Pradaxa (dabigatran) or warfarin.

The bottom line for this retrospective cohort study is that the patients treated with Pradaxa appeared to be at higher risk for 30-day hospital readmission due to bleeding.

In his “Perspective” piece, Moore added some contextual information pertinent to the Hong Kong researchers’ findings:

… This new study’s annualized hospitalization rates of 5% and 5.8% for [Pradaxa (dabigatran)] and warfarin for bleeding in patients with atrial fibrillation also are consistent with previously published results. However, had this Hong Kong study been conducted in the United States, one would expect even higher hospital admission rates for [Pradaxa (dabigatran)] because the lower 110-mg dose — taken by 75% in this population — was not available in the United States until recently, and is not recommended for use in atrial fibrillation.

The study also identifies an important new anticoagulant safety issue — high rates of rehospitalization for bleeding within 30 days affecting 13.5% of dabigatran patients compared with 5.1% of warfarin patients. After a bleeding event, the warfarin dose can be adjusted downward, a flexibility not available for [Pradaxa (dabigatran)] except for the untested 75-mg dose….

Given these still-present safety issues when using Pradaxa, we continue to investigate possible drug injury cases against the responsible drug company, Boehringer Ingelheim, for patients who have suffered serious bleeding events.

[Read article in full at original source]

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Earlier Pradaxa Settlements Do Not Stop Filing Of New Pradaxa Lawsuits

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As can be seen from the following set of drug safety alerts, Pradaxa has caused significant concern among doctors and patients since soon after it first became available for use in the US.

In early December 2011 the FDA announced it would evaluate reports of bleeding in patients taking Pradaxa that have been submitted to the agency’s Adverse Events Reporting System (AERS) database to determine whether serious side effects are occurring at a higher rate than should be expected.

From the ISMP QuarterWatch 2011 Quarter 1 edition, which was published January 12, 2012, we get this summary of those adverse event reports to the FDA as regards the “substantial bleeding risks” associated with Pradaxa. In particular, gastrointestinal hemorrhages and hemorrhagic strokes were identified as some of these serious side effects in those elderly patients using Pradaxa.

The next Pradaxa safety “update” came from the ISMP QuarterWatch 2011 Quarter 2 edition, which was released April 5, 2012:

[Pradaxa], a new anticoagulant intended to reduce the risk of stroke, was a suspect drug in 856 reported cases, more than any other regularly monitored drug, but showed a decrease from 931 reports in the previous quarter. The new quarterly total included 117 reported patient deaths. With 511 reported cases of hemorrhage, and a median patient age of 80 years, these new bleeding reports reinforce our concern that vulnerable older patients may be receiving an overdose of this one-size-fits-all drug.

Due to these serious side effects, beginning in 2012 a growing number of personal injury and wrongful death Pradaxa lawsuits were filed against Boehringer Ingelheim Pharmaceuticals, Inc.

In August 2012 this federal court Pradaxa MDL, or case consolidation, was created: IN RE: PRADAXA (DABIGATRAN ETEXILATE) PRODUCTS LIABILITY LITIGATION, MDL No. 2385.

In May 2014, following several years of legal proceedings in the Pradaxa MDL, the defendant Boehringer Ingelheim agreed to settle most if not all of the approximately 4,000 filed Pradaxa lawsuits. This so-called “global-settlement” deal was reached just as the first federal court Pradaxa cases were set to go to trial in September 2014.

In May 2015 U.S. District Judge Herndon issued an Order which disbanded and ended the federal court Pradaxa MDL litigation he had presided over since August 2012. His reason for doing so: There were no active federal court Pradaxa lawsuits pending other than those which were part of the 2014 global settlement by Boehringer.

But at about the same time as Judge Herndon’s Order, there began to be a number of new Pradaxa lawsuits being filed in various state courts around the country. And this was the start of what has been referred to as a “round two” or the “second wave” of Pradaxa drug injury litigation.

The only difference, essentially, is that this round two or second wave of Pradaxa litigation is being pursued at the state court level.

The bottom line is this: If you experienced serious side effects from the use of Pradaxa, or a person died due to an adverse reaction while taking Pradaxa, you may still have a claim for legal compensation.

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Defendants BMS And Pfizer Ask For Eliquis Federal Court Consolidation

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On October 13, 2016 attorneys for Bristol-Myers Squibb Company and Pfizer Inc. filed with the United States Judicial Panel on Multidistrict Litigation (JPML) this court document, “BRISTOL-MYERS SQUIBB COMPANY AND PFIZER INC.’S MOTION FOR TRANSFER OF RELATED ELIQUIS (APIXABAN) PRODUCTS LIABILITY ACTIONS FOR COORDINATED PRETRIAL PROCEEDINGS PURSUANT TO 28 U.S.C. § 1407, which will refer to as “Defendants’ MDL Motion” hereafter.

As for why these two drug companies think that Eliquis lawsuits filed in the federal court system should be consolidated as a Multidistrict Litigation (MDL) case, we get this statement from the aforementioned Defendants’ MDL Motion:

While the claims vary slightly among the various complaints, the crux of the Related Actions is that each Plaintiff experienced bleeding while taking Eliquis, and that Defendants should be held liable for Plaintiffs’ injuries under a variety of theories, including that: (1) Defendants failed to warn adequately about the risk of bleeding; and (2) Defendants should not have sold Eliquis without precautions for blood monitoring or an additional drug to reverse its anticoagulant effect. Thus, Plaintiffs’ claims are based on a common set of core facts.

In a separate court document, “BRISTOL-MYERS SQUIBB COMPANY AND PFIZER INC.’S MEMORANDUM OF LAW IN SUPPORT OF THEIR MOTION FOR TRANSFER OF RELATED ELIQUIS (APIXABAN) PRODUCTS LIABILITY ACTIONS FOR COORDINATED PRETRIAL PROCEEDINGS PURSUANT TO 28 U.S.C. § 1407”, the two drug companies suggest to the JPML that this possible Eliquis MDL be assigned to U.S. District Judge Lewis A. Kaplan of the Southern District of New York.

It is currently anticipated that the Defendants’ MDL Motion will be considered by the JPML at the upcoming hearing session scheduled for January 26, 2017, in Miami, Florida.

Be assured we will be watching for the JPML’s determinations about the requested creation and suggested assignment of this federal court Eliquis MDL case.

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Is Eliquis A Safe Alternative To Warfarin For Patients On Dialysis?

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In this article published online by Pharmacy Times in August 2016, “Is Apixaban Safe and Effective for Patients on Hemodialysis?”, Brandon Dyson, PharmD, BCPS, who is a clinical pharmacist at an academic medical center, puts some scrutiny on Eliquis, an increasingly popular blood-thinner drug:

[Eliquis (apixaban)] is the only [novel oral anticoagulants (NOAC)] approved for use with creatinine clearance <15 mL/min. In fact, according to its package insert, there isn’t even a dose adjustment….

[T]he clinical trials for [Eliquis (apixaban)] didn’t include hemodialysis (HD) patients, but they’re able to recommend [Eliquis (apixaban)] use in HD patients with no dose adjustment. How?

You must dig deep to find the answer. The [Eliquis] package insert mentions a single-dose pharmacokinetic study in HD patients. If you dig a little further, you’ll eventually find it, and you’ll find out it only involved 8 patients….

What happens if you give multiple doses? [Eliquis (apixaban)] dosing is 5 mg BID in most patients. Does it accumulate in HD? We don’t know; it hasn’t been studied.

All we currently have is data from a single-dose trial in 8 patients. And that’s the point I’m trying to make. [Eliquis (apixaban)] may very well be safe and effective in HD, but we don’t actually know. It might be safe, but not effective, or it might be effective, but not safe. It also may be neither.

As for his mention of that eight (8) patient study, he referenced this medical journal article, “Pharmacokinetics, pharmacodynamics, and safety of apixaban in subjects with end-stage renal disease on hemodialysis.”, published in the May 2016 print edition of The Journal of Clinical Pharmacology.

Of course, this clinical pharmacist’s concern about — or skepticism of, perhaps — Eliquis use in the setting of hemodialysis piqued our interest.

The only thing we were able to readily find on-point was this item, “Apixaban in Hemodialysis”, on the ClinicalTrials.gov website, which provided us some rather limited information:

  • This study has been completed.
  • Sponsor: Jewish General Hospital
  • First received: January 12, 2016
  • Last updated: August 29, 2016
  • No Study Results Posted on ClinicalTrials.gov for this Study

So, it seems, there is not much publicly available data about the safety of using Eliquis in the setting of hemodialysis. Yet, such use was apparently approved by the FDA.

[Read this article in full at original source]

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Eliquis Lawsuits Being Filed Across The Country In Increasing Numbers

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It is important to know that as of September 2016 Eliquis does not currently have an FDA-approved antidote, or reversal agent, for a patient experiencing a trauma-induced bleeding event or needing emergency surgery. Eliquis (apixaban) was approved by the FDA in December 2012.

These serious medical conditions have been associated with the use of Eliquis:

• Serious Bleeding Events
• Irreversible Fatal Bleeding Events
• Trauma-induced Atypical Bleeding Incidents
• Gastrointestinal (GI) Bleeds
• Rectal Bleeding
• Hemorrhages
• Brain Hemorrhage
• Intracranial Hemorrhage
• Hemorrhagic Stroke
• Cardiac Bleeds

In recent months we have seen Eliquis lawsuits filed in various states across the country, from New York to Hawaii, from California to Kentucky, from Illinois to Louisiana, as well as in Pennsylvania and elsewhere. We estimate that less than 50 Eliquis lawsuits have been filed to date. This relatively low number of filed Eliquis cases, however, is expected to increase significantly in the months to come.

Our law firm is handling Eliquis cases which involve people who had excessive bleeding, bled to death, or experienced other serious side effects of Eliquis.

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Possible Blood Level Testing For Eliquis / Xarelto / Pradaxa / Savaysa

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As background, Xarelto (rivaroxaban) belongs to a class of medicines known as the direct oral anticoagulants (DOAC), which also includes Pradaxa (dabigatran), Eliquis (apixaban), and Savaysa (edoxaban). These still relatively new blood thinners have gained popularity in place of warfarin for the prevention of ischemic stroke in non-valvular atrial fibrillation because, as currently approved by the FDA, routine blood monitoring is not required.

According to this BMJ medical journal article, “Rivaroxaban: can we trust the evidence?”, published on February 3, 2016, a faulty medical device used in the clinical trial leading to the FDA’s approval of Xarelto (rivaroxaban) has called those results into question.

But in this letter to the New England Journal of Medicine (NEJM), “Point-of-Care Warfarin Monitoring in the ROCKET AF Trial”, also published on February 3, 2016, the medical researchers who conducted that Xarelto clinical trial conclude that the use of this device “did not have any significant clinical effect on the primary efficacy and safety outcomes in the trial.”

However, going back to the BMJ article, we get this counterpoint:

In a letter submitted to the NEJM (as yet unpublished) and shown to The BMJ, former FDA cardiovascular and renal drug reviewer, Thomas Marcinicak, says: “The care for the warfarin control arm patients [in ROCKET-AF] appears to have been compromised.”

The medical device at issue, which was later recalled by the FDA, allegedly is prone to giving falsely low INR readings. In the context of this Xarelto clinical trial, such readings would have prompted higher doses of warfarin being given to participants — resulting in higher bleeding risks for those given that warfarin — making Xarelto seem comparatively safer.

Perhaps the most interesting part of the February 2016 BMJ article, “Rivaroxaban: can we trust the evidence?”, is a possible unexpected result flowing from this current Xarelto controversy:

At the end of 2015, both the EMA and the FDA held meetings to discuss the need to measure blood levels of direct oral anticoagulants and adjust the dose accordingly to maximise benefit and minimise harm—despite all the manufacturers claiming that this is not necessary. The meetings were held after The BMJ revealed that Boerhinger Ingelheim, manufacturers of dabigatran, withheld analyses from the regulators that showed how many major bleeds could be prevented by monitoring anticoagulant activity and adjusting the dose.

A presentation to EMA last year by Robert Temple, deputy director for clinical science at the FDA’s Center for Drug Evaluation and Research, suggests that the FDA believes there is a scientific argument for measuring the blood levels of these drugs and adjusting the dose.

However, the latest on this front is found in the February 16, 2016 Reuters news report, “Xarelto trial results reaffirmed despite faulty device”:

Europe’s drug regulator said on Friday the defective blood clotting test device used in a key trial for the approval of Bayer’s top-selling anti-clotting drug Xarelto did not distort the study’s main findings.

“Xarelto can continue to be used as before, in line with the current prescribing information,” the European Medicines Agency (EMA) said on its website.

While the EMA has now made its determination, we wait to see what this current Xarelto fiasco leads to in terms of possible action by the FDA and other drug regulators.

[Read this article in full at original source] _______________________________________________________________________

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Eliquis Might Be Safer Than Xarelto, But Neither Has Approved Antidote

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In a November 9, 2015 news report, “Antithrombotics Have Varied Risk of Causing Major Bleeds”, there is a summary of one presentation the American Heart Association 2015 Scientific Sessions:

Clot-busting drugs work, but they sometimes cause dangerous major bleeding. Reporting at the American Heart Association 2015 Scientific Sessions in Orlando, FL, a team of drug company researchers offered results of a retrospective cohort study showing that apixaban (Eliquis/Bristol-Myers-Squibb/Pfizer) had a lower risk of bleeding….

Compared to warfarin patients, those on [Eliquis (apixaban)] had about half the risk (HR=0.53) of a major bleed. The research is presented in [“Abstract 18465: Real World Comparison of Major Bleeding Risk Among Non-valvular Atrial Fibrillation Patients Newly Initiated on Warfarin versus Apixaban 5mg BID, Dabigatran 150 mg BID, or Rivaroxaban 20 mg QD.”]

It seems from the summary report of this presentation that the pharmaceutical companies responsible for Eliquis were seeking to distinguish their blood thinner medicine from Pradaxa, Xarelto, and Savaysa. All of these medicines are in the non-vitamin K antagonist oral anticoagulants (NOACs) class of drugs.

But when it comes to there being a specific reversal agent to stop an acute bleed once it start, Eliquis, Xarelto, and Savaysa share the dubious distinction of not currently having one that is FDA-approved for use. For more about this unfortunate and unsafe situation, see this recent article, “Still No Approved Reversal Agents Or Antidotes For Eliquis, Savaysa, And Xarelto To Stop Acute Bleeding”, which has this sub-headline: None Available To Help Patients Who Undergo Emergency Surgery Or When There Is Life-Threatening Uncontrolled Bleeding.

Only Pradaxa has a so-called antidote at the present time. In more detail, On October 16, 2015 the FDA granted accelerated approval to Praxbind (idarucizumab) for use in patients who are taking the anticoagulant Pradaxa (dabigatran) during emergency situations when there is a need to reverse Pradaxa’s blood-thinning effects.

[Read this article in full at original source]

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Xarelto / Savaysa / Pradaxa / Eliquis: Effect Of Platelet Inhibitors

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Some newer oral anticoagulants have been associated with bleeding-related adverse reactions including gastrointestinal and intracranial bleeds. And that problem is the primary complaint that the Institute for Safe Medications (ISMP) has with these blood thinners.

The ISMP Quarterwatch published on September 23, 2015 includes an examination of the safety profiles of Eliquis, Pradaxa, and Xarelto, which are characterized as “novel” oral anticoagulants. Savaysa is not included in this ISMP study because it draws on FDA data from the second half of 2014 and Savaysa was not approved by the FDA until January 2015.

This September 2015 edition of the ISMP QuarterWatch publication then goes on to cover a safety issue with Savaysa, Eliquis, Pradaxa, and Xarelto that has not received much attention: The effect of platelet inhibitors in combination with those new anticoagulants.

From the ISMP report, we get these 3 points about the effect of platelet inhibitors:

1. The adverse event data for 2014 raised questions about why no clear guidelines existed about when or even whether patients should take two different kinds of drugs that inhibited the formation of blood clots. The anticoagulants reduce blood clot formation by inhibiting the enzyme that triggers the formation of fibrin threads that help seal the platelets that aggregate to plug bleeding site. Aspirin, clopidogrel, and other nonsteroidal anti-inflammatory drugs inhibit the aggregation of platelets.

2. In the adverse event data, we found that concomitant therapy with platelet inhibitors increased the odds of a hemorrhage event by threefold (OR 3.01 p < 0.01). The increased risk was found across all three of the novel anticoagulants and warfarin.

3. The prescribing information for all three drugs [Xarelto, Pradaxa, and Eliquis] contains no guidance on the concomitant use of antiplatelet agents other than a warning that an increased risk of bleeding was observed.

It seems sensible that the FDA should require studies be done to develop clear and definitive guidelines for whether to use these new anticoagulant drugs at the same time, i.e., concomitant use, that a patient is taking one or more of the platelet inhibitors.

[Read this article in full at original source]

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No Antidotes For Eliquis, Savaysa, And Xarelto To Stop Acute Bleeding

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When we read this September 25, 2015 Medscape article, “EMA Recommends Approval of Idarucizumab (Praxbind), a Dabigatran-Specific Antidote”, we recalled this alarming fact: At the present time there is no available antidote for Pradaxa nor Xarelto, Savaysa, and Eliquis such that irreversible bleeding events, which can result in deaths, remain a real and serious safety issue for these newer blood-thinning drugs.

Returning to that recent article, Praxbind will be useful in cases where patients have to undergo emergency surgery or when life-threatening or uncontrolled bleeding occurs when on Pradaxa (dabigatran).

As suggested by that article’s headline, however, Praxbind will only work to stop excessive bleeding associated with Pradaxa, which is a direct thrombin inhibitor. It is not intended for use in patients with acute bleeding while on Eliquis, Savaysa, or Xarelto.

Portola Pharmaceuticals is in the process of developing Andexanet alfa, a reversal agent or antidote for all Factor Xa inhibitors, such as Eliquis, Savaysa, or Xarelto.

So when will Praxbind and Andexanet be approved by the FDA and become available to patients in the US?

And from an August 27, 2015 Portola News Release about the status of Andexanet: “The Company expects to submit a Biologics License Application (BLA) for Andexanet alfa to the FDA under an Accelerated Approval pathway at the end of 2015.”

So while Eliquis, Savaysa, and Xarelto are touted for their ease of use as regards both patient and physician, these FXa inhibitor class anticoagulants have one major drawback in common: There is no antidote.

[Read this article in full at original source]

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New Blood-Thinner Savaysa Has No Antidote To Reverse Acute Bleeding

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Savaysa (edoxaban) is the fourth new oral anticoagulant (NOAC) that has been brought to the US market in recent years before any so-called “antidote” was approved by FDA — like Pradaxa, Xarelto, and Eliquis.

In a January 2015 FDA News Release about this new blood-thinner drug, however, a significant drug-safety issue was acknowledged. From this item, “FDA approves anti-clotting drug Savaysa”, we get the following relevant information:

The U.S. Food and Drug Administration today approved the anti-clotting drug Savaysa (edoxaban tablets) to reduce the risk of stroke and dangerous blood clots (systemic embolism) in patients with atrial fibrillation that is not caused by a heart valve problem….

The most common side effects observed in clinical trial participants were bleeding and anemia. As with other FDA-approved anti-clotting drugs, bleeding, including life-threatening bleeding, is the most serious risk with Savaysa. There is no treatment that has been proven to reverse the anti-coagulant effect of Savaysa… [emphasis added]

Recently there was a Milwaukee Journal Sentinel / MedPage Today investigation which resulted in this news report by John Fauber and Coulter Jones, “New anticoagulant drugs provide stroke prevention with dose of danger”, from which we get this disturbing information:

Concerns about the new drugs causing bleeding that could not be stopped have been raised for years:

■   In a 2011 letter to the New England Journal of Medicine, doctors in Houston warned about trauma patients using Pradaxa who had poor outcomes because of excessive bleeding. They described one patient who fell and died a short time later.

■   In a 2012 letter in the Journal of Neurosurgery, doctors in Salt Lake City warned of a similar case involving an elderly man who fell and suffered a brain hemorrhage.

Now, with Savaysa starting to get some market share in the US, we expect to hear about Savaysa-related injury and death cases which involve people who had excessive bleeding, some who bled to death. And, again, this is because Savaysa — like Pradaxa, Xarelto, and Eliquis — does not have an FDA-approved antidote, yet, for a patient experiencing a trauma-induced bleeding event or needing emergency surgery.

[Read this article in full at original source]

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