Pradaxa Side Effect Reports Were Hemorrhaging
9 CommentsBy Ed Silverman // January 11th, 2012 // 12:11 pm
Just when you thought the clouds hovering the Pradaxa bloodthinner could not get any darker, yet another report underscores concern about the Boehringer Ingelheim drug. The latest missive shows there were 505 cases of hemorrhaging reported to the FDA in the first quarter of 2011, shortly after the med was approved for preventing stroke and blood clots in people with atrial fibrillation.
The cases resulted in death, disability, hospitalization or some other serious outcome, and the median age of the patients was 80, suggesting that the oldest and most vulnerable patients were hemorrhaging due to a drug overdose, according to the Quarter Watch reported from the Institute for Safe Medicine Practices, a non-profit. In fact, 25 percent of the affected patients 84 years or older.
The findings come three months after European regulators asked doctors to exercise caution about using the Pradaxa bloodthinner. At the time, the European Medicines Agency was aware of 256 cases of serious bleeding that resulted in patient deaths associated with the drug. More recently, the FDA decided to investigate post-marketing reports of serious bleeding patients (read this).
And earlier this week, an analysis of seven clinical trials that was published in the Archives of Internal Medicine found Pradaxa was “significantly associated with a higher risk” of heart attacks and acute coronary syndrome, which includes heart attacks and chest pain. Of 20,000 patients taking Pradaxa, 237 had a heart attack or chest pain, compared with 83 patients out of 10,514 on warfarin, which is the decades-old standard treatment, or a placebo (here is the abstract).
The mounting evidence that Pradaxa is associated with serious adverse events is a boost to rivals. Two months ago, the FDA approved Xarelto, which is sold by Bayer and Johnson & Johnson, although the bloodthinner received a Black Box warning (see this). And Eliquis, which will be sold by Pfizer and Bristol-Myers Squibb and has generated heady predictions of success on Wall Street, received a priority review (look here).
The adverse events, meanwhile, suggest that the FDA should revisit dosing for Pradaxa, according to ISMP. The non-profit noted that in the 2011 first quarter, there were 272,119 prescriptions dispensed to outpatients, and 932 overall serious adverse events reports in which the bloodthinner was the primary suspect, including 120 deaths, 25 cases of disability and 543 cases requiring hospitalization.
A key issue, according to ISMP, is that Pradaxa was approved at a dose of 150mg twice a day, but the frequent laboratory tests needed to manage warfarin blood levels - every one to four weeks - were not recommended. The INR (International Normalized Ratio) test used to optimize warfarin treatment does not provide reliable results for Pradaxa, the non-profit notes. As a result, patients are not routinely monitored to see if they are getting too much of the drug.
And while declining or impaired kidney function is another potential safety issue, the prescribing info does not recommend a dosage adjustment, except in cases of severe renal impairment, and does not recommend regular testing of renal function, ISMP writes. The non-profit notes mild kidney impairment raises Pradaxa blood levels by 50 percent and moderate impairment can increase levels by 300 percent.
“While more study is needed, it may turn out to be a major drug safety mistake for the FDA to have approved a one-dose-fits all drug intervention as risky and sensitive as an anti-coagulation in older patients,” Thomas Moore, senior scientist at ISMP, tells us (here is the ISMP report).
ISMP adds, by the way, that Boehringer was approached for comment, and the drugmaker responded by acknowledging the large volume of serious adverse events were known, but noted that bleeding risks were known and warnings were issued. The drugmaker “attributed the report volume in part to the rapid acceptance of the drug into the market and an active sales force with extensive contact with physicians, resulting in more frequent reports,” according to ISMP. Boerhinger added that it is working with the FDA to provide better guidance to physicians. Separately, we asked Boehringer for a response and will update you accordingly if one is received.
Dan
I don’t know of any experts in pharmacovigalence who would assume that MedWatch detects the majority AE cases that are actually occurring in the population. Fifty percent is a VERY generous estimation…some pessimistic estimations range as low as 10%. This problem is likely worse that it appears on the surface.
John Urquhart, MD, FAAAS, FISPE
Further to Dan’s comments: there’s a phenomenon in pharmaco-epidemiology called the ‘Weber Effect’: adverse reaction (AR) reports of new agents rise to a peak at about 2 years after market introduction, then decline thereafter. At the present time, bleeding reports re PRADAXA are ‘new-news’, whereas bleeding reports re warfarin are ‘very old-news’ and are correspondingly far less likely to be reported. This asymmetry in AR reporting leads to biased impressions about the relative risks of AR’s of new vs old products. Another problem possibly vexing PRADAXA is the channeling phenomenon, whereby claims, explicit or implicit, for superiority of the new product leads to its selective prescribing for patients with especially difficult medical problems, which may make recipients of the new product more than usually prone to AR’s to anticoagulation with any agent of that category.
Gopal Pandey
Why the surprise about hemorrhaging! The mother drug warfarin came into existence only because the rats were dying of internal bleeding at the University of Wisconsin in silage for animals at the University Farm where Warfarin was discovered and inducted into human medicine as a blood thinner only after is debut as a rodenticide for use at the farms.
Charlotte, NC
Jan. 11, 2012
original industry insider
Call me old fashioned, but I’ve seen many patients now in their 60’s and 70’s who had heart attacks in their 40’s when a typical business lunch consisted of a jumbo shrimp cocktail, a 24 oz heavily marbled sirloin steak the size of a B-17 with hollandaise sauce, baked potatoes as large as a regulation size NFL football, encrusted in butter and cheese, then topped off by apple pie a la mode made with a lard-based crust for dessert, with coffee and the traditional post lunch unfiltered Camel cigarette. This does not even include the two martinis pre lunch and the never-empty carafe of table wine with lunch.
Standard treatment post MI and pre statins included coumadin in those days. When properly managed I’ve seen very few cases of clinically significant bleeding, and in most cases was due to noncompliance and/or poor management.
Justice in MI
Related to above, check out the membership list of the “California Healthcare Institute” (follow Ed’s link)–pretty much every drug and device company on the planet.
Let the spin begin!
Observer
JIM - don’t feel bad about posting here - I do think this really links well to that earlier post.
http://www.pharmalot.com/2012/01/a-lack-of-progress-blame-it-on-the-fda/
Thomas Moore
As an author of the QuarterWatch report who publishes regularly using adverse event data, I agree (and we say) that the reporting reporting rates are variable and unknown.
But the ‘Weber Effect’ documented for a small group of NSAIDS more than 20 years ago has not been confirmed in numerous published studies since.
That said, it is likely that the reporting rate for a new brand name drug being aggressively promoted to physicians will have a higher reporting rate than warfarin, a 57-year-old generic.
While ‘industry insider’ above hardly ever sees warfarin bleeding case, the best published study shows that a shocking 33% of all emergency hospitalizations in the elderly for drug adverse effects are attributed to warfarin. (See QuarterWatch for more detail and citations.)
Doc
Pradaxa is a prime example of what you get by approving drugs now and tracking potential worrisome areas later.
Ask any physician, most adverse events go unreported, the paperwork volume to report one is burdensome.
Robert
What is Boehringer doing?? Nothing!!