Heart Stopper: Mirapex And Undisclosed Data

[Kimberly]

I'm not great at site searching, but did try and did not find this article posted. I was on Mirapex for 10+ years and quit cold turkey after discovering on my own that I was experiencing almost ALL of the worst side effects listed for the drug. In pre-screening for an upcoming surgery, today I learned that something is wrong with my heart. Am I surprised...not in the least. I've been complaining for the last few years that long-term sleep deprivation and the 8-10 hours of nightly, torturous movement were taking a great toll on my health. After finding this article, now I'm wondering.....and wanted to share...


Heart Stopper: Mirapex And Undisclosed Data

By Ed Silverman // May 2nd, 2012 // 9:16 am

Over the past few years, a debate has intensified over the extent to which drug makers should disclose all clinical trial data pertaining to their medicines. The issue has drawn bitter complaints from some physicians and consumer watchdogs, among others, who argue anything less than complete disclosure may deprive the medical community of important info needed for treating patients.

Consider the case of Mirapex. The drug, which is sold by Boehringer Ingelheim, was initially approved in 1997 to treat Parkinson’s disease and, six years ago, the approval was extended to combat Restless Legs Syndrome. At that time, cardiac failure was listed in the labeling among dozens of adverse events that were noticed during clinical trials but for which causation was never determined (look here).

Since then, cardiac failure has been cited in connection with the drug. A study that was funded by Pfizer, which was comparing its own Dostinex against other medicines, found a statistically significant increased risk of heart failure with Mirapex. The results were presented at the European Society of Cardiology meeting in Sweden two years ago (see this) and published online last November in Pharmacological Research (read here and here).

Yet another study appeared a few months ago in Pharmacoepidemiology & Drug Safety. Supported, in part, by Boehringer Ingelheim, the study reached the same conclusion about both Mirapex and the Pfizer drug. But the text yielded some revealing passages that suggested Boeheringer Ingelheim had been tracking cardiac failure for some time without any public disclosure (look here and here).

The introduction to the study, which was entitled ‘Dopamine Agonist Use and The Risk of Heart Failure,’ noted that, “recently, adverse events of heart failure have been observed in association with the dopamine agonist pramipexole (the chemical name of Mirapex) in randomized trials.” The authors cited Boehringer “internal data” and a “personal communication from Dr. Bartels.”

The reference was to Dorothee Bartels, who is corporate vice president and head of global epidemiology at the drugmaker. She provided the results of a pooled analysis from randomized Mirapex trials. Specifically, the introduction mentions a “signal of a potential risk of heart failure arose in pooled data from 26 placebo-controlled, randomized trials” in Parkinson’s and RLS patients.

Those trials involved 4,157 patients who were taking Mirapex and another 2,280 on a placebo, but the outcome was too small to draw reliable conclusions, the authors wrote, and raised questions about the potential for the risk to occur with other dopamine agonists. This led them to conduct the study. Yet those 26 trials were never made available. It is also not clear how far back they go in time.

We asked the corresponding author, Samy Suissa, a professor of epidemiology, biostatistics and medicine at McGill University, if Boehringer provided underlying data. He wrote us that “the only data I have are in the paper – rates, numbers, etc.” We should note that Suissa received research grants and honorarium from Boehringer over the last three years.

There was, however, one curious disclaimer at the bottom of the study. The authors maintained they had ultimate control over “all aspects” of the research, including control over publications. “During the study, however, any differences about the presentation or interpretation of findings that arose between the authors and the company were resolved through honest scientific debate,” they added.

We asked a Boehringer spokeswoman when the drugmaker learned of the risk of cardiac failure in the pooled trials, whether a report about the findings was compiled and, if so, would a copy be made available. But those questions went unanswered during two separate efforts. Instead, we were sent copies of the product labeling along with a brief statement.

She wrote us that labeling for Mirapex and Mirapex ER, a newer version approved in 2010, “include language related to cardiac events, and specifically heart failure or cardiac failure. Post-marketing surveillance studies continue to assess the safety and efficacy of our products… We continue to work closely with the FDA to ensure our products are appropriately labeled and are used safely.”

The labeling, which was revised last year, provides the same language that appeared in the 2006 labeling, with the addition of one line: “In a pharmacoepidemiological study, pramipexole (Mirapex) use was associated with an increased risk of cardiac failure compared with non-use.” This appears under the post-marketing experience section. There is no mention, however, of two studies or the undisclosed data (see here and here).

In Europe, meanwhile, the 2011 labeling mentions cardiac failure as a possible effect (read this). The European Commission Guideline on Summary of Product Characteristics notes that adverse events are not added to the European Union labeling unless they at least are suspected to be causally related to the drug (see page 11 here).

The mysterious fate of the internal data troubled one expert, who has regularly advocated for greater dissemination of clinical trial results and last year suggested the creation of an “external coordinating organization,” which would be independent and have legal resources to contract with drug and device makers for providing access to patient-level data, documents and case reports (read this).

“I am disturbed that there seems to be a pooling of internal data indicating a potential problem with heart failure and there has been no opportunity for independent review,” wrote Harlan Krumholz, a cardiologist, a professor of medicine, epidemiology and public health at the Yale University School of Medicine, and a board of governor of the Patient-Centered Outcomes Research Institute.

He reviewed the studies and related documentation at our request. “This is an ideal situation where sharing of individual patient-level data with the entire research community, or at least with independent investigators, can provide information about the risk that was conveyed in the company’s personal communication to their consultant,” he continued.

“Such sharing would deflect concerns that the company is hiding something and allow a fair evaluation of the risk. With no record in the medical literature and no sharing of the data, we are left to wonder about these risks and the reason that the company has not been more forthcoming. I applaud them for doing analyses on harm, but they need to go further.

“The privilege of selling a product should be accompanied by the responsibility to share data you have that is germane to the risks and benefits of the drug. Patients deserve access to information that could influence their decisions about clinical strategies. If it is true that the company has data from their trials that is relevant to concerns about the drug’s safety profile and that data has not been shared, then I hope they will move quickly to make it available.”

At around the same time that Boehringer was accumulating the pooled data, by the way, the drugmaker was tagged by the FDA for improperly promoting Mirapex. A warning letter from 2008 noted the drugmaker prepared promotional materials that omitted risk information and an untitled letter in 2009 pointed to sponsored links on Google that also failed to contain risk information.

http://www.pharmalot.com/2012/05/heart- ... osed-data/

[ViewsAskew]

I wish it wasn't so, but it doesn't surprise me. All the other dopamine agonists have been removed because of heart problems. They said that the non-ergot DAs didn't cause problems (Requip and Mirapex).

Wonder what this means for Requip and Neupro...

Looks like our options may be getting narrower.

[veldon7]

It doesn't surprise me either, I've been taking Mirapex for aprox. 10 yrs also, nothing else has really worked for me. I have some Neurontin the Neuro gave me, but it doesn't help much. I guess I will have to take the Neurontin anyway and try to cut back on the Mirapex, thanks for the info.

[Polar Bear]

My thoughts as I read the article were also.... what does this mean for requip.... etc.

[Betty/WV]

Mirapex is the only med that has helped me. The best I can remember is that I started taking it in 2008. I did have a mild heart attack in 2002, but no problems with the heart since then. But I do wish the drug companys would be more open about their meds.

[Chipmunk]

The book Our Daily Meds was a real eye-opener for me in regards to the pharmaceutical industry. I can't say anything in there shocked me (it's nothing less than what I would do if I valued profits over strangers' welfare), but some of the details were disturbing, especially about drugs I either have taken, or take now.

It's given me a good nudge to really examine whether all of my RXs are necessary, and make sure that if a side effect for one of my drugs comes out, like heart damage or liver failure or whatnot, that I can honestly say that I really needed the drug and need to take it despite the risks.

Unfortunately, Big Pharma has every reason to keep adverse reactions quiet, especially when the evidence isn't ironclad. However, one positive thing from their obsession with making money is that they continually have to invent new drugs that are similar to but slightly different from existing drugs. People argue that the new drugs aren't needed because they don't work any better than the old ones, but I'm grateful to have more choices in a particular class of medicines. Every drug has slightly different effects and I'm glad to have more drugs to try to get the one that works well for ME.

[Betty/WV]

So, if you are taking one of these drugs, like I take Mirapex what should I do. I hate the thought of going back to what I was before. Walking the floor all night, many times, crying. Being sleep deprived, not able to think clearly and on and on and on. WHAT SHOULD A PERSON DO??????? Or, risk a heart attack, and family members are cursed with a history of heart attacks at a young age. And if you question your doctor about this, he will tell you, "all medicines are a risk, you have to weigh the benefits. Never admitting it could be possinble the meds are a risk.

Betty

[Chipmunk]

So, if you are taking one of these drugs, like I take Mirapex what should I do. I hate the thought of going back to what I was before. Walking the floor all night, many times, crying. Being sleep deprived, not able to think clearly and on and on and on. WHAT SHOULD A PERSON DO??????? Or, risk a heart attack, and family members are cursed with a history of heart attacks at a young age. And if you question your doctor about this, he will tell you, "all medicines are a risk, you have to weigh the benefits. Never admitting it could be possinble the meds are a risk.

Betty

I just try to take the lowest dose possible to relieve my symptoms - many times side effects only get serious at higher doses.

If you do need to take a high dose of a drug that can cause damage, you can have periodic screening, like they do with people who are on statins. My husband has liver function tests done every 3-6 months to be sure there is no sign of liver damage.

In your case, it seems like Mirapex is worth the risk of a heart attack if it's the only thing that works for you.

My issues:
I am on an SSRI (anti-depressant) that they don't even know how it works, but when I try to go off it, I get suicidal, so the risk of my brain getting permanently re-wired is one I'm going to have to take.

I take Adderall for ADHD. Again, they really aren't too sure how it works, but I can't do what I love (doing research and writing about it) without it.

Lamictal is one of the drugs they mentioned in Our Daily Meds as being way over-prescribed for arbitrary conditions, and they mention RLS as one of them. Well, I could care less what they invented it for, it works for my RLS and I'm going to keep taking it.

Now another issue is the interaction among all these drugs, which is something I know they don't have data for, but, again, my life without them is not a life at all.

Ultimately, it would be very sad if the cost for taking these drugs was 15 years at the end of my life traded for 30 years now, but it would be more tragic to have 45 years of something that was really no life at all.

[Betty/WV]

Thanks for your insight, I could try to cut down on the Mirapex. I take .25 mg twice a day. Which is higher than what is recommend to begin with. Once I tried to cut back and the old RLS popped its head up again. But I could try again to see what happens.

And I take other meds which always make me wonder what interaction is going on in my body. My doctor does keep a check on my liver etc. with regular blood work.

When I was put on Mirapex I was at the end of my rope. I don't think I could take it any longer. The Mirapex works about 80% of the time. Which for me is wonderful. I can take those times when I have a little flare up. But I couldn't take it night after night.

I'm 76 so I would like a little time at the end of my life to have some peace without the WED/RLS. Which for me has been curse for over 40 years.

Take care and thanks for your comments.

Betty

[ViewsAskew]

Betty, I don't think that is higher than recommended. Where did you see that this dose was too high?

[Betty/WV]

I think in Dr. B's book it says to start with .125 but my doctor started with .25. I talked to Dr. B about it and he told me to try to lower the dose and if it was to low, I would know it. And I did, so I went back on the original dose. So, I will stay on the Mirapex, until I can't take it any longer. I can't go back to the way I was before the Mirapex. The night I found RLS.org and poured out my heart on here, I was at the end of my rope. I couldn't go on any longer the way I was. I had no life, I was just barely existing. So finding RLS.org kept me going until I found the neuro that I go to now and he put me on Mirapex.

Thanks for your thoughtfulness and concern.

BETTY/WV

[ViewsAskew]

They do recommend starting at .125 to minimize side effects, but most people go up to .25 or more. I'm glad you found us and that you stayed .

[Chipmunk]

Betty,
I remember how horrible things were for you last year, and (at the risk of dispensing medical advice over the internet) I think you should stay on the Mirapex as long as it's working for you. I'm so glad to hear that you have found something that helps.
Tracy

[Betty/WV]

I am doing better than before. Not perfect but I can deal with it now. I was getting to the point where I was desperate. At least now I can lay down, and sleep. My sleep is fragmented, I sleep 3 or so hours at a time, but when I wake up after that time, I at least can go back to sleep.

Thanks for your concern. I appreciate it.

Betty