Those people who know me would probably agree that I am not one to say "I told you so," but in this case I will make and exception.
The RECORD study, as I described the other day, was just presented and the results are GOOD. Dr. Home, the lead author of the study (from Med Page Today), stated, "in terms of overall cardiovascular risk, the drug is safe. There's no increased risk, no decreased risk. And that includes the heart failure element."
I told you in one of my first posts that the Nissen article was likely a lot of media hype.
I told you when the VADT trial came out that Avandia had been vindicated, and did not cause heart attacks.
I told you all about the flaws of the Nissen study and how politically motivated the entire Avandia scare really was, outlined in my post Diabetes Conspiracy
I told you before the results were presented in my post Get Ready for RECORD the likely outcomes of the study, which I also warned that the naysayers would be out in full force (more below)
Here's the actual results which can be found in The Lancet
- For the primary outcome of combined cardiovascular hospitalization and cardiovascular death- they were exactly the same
-for cardiovascular death alone, no difference (avandia slightly favored)
-for heart attack - no difference
- for stroke no difference (avandia slightly favored)
-diabetes was also better controlled in the avandia group (though we don't know by how much...yet.
-the only bad thing was that heart failure causing admission to hospital or death occurred in 61 people in the rosiglitazone group and 29 in the control group. However, this is not unexpected, since heart failure is a known risk for the drug. In fact, it is comforting to know that even with a double risk of heart failure, there was no overall increase in risk of hospitalization or death from cardiovascular causes in the study- which was the whole point of the study to begin with.
As mentioned, it should not be surprised that certain people are going to try to raise doubts about the study. Dr. Steve Nissen, whose meta-analysis is essentially completed refuted by the study claims that it is still unresolved is whether rosiglitazone is associated with an increased risk of myocardial infarction stating, "In The Lancet manuscript, the authors don't reveal the number of patients who were still taking Avandia by the end of the study. Obviously, it is impossible to assess the safety of a drug when patients are not actually taking it."
Guess what Dr. Nissen? At the end of the study, 1,344 patients 61% of the Avandia group were still on the drug, while 1,131 patients, or 51% of the control group, remained on their medicines (from Forbes). In other words, there was high and similar drop out in both groups. It is actually surprising that even more patients didn't drop out, given your study unnecessarily scared the socks of these folks!
Dr. David Nathan is another likely naysayer, given that his newest guidelines recommend that Avandia shouldn't be used.
From MedPageToday: Although the data released today showed no associated risk of overall cardiovascular morbidity or mortality, Dr. Nathan noted that the study still doesn't put to rest the concerns about the drug
This should not come as a surprise from someone who believes we need no more new diabetes medicines.
If you are still skeptical, I encourage you to read all my diabetes posts, particular the Diabetes Conspiracy, as it outlines how flawed and political the whole controversy is.
In addition, please consider that gold standard of science is not a meta-analysis, but large, randomized controlled trials designed to answer a specific question like RECORD. Given RECORD, ACCORD, ADOPT, DREAM and VADT there have been randomized, controlled trials of 26,000 patients that have been studied over 4 to 5 years, of which more than 15,000 patients took Avandia and showed absolutely no difference in heart attacks .
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5 comments:
Thank you very much for your continuing,scholarly reviews and updates on Avandia and on diabetic treatment issues in general.One point you raise, however, leaves me a bit confused. You mention "political" motivation possibly involved in some whose positions defer from yours.Can you expand on what some of politics that would be?Personal aggrandizement motivations I can understand but what beyond that drives certain critics leaves me at a loss. Again great work on your reviews.
thanks. let me try and clarify political motivations:
1. Nissen might have wanted to head the FDA, and his name was mentioned multiple times. By publishing a flawed study that garners a lot of attention and positions him as the defender against evil pharma, he puts himself in a better position (and it almost worked)
2. Dr. David Nathan, Harvard endocrinologist and guideline publisher, might have muliple agendas for bashing Avandia and not wanting any new diabetes drugs. First, his ultra conservative approach might garner him respect within the ADA, possibly moving him to a higher office. Second, endocrinologists have a vested interest (in my opinion) by keeping diabetics on injectable medicines. Bashing the study and the product moves more people to injectable products, specifically insulin.
3. FDA insiders ( I have my suspicions who this was) likely leaked classified data to Nissen, because the safety folks were not happy with the FDA head's decision that a cautious approach ought to be taken before letting the public know about a possible dange. He was right, they were wrong.
4. Congressmen-particularly Grassley, gain political clout by bashing evil pharma. He and others called for congressional hearings within hours after the Nissen article was released, almost as if they had been tipped off to the story.
5. The media. Though technically not political and more monetary, the media knows that scary "sells more papers" then good news. Even today, despite the excellent news from the RECORD study, some of the headlines still read "critics" and "doubts." Those people who are critics and raising doubts? You guessed it, Nissen and Graham.
This is why so many of my posts are labeled with the title "diabetes conspiracy."
The RECORD study design was flawed from the get go. Wasn’t that why the FDA asked GlaxoSmithKlein, who sponsored the trial, to conduct another study to overcome the study’s limitations?
One should stop and think if a company sponsored trial cannot produce favorable results for their product.
Having said that even by when the 2007 interim numbers were released about 30% of participants on the rosiglitazone arm were already off the medication. Neither The Lancet paper nor the accompanying shindig at the American Diabetes Association meeting revealed how many people were still on rosiglitazone by the end of the study.
If rosiglitazone is really precipitating the development of overt heart-failure in susceptible individuals as suggested by the RECORD results, isn’t it enough for us to stop prescribing this medication.
It is also interesting that the medication has been shown to have a neutral effect on the risk of myocardial infarction. Why would a molecule whose sole job is to optimize glycemia and hence improve risk have a neutral effect on myocardial infarction? Isn’t it at least supposed to show an effect towards the decrease risk?
To me, it does not make any ethical sense to say to a patient “well, this medication may double your risk of developing congestive heart failure but guess what you won’t die from it.” Interestingly this is the message being pushed out by this campaign of trying to rescue Avandia which appears to be hanging by a thread. If you check you regular news sources today and conduct a search for rosiglitazone and RECORD you’ll see that the news articles returned will mostly be titled something like “Rosiglitazone does not increase CV risk,” or “Rosiglitazone safe for the heart.” Really? I mean really?
I think I’ll stick by January 2008 consensus statement released by ADA and cautiously prescribe pioglitazone until the air is cleared.
Mehmet, excellent questions.
RECORD was not flawed from the start because it was not designed to look at heart attacks specifically. No one had even thought of heart attacks being a problem with Avandia. If anything, Avandia should have prevented heart attacks. This is why when the FDA saw GSK's data (which didn't make any sense) they decided to not make any rash decisions until studies like ADOPT, DREAM and RECORD were done. However, Nissen (who likely got a tip from inside the FDA) decided to publish the results anyway. The new study that the FDA asked GSK to do was designed to specifically look at heart attacks. This is wasted money I believe since every other available study seems to refute the Nissen article.
As in the post, Forbes found out the answer regarding who remained in the study. At the end of the study, 1,344 patients 61% of the Avandia group were still on the drug, while 1,131 patients, or 51% of the control group, remained on their medicines. Also, since this is a safety study and not an efficacy study, who remained on the drugs is not as much a factor since you are looking at patient exposure of a drug and not whether they stopped taking it.
It is disappointing that no benefit was shown. My suspicion is that Avandia (and other TZD's) prevent heart attacks by preventing the buildup, and possible slightly reducing, atherosclerosis in the coronary arteries. In order to show a benefit, it probably takes longer than 5 years. Recall that the benefit of glycemic control on heart attacks specifically was not shown until 30 years after the study was started.
Finally, even if rosiglitazone shows no benefit on reducing heart attacks, reduces the need for insulin as well as associated hypoglycemia.
Too bad we cant revisit the other meta analysis that Nissen did that destroyed a new class of diabetes agents to basically have research all but halted.... the dual PPAR agonists. Nissen wrote a paper in about 2004 showing muraglitizar, despite getting thru an FDA advisory committee meeting, incrased CV death. The FDA basically ditched the drug and BMS gave up on it. Now a PPAR is in development - by Roche, I think, but is years away.
Thanks Steve Nissen, for throwing an entirely new class of diabetes medicines off the rails for six years.
The kicker with Nissen is that he defended his surrogate endpoints to the death when it came to Crestor.
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