Monday, June 9, 2008

Avandia Vindicated!

I suppose with the flurry of press on the ACCORD and ADVANCE trials presented at the ADA, the third similar study, the VADT, did not garner that much excitement in the media, with barely a mention. But the one headline from the good folks at MedPage today clearly caught my attention: VA Diabetes Trial Appears to Vindicate Rosiglitazone (Avandia) Safety

This 3rd trial was consistent with ACCORD and ADVANCE (which I blogged recently) in that it was unable to prove that aggressive diabetes management improved rate of heart attack and stroke. However, like the two prior studies, the expected event rate was lower than anticipated (likely due to better control of cholesterol and blood pressure) indicating in my opinion good news for the overall management of diabetes. However, unlike the Triple Crown, this 3rd leg did not disappoint with news about Avanida. However, before getting to this, let's review.

In May of 2007, Dr. Steve Nissen published a meta-analysis of diabetes studies containing Avandia. This now famous (or infamous) study started the entire Avandia safety controversy. Dr. Nissen analyzed 42 randomized trials lasting over 24 weeks involving Avandia, and found a 43% increase in risk of for myocardial infarction (for you stat folks, odds ration for MI was 1.43, 95% confidence interval [CI], 1.03 to 1.98; P=0.03).

1. Discrediting Nissen's study. In addition to concerns about how quickly the study was published in the NEJM and the political nature of the study's use as a lightning rod to shape public policy, scientific holes in the analysis were also raised. Diamond, et. al did a re-analysis of the same data published in the Annals of Internal Medicine in October 2007, and found no difference in heart attacks. As a side note, no scientist or statistician has ever been able to explain to me how if the rates of myocardial infarction were 0.58% in the Avandia group and 0.62% in the non-Avandia group, how it could be possible to have a 43% increase in myocardial infarctions with Avandia.

2. RECORD. The FDA had known about the concerns of myocardial infarctions, and was likely the primary source of Nissen's investigation. However, they were apparently holding off on any decisions, because the RECORD study, a large, randomize prospective trial to answer the very question of cardiac effects of Avandia was ongoing, and interim monitoring of the study seemed to indicate no cause for concern. However, when Nissen went public and started all the controversy, the RECORD investigators felt obligated to respond, and on July 5th, 2007, preliminary data from the RECORD study was published in hopes of answering any Avandia concerns. This study looked at over 4000 patients with uncontrolled diabetes not previously on Avandia. Half received Avandia and the other half did not, with the primary outcome of cardiac events. After 3.75 years there was no difference in heart attacks in the patients taking Avandia the on those not taking the medication. Not one, but three editorials accompanying the article suggested that these findings were not reassuring because the study was not statistically powered to show a difference.

3. The FDA investigates. In response to the controversy, and pressured by Congress, the FDA extensively reviewed Avandia safety data. In addition to a meta-analysis similar to Nissen's, the FDA looked at RECORD and two other large, randomized prospective trials; ADOPT (which showed Avandia to be superior to metformin and glyburide in keeping diabetes under control) and DREAM (which showed Avandia to prevent diabetes in patients who were at risk). These studies combined or individually, along with retrospective analysis from large data sources did not show any risk for Avandia related to heart attacks. In November 2007, the FDA added a boxed warning to Avandia which mentioned data discussed in Dr. Nissen's meta-analysis as well as data from ADOPT, DREAM and RECORD, stating, "In their entirety, the available data on the risk of myocardial ischemia are inconclusive."

4. ACCORD is stopped. In February of 2008, the intensive arm of the ACCORD study was stopped because of increased deaths. Since the results were just presented, we know that in the over 10,000 diabetics studied for 3.5 years, there was no difference in intense vs. usual care for prevention of heart attacks, and in fact there were more deaths in the intense group. According to the study, more than 90% of the patients in the intense group were taking a TZD (almost all Avandia) and more than half the patients in the standard care groups were taking a TZD. Three accompanying editorials to the recently published results imply that since more patients were on Avandia in the intense group, this might account for the increased risk of death in the intense group. However, we know this not to be the case because when the ACCORD was stopped, the NIH specifically looked at Avandia and found this not to be associated with increase risk. “Because of the recent concerns with rosiglitazone, our extensive analysis included a specific review to determine whether there was any link between this particular medication and the increased deaths. We found no link.”

5. VADT. June 8th, 2008, the results from the Veterans Affairs Diabetes Trial (VADT) were released. This study also looked of almost 2000 veterans for almost 8 years similarly found no improvement in heart attack and stroke in the intensively treated group as compared to the standard group. However, like the previous studies, the rate of cardiovascular events was substantially lower than expected, and about 80% of the patients in both groups were taking Avandia. When the investigators presented their results of their analysis at the ADA meeting, these results showed that, if anything, Avandia may have actually prevented heart attacks!

What does this all mean?
The gold standard for research is a large, prospective, randomized clinical trial (RCT). This is considered one of the best ways to answer a question about whether a drug causes a side effect or an improvement. A meta-analysis is done when large RCT's are not available. Meta-analysis uses statistical techniques to combine data from smaller trials in an attempt to statistically replicate a large, prospective RCT. Since Dr. Nissen's meta-analysis showing risk with Avandia that is fraught with controversy, we have had multiple large, prospective, randomized clinical trials that show the opposite result. Between RECORD, ADOPT, DREAM, ACCORD and VADT; there have been over 26,000 patients studied for over 3.5 years, of which more than 15,000 patients took Avandia and showed absolutely no difference in heart attacks or myocardial ischemia. I think it is clear based on the inherent limitations of Nissen's findings and the substantial evidence from the aforementioned studies that Avandia is not, and has never been associated with heart attacks or myocardial ischemia.


Anonymous said...

Thanks! Although it might not be front page news, your focus on the long-term evidence is refreshing. Thank you for taking the time to post the information.

Anonymous said...

A nice timeline perspective you've put together. Not mentioning Dr. Nissen's financial associations with several pharmaceutical companies (notably not GSK and Merck which have been his primary targets to date) helps avoid some additional controversy but since I'm adding commentary, let me just suggest everyone who has not done so read Dr. Nissen's 'disclosure' statement in his NEJM meta-analysis.

I would point out that GSK itself had approached the FDA about some potential concern regarding increased risk of MI months before the Nissen meta-analysis. So to be emphatic that avandia 'has never' been associated with MI may be a bit strong. The current studies are entirely encouraging but I think an honest evaluation of the data suggests there were some earlier concerns.

FeminizedWesternMale said...

Personally, I'd like to see Dr. Nissen in a jail cell for practicing economic terrorism, and graft.

Thanks for doing this foot work. It will be easier to reassure my patient's

Dr. Matthew Mintz said...

I purposely left out any conjecture about financial or any other reasons why Nissen might be "out to get" GSK/Avandia, but your point is well worth considering.
As part of their post-marketing vigellance given known issues of heart failure, GSK studied their trials and notified the FDA of there finding of a potential problem with myocardial ischemia (not infaction). Thus, the FDA was aware of this issue long before the Nissen publication, and based on conflicting evidence and ongoing trials (DREAM RECORD, ACCORD) decided that this was not a major concern, and that it was safe to wait until the data from these studies became available. Nissen got wind of the information and published his own meta-analysis of the publically available data.
One reason the FDA may have chosen to reserve judgement and not warn patients about a theoretical concern was to prevent the kind of panic and hysteria that the Nissen paper caused. Patients on Avandia did not simply switch to a similar medication (Actos) or try a newer med (Januvia). In most cases, patients just stopped taking Avandia, many without informing their physicians.

Anonymous said...

"the VADT did not garner that much excitement in the media" you say; however as an attendee I can tell you that many, many presenters made reference to this study;and many more international/national attendee looked forward to this presentation which was moved to a much larger room to accomodate the thousands that attended. It is unfortunate Dr. Nissen's article alarmed many who have benefited from the drug for so many years. Those who participated in the VADT were not given the drug if they had a history of CHF, and those who were on the drug were monitored closely.

Anonymous said...

How can you call this vindication for Avandia when only 62% of patients were on the drug in some arms of the trial by the end of the study? This study doesn't vindicate Avandia whatsoever. The devil is always in the details.

Dr. Matthew Mintz said...

Tara Dairman at reviewed the study and answers your questions with the statement:
"The oral diabetes drug rosiglitazone (brand name Avandia) was the most commonly used drug in the first year of the VADT, when it was prescribed to 85% of people in the intensive group and 78% of people in the standard group. By the third year, it was being used by 72% of the intensive group and 62% of the standard group. The researchers found no association between use of rosiglitazone and risk of cardiovascular events or death in this study; in fact, they stated that, if anything, it appeared to provide a protective effect. These findings contrast with the highly-publicized meta-analysis study that linked rosiglitazone to heart attacks and death earlier this year"
This was a large trial over a long period of time. According to Nissen, Avandia causes a 43% increase in heart attacks. If there really was a problem with Avandia, we should see substanitally more heart attacks in the hunders of patients taking it over several years. This simply was not the case, and if anything, Avandia seemed to prevent heart attacks.
The VADT alone does not vindicate Avandia, but combined with ADOPT, ACCORD, RECORD, DREAM as well as millions of patients reviewed by the FDA in retrospective claims data bases there seems to be no evidence of a problem.

Anonymous said...

What an asinine statement. Vindication? At which point do you address the fact that the "studies looking at Avandia" were not looking at Avandia, rather looking at the effects of reducing blood sugars beyond current recommendations? The look at Avandia is an analysis. And beyond the fact that these studies were not setup to look at any drug in particular you've also forgotten to mention that there are no control arms in these studies. With a minimum of 80% of patients in all arms of the study on Avandia, how do you know there was no increase?

Furthermore, you and others continue to fight for a medication that you cannot claim is safe by any standard, rather you can state, "we're not sure," the same as the FDA has already done. Why don't you take a moment to reconsider a medication in the same class with a proven safety record that utilized a prospective, randomized, placebo-controlled, multi-centered trial looking at cardiovascular outcomes, of which proved no increase in macrovascular events? That would be ACTOS. Beyond the fact that the conversion trial from rosiglitazone and metformin to pioglitazone and metformin showed a 10% reduction to in total cholesterol, ACTOS has competitive advantage in all realms. Why would you use a sub-par drug with the patients you care about so much?

Neither drug, statistically, is shown to reduce or increase total-c, so why does ACTOS reduce total-c by 10% after being treated with rosi first? Take a look at the Avandia package insert and compare data to the ACTOS package insert. There's really no reason to use Avandia which makes all this analysis and "vindication" junk, null and void. Please practice evidence based medicine for the care of your patients.

Dr. Matthew Mintz said...

You are correct that these studies are not designed to show that Avandia has no cardiac problems. The study that is designed to show this is the RECORD study which will not be completed until 2009. However, an interim analysis of this study published immediately after the Nissen study showed no problem. The FDA's analysis of the studies Nissen looked at, the RECORD data, as well as two other long term studies where information could determine this also did not find any problems with heart attacks.
Although these new studies do not have comparator arms similar to the previous studies looked at by the FDA, the sheer number of patients in these studies taking Avandia, showing a lower heart attack and death rate then one would normally expect, would suggest that the 43% increase Dr. Nissen found is just not true. Dr. Nissen's statistcal methods have been criticized elsewhere. Even in his study, there were fewer events with Avandia patients then patients not taking Avandia.

Anonymous said...

It seems that Dr. Mintz should reevaluate this post and possibly update his viewpoints.

Dr. Matthew Mintz said...

Please see all my posts on Avandia on this blog (there are many). My position has not changed. We will know more in July when the FDA convenes to review all the data since 2007. If science and not politics prevail, Avandia will have an official FDA vindication.