Do You Need To Stop AVANDIA?

May 28, 2007

images.jpgMy email alerted me on this headline regarding the alarming news on a most commonly prescribed drug for diabetes called rosiglitazone or Avandia manufactured by GSK and the apparent increased risk of heart attack among those taking the drug! 

The problem is: New England Journal of Medicine article was only a meta-analysis of different articles that studied the drug but not with cardiovascular diseases as a primary endpoin.  The RECORD trial which will be available in 2009 is the ONE that we have to wait to fully answer the question of avandia and the risk of heart disease.

The comments of different societies complement my thoughts of the safety of this drug…meaning for me…the benefits continue to outweigh the risks.  I am a prescriber of this drug because it really helps my patients get into control, lower the rquirements for insulin with beneficial effects in protecting and preserving beta cells and therefore delays the progression of the disease.  This for me is important if we want to prevent long term complications.

1. Lancet‘s response to the NEJM article (23rd May) entitled “Rosiglitazone: seeking a balanced perspective.”

The editorial
criticises the NEJM publication
– states that the’ two most reliable studies to inform decision-making’ currently available are ADOPT and DREAM
– acknowledges that, although the recent NEJM meta-analysis (based on a small no of events) raise a signal of concern, before the results of RECORD are available it would be premature to overinterpret a meta-analysis

The editorial concludes by saying

To avoid unnecessary panic among patients, a calmer and more considered approach to the safety of rosiglitazone is needed. Alarmist headlines and confident declarations help nobody

2.The European Medical Association (US FDA counterpart in EU) recommends that, in EU markets, ‘patients are advised not to stop treatment with rosiglitazone and to discuss the medication with their doctor at their next regular visit’. societies:

Statement from US organisations

Statement from Canadian Diabetes Association

Statement from Diabetes Australia

Statement from Diabetes UK

Lastly, a fellow blogger Kevin MD had his thoughts on this and pointed out Dr Steven Haffners comments in his post:

Dr Steven Haffner (University of Texas Health Science Center, San Antonio), who was involved in the ADOPT study of rosiglitazone, said the paper needed to be published, but it should have undergone a more extensive review, and there should have been a different editorial with more emphasis on the flaws of the study. “The NEJM was irresponsible to go to [Drs Bruce] Psaty and [Curt] Furberg for the editorial–they were always going to emphasize concerns about drug safety; that’s what they do,” he commented. “But I’m not surprised this paper was published like this. The three major medical journals are becoming more like British tabloid newspapers–all they lack is a bare-chested woman on page 3,” he jibed.

For me….I will continue to believe in this drug as one helpful arm in my quest for a better treatment regimen for my patients with diabetes. The NEJM article is not the perfect study we look for to answer the questions of safety.  A Meta-analysis has its flaws which will be corrected by future proscpective studies with cardiovascular disease as a primary endpoint.

If you have your doubts… talk to your doctor.

If you believe in the drug and your doctor asked you to stop it based on NEJM article and its editorial …talk to a Specialist!

The Editorial of the well respected Lancet says it all:

Alarmist Headlines and Confident Declarations Help Nobody

4 Responses to “Do You Need To Stop AVANDIA?”

  1. Dorothy Says:

    What a relief! I trust in your decision Doc. God bless

  2. Doc Gerry Says:

    Here are more stuff for reassurance from the world experts. I did not include these in my post as they will be too scientific but nonetheless I thought of including them here as a remark: These are remarks of Dr Haffner of the University of Texas and Dr Brian Storm of the university of Pennsylvania

    Don’t panic

    The FDA was well aware of the cardiovascular data with rosiglitazone. The cardiorenal advisory board has a calm and sedate head, unlike Steve Nissen.

    An editorial published online May 23, 2007 in the Lancet weighs in on the debate, urging calm [3]. It points out that the two most reliable studies to inform decision-making are ADOPT and DREAM. The DREAM study showed MI rates of 0.6% for rosiglitazone group vs 0.3% for controls, and the MI/stroke/cardiovascular composite occurred in 1.2% of rosiglitazone vs 0.9% of control patients, with neither result reaching statistical significance. The only significantly relevant finding in the ADOPT trial was an excess of congestive heart failure episodes for rosiglitazone-treated patients compared with glyburide (22 vs 9 events), the editorial adds.

    “Taken together, these results, although based on very small numbers of events, certainly raise a signal of concern and indicate the need for more reliable information about rosiglitazone’s safety. But the FDA, physicians, and patients can reasonably await the results of RECORD, a phase 3 trial designed specifically to study cardiovascular outcomes. Until the results of RECORD are in, it would be premature to overinterpret a meta-analysis that the authors and NEJM editorialists all acknowledge contains important weaknesses. To avoid unnecessary panic among patients, a calmer and more considered approach to the safety of rosiglitazone is needed. Alarmist headlines and confident declarations help nobody,” the Lancet editorial concludes.

    Inaccurate estimate of risk
    On the limitations of Nissen’s analysis, Haffner explained that one of the main concerns he has is the fact that it used a statistical technique that weighted the studies by the number of subjects included. “This would be acceptable if the studies were of a similar length, but the analysis included two large-scale studies with long-term follow-up and 40 smaller studies with much shorter follow-up. Under these circumstances, the smaller studies have been overweighted,” he said.

    Haffner added that if the 43% increase in risk shown in the analysis had occurred in the ongoing RECORD study with rosiglitazone, it would have been stopped a year ago. “I think if a proper meta-analysis were done with rosiglitazone, it would probably show some increased risk, but this would not be significant. The hazard ratio would not be 43%—but it may be 30%. That doesn’t mean it has a clean bill of health, but it doesn’t justify pulling it off the market, either. It’s ludicrous to suggest taking a drug off the market based on flawed data showing p values of 0.03 and 0.06.”

    Strom also feels there has been an overreaction to these data. “Nissen did a good job with the data he had, but this meta-analysis is very far from being definitive. If this is all the evidence they have for harm, then people are overreacting. Yes, this meta-analysis is important—but it should be viewed as raising questions, not providing answers.” Alarmist headlines and confident declarations help nobody,

    Strom makes the point that a meta-analysis cannot deal with studies in which no outcomes were seen, which is why such studies were excluded, but from a safety point of view, these studies give important information. He also highlighted the lack of individual data as a huge drawback. “They recognized this and stated it as a limitation in their paper, but you can’t do the correct analysis without the individual data, and maybe they shouldn’t have tried. They ended up doing the wrong analysis. These are very borderline findings—p values of 0.03 for MI and 0.06 for CV death, and doing a different analysis could easily have generated a different answer. Their findings are therefore only suggestive at most.

    “I’m not panicking about this. I think these drugs are overused, but I do have some patients on rosiglitazone, and I will not take them off it just because of this study. It is an interesting hypothesis but far from conclusive,” Strom added.

    What is the absolute increase in risk?
    McGuire believes a cardiovascular safety signal does exist within the rosiglitazone data set, but he adds that “to present the data as point estimates of risk without the clear context of the absolute signal is irresponsible and alarmist.” He explains that the worst-case scenario from these data is that rosiglitazone would elevate risk for MI from 1.4% to 2%. “So, a safety signal—yes. An emergency call to remove the drug from the market and cause global chaos among patients taking the drug? No. At least three large-scale trials currently under way will have much more robust power to evaluate these effects. With this small safety signal, we can afford to wait for the additional data being accumulated.”

    Dr Storm sums it up: “Drugs are given because they have benefits. Where there’s a scare, people stop taking them. So you can do more harm than good if the scare is not based on correct information. I do believe this meta-analysis should have been published, but a less sensational editorial would have been better!

  3. Joshua Says:

    extensive review and thanks. As a patient, our trust in our doctors is paramount to our safety in terms of the different medications we take.

  4. Malong Bonono Says:

    I really appreciate your very objective & factual comments regarding the issue. This gives me an assurance both as a marketeer and patient of Avandia.

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