Wednesday, June 06, 2007

Avandia and the Heart

On the 21st of May, when I had just landed in Barcelona, the New England Journal of Medicine, a premier medical journal, published in their on-line edition, an article by Dr Nissen SE and Wolski K, entitled,  " Effect of Rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes."  (N Engl J Med 2007;DOI 10.1056/NEJMoa072761. Available at:

As usual, in USA, this article was taken up by Wall Street and GSK's (GSK is the maker of Avandia) shares dropped. Avandia (pharmacological name is rosiglitazone), is a peroxisome proliferator-activated receptor (PPAR) gamma agonist, which has proven useful in the control of diabetes. It is FDA approved for such, as the clinical papers submitted for approval showed that it was effective in glucose level control, the implication perhaps was that good glycemic control will result in less CVS mortality and mobidity. This assumption has now come under severe attack in the light of Dr Nissen's paper.

Let me go back one step, to say that PPARs are very complex protein molecules (we call them ligands) that can affect genetic coding of cells, in this case, to make them more receptive to glucose (after all, it is an insulin sensitiser). What did Dr Nissen do? He must have ask his medical research team, to go on-line and search all published data on Avandia and the heart (maybe he used google). Besides the online data, he said that he also wrote to GSK to ask for the original data, but they could not agree on terms (I suspect that the conditions imposed by GSK were not acceptable to Dr Nissen - which maybe angered him towards GSK?? ). Anyway, his team proceeded on to analyse whatever data they had, and did a "meta-analysis " of the data on the effect of Avandia on the incidence of heart attacks and death from heart diseases.

Meta-analysis means that you just try and relate the data that you have between the drug and the effect that you are looking for. Even though the study that you pick, did not have their intention to show that, it did not matter. You can also pick and choose which study you wish to include (big, small, relevant, or irrelevant). It is almost like cherry picking a clinical paper, and second guessing the authors, to show what you wish it to show. Not the best way to study the effect of a drug, but certainly, a lot cheaper than doing a large scale RCT (randomised control trial).

42 cinical papers were chosen, involving about 15,000 patients. These clinical papers were all studying different aspects of Avandia treatment, but as long as the paper report any effect on the heart, those numbers were taken and analysed. By doing this off-line analysis (we call it meta-analysis), they came to the conclusion that the use of Avandia was associated with a higher incidence of heart attacks and death from cardiovascular causes. This paper was submitted to NEJM for publication and it was accepted.

To be fair to Dr Nissen, he concluded that their findings should lead to larger clinical trials to specifically study the effects of Avandia on the heart attack rates and death from cardiovascular causes. This conclusion seems fair, as this was a meta-analysis, and not an RCT.We should not make policy decisions and clinical guidelines on meta-analyssis data, as in meta-analysis, we are not comparing apples with apples. We are comparing apples, with orange, with cats and dogs.

What the NEJM did after that was to me unreasonable. They had two people who were well known do meta-analysis, to write a strong editorial, stating basically that  FDA should re-look at Avandia, and maybe withdraw it from medical use. This I thought was thoroughly unfair as they failed to understand (but these two editorial writers are well known to jump to conclusions too quickly), firstly that this is a meta-analysis and not an RCT. A re-look by FDA would be fair, a larger clinical trial to study this effects would be reasonable. Withdrawing the drug? Certainly not yet. We need more data.

Secondly, as responsible doctors, they refused to understand that such sensational news involving a popular drugs treating an important disease like diabetes, would be picked up by the lay press, who may not understand the flaws in meta-analysis, print it as "gospel truth" and frighten many patients, who may stop taking Avandia and produce more deaths and other complications of diabetes. Poor GSK,now they are stuck with a huge PR exercise, to convince their prescribing doctors and patients that Avandia is safe.

What is my take on all this hooha. I do use Avandia. It is a good and effective drug in the treatment of diabetes. I do see the occasional heart attacks in my diabetics, but diabetics do get heart attacks. Some of my diabetic patients do die. I do not think that they are related to Avandia. But I really do not know, as there is no large RCT to tell me this.I have many patients on Avandia, who are doing very well. I do know that Avandia can cause fluid accumulations in some of my patients, and that I should not use Avandia in my patients with heart failure. This paper by Dr Nissen will make me more aware of this problem, and I do hope that GSK will undertake a clinical trial to disprove this worrying effect, if it is not true. Well, I think that GSK has lost a large PR exercise. In the real world, once the press picks up a public health danger, the effects will permutate and permeate, so we have not heard the last of this yet.

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