When you read headlines like "Link found between diabetes drug and heart attack risks," give a sympathetic thought toward offices like mine.
A recent article in the New England Journal of Medicine raised this possibility for the drug Avandia. The study, done by Dr. Steven Nissen of the Cleveland Clinic, is a meta-analysis of previous studies done on the drug. From MedPage Today:
CLEVELAND, May 21 -- A meta-analysis of data from 42 clinical trials found a 43% increase in relative risk of myocardial infarction among type 2 diabetics treated with rosiglitazone (Avandia).
The odds ratio for MI was 1.43 (95% confidence interval 1.03-1.98, P=0.03), said Steven E. Nissen, M.D., of the Cleveland Clinic, lead author of the meta-analysis, which was released online today by the New England Journal of Medicine.
This is the headlines that our patients are reading. The interpretation is: "If you are on Avandia, there is a 43% increase in your chance of having a heart attack." Why would anyone take this drug?
We take care of a large number of diabetics, many of whom are on the drug Avandia. Our office is very aggressive in the care of diabetics, getting nearly 60% of them under the goal of Hemoglobin A1c under 7%. This means that the overall control of our diabetics is very good. The risk of complications of diabetes (heart attack, stroke, kidney failure, peripheral vascular disease, eye damage, and nerve damage) correlates directly to this number. Avandia is one of the many drugs we have available to control this disease. Since there is another drug in this class, we do have alternatives to Avandia, as well as the ability to use drugs of other classes. So why not just change people?
We had an endocrinologist in our office a few days ago (not representing GSK) and we discussed this issue, and his comment was that Dr. Nissen is "the Michael Moore of the medical industry." Strong words. Mr. Moore is a crusader against the big and rich for the protection of the little guy (in his opinion). The problem is (in my opinion) that Mr. Moore does not always come to conclusions based on evidence, but starts with a conclusion and finds evidence to support this. This is precisely the danger of a meta-analysis of the sort that was done in this case.
When you are dealing with a disease where one of the major complications is heart attack, the possible causes for increased heart attack are numerous. Plus the fact that good diabetic control is universally accepted as the standard of care makes using a true placebo in any trial with a diabetic drug unethical. While the overall increase in heart problems appears great, the absolute numbers are not so impressive. The article continues:
But the absolute number of rosiglitazone-associated events was small -- 86 MIs in the rosiglitazone patients versus 72 in the controls and 39 cardiovascular deaths versus 22 cardiovascular deaths in the control arm -- so even a slight change could tip the balance toward a null finding.
Small numbers, however, become big numbers when factored in the context of a drug that according to estimates from its maker currently claims 37% of the market share for oral glycemic control agents. By some estimates, tens of millions of rosiglitazone prescriptions have been written in the eight years the drug has been sold in the United States.
There are multiple other flaws with the analysis that are well-discussed in Medscape. The overall gist of this is that while there is a clear chance that this analysis is correct, there is also a reasonable chance that Avandia may not harm the heart at all.
I believe that at the heart of this is an increasing distrust of the FDA and its methods. The relationship between the agency and the pharmaceutical industry has been at best cozy, at worst, incestuous. This has raised great suspicion about whether there is significant influence-peddling to get drugs approved for which the evidence is either sparse or questionable. The FDA becomes an easy target for people who want to grab a headline (remember that it was also Dr. Nissen who started the process to get Vioxx pulled off the shelf).
The difference between this battle and the one over Vioxx and heart disease is that diabetes is a potentially fatal disease. If this scare causes people to back off of their diabetes drugs and hence worsen their control, it will have done harm. Poorly-controlled diabetics are more likely to develop complications (many of which are life-threatening) than those who are well-controlled. The question in this case is whether the harm done to these patients is greater or less than the potential harm of taking the drug in the first place. In the case of Vioxx, the disease was aimed at improving the quality of life, so the number of patients threatened by stopping this drug was far fewer.
So who do you trust? Do you trust the FDA to be fair and balanced? Do you trust the drug reps coming and telling you that Avandia is safe (we had some today)? Do you trust a flawed study from a doctor who has shown a propensity for high-visibility studies? Clearly the FDA has harmed itself with its relationship with Pharma. Clearly the drug companies have harmed themselves with DTC advertising, huge profits, high priced drugs, and overly aggressive sales reps. Yet does that mean that we stop this drug in response to someone who may have their own self-interest in mind?
Patients and doctors are caught in the middle of this. "First do no harm" is the pledge I made to my patients. What is the right way to go on this one? We have chosen to continue Avandia on patients until further information is out. There are studies going on right now that are prospective trials to look at this exact question: what is the effect of Avandia on cardiovascular outcomes. Until I hear that that study as stopped (as was the case with the Women's Health Initiative) due to adverse outcomes, I will keep giving Avandia to my patients.
So who profits off of this kind of hype? Public "watchdog" groups, conspiracy theorists, and trial lawyers. When I Googled "Avandia," the first items to come up were plaintiffs lawyers lining up to begin the lawsuits.
"Have you taken Avandia and had a Heart Attack? Get legal help"
God bless America!