DREAM Turns to Nightmare: Avandia and Cardiovascular Risks

The just released meta-analysis published in the New England Journal of Medicine that suggests that rosiglitazone (Avandia, by GlaxoSmithKline) is associated with increased cardiovascular risks [Nissen SE, Wolski K. Effects of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 2007; 356, online here] has received a tremendous amount of media attention. So let me just summarize the story in a chronological way to emphasize some particular issues, based on Anna Wilde Mathews reporting today in the Wall Street Journal.

Dr. Nissen began following Avandia closely and was struck last year by the results of two major trials of the drug, published in the New England Journal of Medicine and the Lancet. The two studies showed the drug was effective in controlling blood sugar, but Dr. Nissen thought they held signs of cardiovascular problems.

The two trials were DREAM [The DREAM Trial Investigators. Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomised controlled trial. Lancet 2006; 368: 1096-1105.] and ADOPT. In DREAM, patients with glucose metabolism abnormalities who had not developed diabetes were randomized to get rosiglitazone or placebo, and followed for three years. The outcome of interest was the development of diabetes as defined by elevated blood sugar or abnormal results on a glucose tolerance test (or death). As Nissen noted in a letter to Lancet [Nissen SE. The DREAM trial. Lancet 2006; 368: 2049.], patients who received rosiglitazone were numerically more likely to have cardiovascular events, including heart failure, myocardial infarction [heart attack], stroke, angina, receipt of revascularization, or cardiac death, than were those who received placebo. The differences in rates, however, did not reach statistical significance, and hence could have been due to chance alone.

In ADOPT [Kahn SE, Haffner SM, Heiase MA et al. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med 2006; 355: 2427-2443.], patients with type 2 diabetes were randomized to rosiglitazone, metformin, or glyburide and followed for four years. The outcome of interest was increasing blood sugars leading to the use of another glucose lowering drug. Patients who received rosiglitazone were numerically more likely to have a cardiovascular adverse event, including myocardial infarction, congestive heart failure, and stroke.

Dr. Nissen wrote to GlaxoSmithKline in early January, asking for more data. The company offered to collaborate with him, but said it wanted to crunch the numbers itself. Dr. Nissen countered that the Cleveland Clinic needed full access to all the raw information and the right to publish as it pleased. Talks over the matter were inconclusive.

In mid-April, he found online the 1999 FDA document detailing the agency's original review of the drug. Then, in a Google search, Dr. Nissen found the online database of Glaxo study results. Many of the trial summaries included heart-attack data.

Dr Nissen and statistician Kathy Wolski used the on-line data in a meta-analysis of 42 trials of rosiglitazone. The meta-analysis suggested that the drug was associated with a higher risk of myocardial infarctin (odds ratio 1.43) and death from cardiovascular causes (1.64) than alternative treatments.

Because Avandia is now so widely used, Nissen's and Wolski's study has gotten a lot of press and caused a lot of consternation. Let me note at this point that Dr Nissen and Ms Wolski should be commended for being alert to the data on adverse effects found in the DREAM and ADOPT trials, and then being diligent in their search for more data. Nonetheless, the first big question is why Avandia become so popular in the first place?

When I have taught evidence-based medicine using the venerable "Users' Guides" approach, we came back to the key question to be answered when deciding about what therapy to use: do the benefits of therapy outweigh the potential harms?

A commentary published electronically that accompanied the Nissen and Wolski meta-analysis [Psaty BM, Furberg CD. Rosiglitazone and cardiovascular risk. N Engl J Med 2007; 356, available here] suggested:

Physicians who chose to prescribe rosiglitazone perhaps focused on the single dimension of glycemic control. The underlying assumption represents a kind of linear 'physiological' argument: high levels of glycated hemoglobin increase risk, so a reduction in glycated hemoglobin will automatically translate into improved health outcomes for patients. This perspective ignores the many actions of the genes activated by PPAR-{gamma} agonists, only some of which are currently known. Many physicians did not require proof of health benefits as a criterion for selecting rosiglitazone as a therapy for type 2 diabetes.

Had practicing physicians required this higher standard, they would have been at a loss for evidence from large, long-term trials. Rosiglitazone was approved on the basis of short-term studies of the surrogate end point of glycemic control.

So it appears that the first lesson from this case reiterates the approach used in the "Users Guides." Only use treatments whose benefits to patients outweigh their potential harms, based on a critical review of the best available evidence. When several treatments are available, pick the one whose benefit/harm ratio is superior for the particular patient.

The consternation currently being caused by the results of the meta-analysis by Nissen and Wolski indicates how far many of us have departed from these principles.

But it gets worse,

Dr. Nissen made another discovery in scrolling through the Web site. The company itself had done a meta-analysis similar to the one he was attempting, and quietly posted the result. The analysis, which didn't appear to include the two big trials published last year, tied the drug to a 31% higher risk of events involving an obstruction of blood flow, such as heart attacks. The rate for people taking Avandia was 1.99%, compared with 1.51% for other patients.

So,

One issue coming under congressional scrutiny is whether the Food and Drug Administration should have acted faster to alert the public about possible risk from Avandia. Glaxo performed its own meta-analysis, which also showed a potential danger. It shared an early version of it with the FDA in September 2005 and a more complete one in August 2006. The findings weren't reflected on the U.S. label, which is supposed to give a comprehensive review of the drug's risks.

Robert Meyer, head of the FDA office that oversees diabetes drugs, said the agency is still working on its analysis. 'We have other data that suggests we can't make a definitive conclusion at this point,' said Dr. Meyer, although he called the meta-analyses 'a signal of concern.'

So some people did spot the problems, but did not publicize or act on them. Thus, the next big question is if both GSK and the FDA had data suggesting rosiglitazone may be associated with increased cardiovascular risks (and again, in the absence of any data that the drug has clinical benefits that could outweigh these risks), why didn't they act on, or at least publicize this data?

Well, there is one obvious explanation why GSK may have not been in a hurry to act.

Glaxo rang up more than $3 billion in world-wide sales of Avandia last year. Its share price fell more than 7% after the New England Journal of Medicine released the analysis by prominent cardiologist Steven Nissen of the Cleveland Clinic, who helped raise early safety concerns about Vioxx.

But the FDA does not have to worry about sales or share prices. Its job is supposed to be to protect the public's health and safety. Why didn't it act?

Has its funding by users' fees made FDA officials feel they are responsible first to the drug, device, and biotechnology companies that pay these fees? (See, for example, Furberg CD, Levin AA, Gross PA et al. The FDA and drug safety: a proposal for sweeping changes. Arch Intern Med 2006; 166: 1938-1942.)

Has its dependence on advisory panels often populated by people who have financial arrangements with drug, device and biotechnology companies made it more used to these companies' interests than any others? (See this post and its links.)

We can hope that the Avandia story will mark the tipping point on the way to reinvigorated FDA that sees itself as responsible first and foremost to the public, not specific commercial interests.

See also comments on GoozNews, and on PharmaGossip.

WHAT IS TO BE DONE?

American citizens might advocate these suggested ways to reinvigorate the FDA to their members of congress:

1. End financing by "user fees" that incorrectly suggest that the FDA's clients are drug and device manufacturers, not the public at large.

2. Ban people with conflicts of interest from FDA advisory panels.

3. Make the FDA explicitly responsible for safety of drugs that are on the market, and give it the resources and tools to uphold that responsibility.

4. Require that drugs and devices demonstrate clinical benefits to patients, not just improvement in laboratory test results, prior to marketing.