Avandia News

GSK: RECORD trial results do not change Avandia’s CV risk stigma, bone fracture risk, physicians say

-Pharmawire

06/20/2009 - The final results of the RECORD study demonstrated that overall rates of cardiovascular (CV) hospitalization and cardiovascular death - the two primary endpoints - were similar in patients taking Avandia (rosiglitazone) compared to those receiving metformin and sulfonylurea.

While there were fewer deaths from cardiovascular disease in the Avandia group, the rates of chronic heart failure (CHF) were higher in the group randomized to Avandia (61 events versus 29 events), which was a statistically significant difference. In addition, there were more heart attacks in the Avandia arm (64 out of 2,220 patients versus 56 out of 2,227 patients).

”Drugs used to treat Type II diabetes should reduce CV events, not increase them. The findings of the seriously underpowered RECORD trial were inconclusive regarding the risk of myocardial infarction (MI) with Avandia,” said Dr Sonal Singh, assistant professor at Wake Forest University School of Medicine.

These findings are consistent with his group’s previous analysis (in the September 2007 issue of JAMA), which showed an increased risk of MI and heart failure with Avandia without an increased risk of cardiac death due to lack of statistical power, Singh said.

The RECORD study is a pretty good study but does not exclude the possibility of harms, noted Dr John Buse, president of the American Diabetes Association. As is true of any study, it has its issues, he said.

GSK did not return calls for comment.

Dr Graham McMahon, assistant professor of medicine at Brigham and Women’s Hospital, agreed that the CV risk is a substantial concern. The RECORD study does not answer most questions that physicians had based on the preliminary results, he said.

McMahon described the study as ”flawed” and ”more of a marketing study than true science.” He added that he would have preferred to see MI rates over hospitalization rates as an endpoint - which would have provided clearer evidence of the efficacy of the drug. The study did not provide any information on the role of the agent in patients with heart complications, he added. McMahon also concurred that the study was underpowered, which he said is evidenced by the low event rate and wide confidence intervals. The flaws of this study are too great to make reliable claims, he added.

Since Avandia is known to increase LDL concentrations, patients were also treated with statins, which led to approximately a 30 percent risk reduction and a net three percent lower mortality in the Avandia arm, said McMahon. For these 60-70 patients, had they not been simultaneously given statins, Avandia would have appeared even less efficacious and shown greater risk, he said.

Dr L. Keoki Williams, a physician at the Center for Health Services Research at the Henry Ford Health System in Detroit, said physicians should be concerned with the CV risk as the increased risk of congestive heart failure appears clear both in clinical trials and oberservational studies. The potential increased risk for heart attacks was not conclusively addressed in RECORD, and the weight of evidence from meta-analyses and observational studies suggest that there is an association, he noted.

The RECORD trial also showed a near doubling in the risk of fractures with Avandia which Singh said he had previously reported (Canadian Medical Association Journal in December 2008). This risk is in addition to the adverse effects of macular edema with the thiazolidinedione (TZD) class, he added. There is no clinical trial evidence that Avandia provides any beneficial effect on microvascular or macrovascular outcomes; hence, in the context of overall evidence, clinicians should not prescribe Avandia, because safer and cheaper alternatives are available to treat Type II diabetes, he said.

Dr Suzanne Steinbaum, director of Women and Heart Disease at Lenox Hill Hospital, said the RECORD trial results showed Avandia increased the risk for heart failure and osteoporosis.

The data on fracture risk is useful, according to McMahon, who explained that the suspected fracture risk associated with Avandia was confirmed by the RECORD study despite the fact that patients stopped taking the drug and crossed over to the other treatment arm. This was a more definitive piece of information, he said.

Despite the CV risk and fracture risk, Dr Joel Zonszein, the director of the Clinical Diabetes Center at the University Hospital of the Albert Einstein College of Medicine, said that using echocardiograms or Dexa scans to screen patients is not helpful, nor is it recommended.

”I’m not sure even if you screen patients with an echocardiogram, if that will prevent patients from getting heart failure,” Steinbaum agreed.

The issue regarding the appropriate timing and frequency of DEXA scans is more complex and not known at this time, Williams said. The literature has shown that women appear to be disproportionately affected by bone fractures - which suggests that these fractures may be related to bone loss, he explained. However, the locations appear to be mostly distal extremities and not hips or vertebra. ”Individuals should receive routine preventative bone densitometry screening as otherwise indicated until we know more about the nature and risks of these fractures,” he said.

“I have a hard time reconciling this,” Steinbaum said, as most of her patients are women, who have an increased risk of osteoporosis to begin with. Each patient has to be screened individually, to see what her risk-benefit ratio is, she explained. Steinbaum said that she would not start treatment with Avandia in patients with coronary artery disease, heart arrhythmias, or an underlying substrate that leads to heart failure. Individualized treatment is necessary with the agent, she said.

Due to the increased risk with Avandia and the availability of safer options, a patient’s A1c levels should be reduced to less than 7.1 percent, according to Steinbaum. ”I’m just not using this drug,” she said.

There are alternative agents for treating patients, McMahon concurred. Furthermore, it is unclear what the role of TZDs is in treating diabetes - particularly Avandia, he said, noting that the agent is mildly effective, associated with an increase in heart failure and expensive. Physicians have alternatives like DPP4 inhibitors, metformin, and sulfonylureas that are effective and safe, he said. The bottom line is that physicians look for microvascular and macrovascular changes, he said.

With the exception of congestive heart failure, the potential increased cardiovascular risk has not been demonstrated in meta-analyses and observational studies for Actos (pioglitazone), Williams noted, referring to Takeda’s TZD. He cited a retrospective study conducted at Henry Ford Hospital that demonstrated that Actos appeared have a lower risk of congestive heart failure and coronary heart disease events when compared to Avandia. Williams explained that while there has not been a head-to-head study of these two medications with regard to these outcomes, the cumulative evidence to date suggests that Actos may be the safer choice.

If you or a loved one have experienced an Avandia heart attack, or Avandia stroke, Avandia congestive heart failure, Avandia cardiovascular disease or if you have lost a loved one to an Avandia death you may be entitled to compensation. Contact the Avandia lawyers of Ennis & Ennis, P.A. today about an Avandia lawsuit. Call us toll free for a free, confidential case evaluation or fill out our online Avandia case evaluation form