Sunday, March 25, 2012

 Some drugs just never go away< but they should

We first criticized this drug in 2006, when in the BMJ we first mooted rosiglitazone in the DREAM trial – which cost $23million - caused a significant increase in heart failure, despite the population being at low risk of such a problem. The drug showed no clear benefit at 3 years on clinical outcomes and the rate of all cardiovascular events tended to be higher in the treatment group. What happened after that was good news, in that Steven Nissen in 2007 from the Cleveland Clinic undertook a systematic review of the effects of rosiglitazone, combining results from a total of 42 trials. The results clearly showed rosiglitizone was associated with a significant increase in the risk of heart attack and death confirming what we had suspected. Around the same time a Cochrane review also found there was no evidence of any benefits with the drug over other available treatments for diabetes and, because of side effects such as edema, fractures, and possible increased risk of MI, recommended other antidiabetic medications be used in preference. The uses of composite end points in the DREAM trial were also aptly criticized by Victor Montori in the BMJ. These drugs were making significant inroads in the drug market with more than 1.5 million prescriptions for rosiglitazone and pioglitazone issued in England alone in 2007. The week of the 5th of June, to my surprise the Lancet published the RECORD trial of rosiglitazone as an oral agent combination therapy. In English that means they combined it with another therapy. What they showed is rosiglitazone increased heart failure; but they then went on to report it doesn’t reduce cardiovascular death and the data was inconclusive on myocardial infarction rates. This is one of those interpretations designed to keep the drug on the market. Highly marketing driven and usually highly dangerous. A couple of points however are worth noting: more people were on a statin (9%) in the rosiglitazone group, they had an excess of heart attack, and although this was not significant it adds to the findings in the Nissen systematic review. Also, in the subgroup of RECORD patients with pre-existing heart disease, there was a 26% increase in heart attack. In addition, it seems the treatment also raises the risk of fractures. Finally, the RECORD trial had an unexpected low event rate, 2.5 % per year, whilst the trial was powered on an expected event rate of 11% per year; taken together with losses of 3% per year leads to very significant concerns about the results. The final nail in the coffin of this drug is that at the time of Nissen’s original review, approximately 30% of patients in the trial assigned to receive rosiglitazone had stopped taking the drug. By the time of the recent Lancet publication there is no mention of how many were actually on the drug. This is a no brainer, how can you assess the safety of a drug if you can’t tell who is actually taking it.

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