Tuesday, June 14, 2011

Look SHARP

(well, maybe not)

Last week, results of the SHARP trial were released with great fanfare. In this study, investigators randomized over 9000 patients with chronic kidney disease (creatinine ≥ 1.7 mg/dL in men and ≥ 1.5 mg/dL in women) to placebo vs. a combination of ezetimibe and simvastatin, marketed under the brand name Vytorin. Over a median follow-up of 5 years, patients who received the study drug had a 1% lower risk of stroke and a 1.5% lower risk of requiring opening or bypassing a blocked artery in the heart or elsewhere. However, there was no difference in rates of heart attack, death from heart disease, or death from any cause.

What is extraordinary about this trial is not the mixed effect on outcomes, but the fact that it represents yet another wasted opportunity to learn whether ezetimibe actually has any clinical benefit. This drug, launched in the US in 2002, has enjoyed a meteoric rise in sales. By 2006, ezetimibe accounted for 15% of all prescriptions for cholesterol-lowering drugs, and in 2010 over $4 billion was spent on the drug. However, there is practically no data about whether ezetimibe yields any clinical benefit, either when given alone or when used to augment statin therapy.

In a list of clinical trials of ezetimibe, only one completed study to date has evaluated whether ezetimibe on top of a statin drug is better than the statin alone. This study, published in 2008, found that adding ezetimbe had no beneficial effect on a marker of atherosclerosis – and if anything, was slightly worse than the statin alone. Nearly all other completed trials have evaluated the combination of ezetimibe and simvastatin against placebo - which tells us almost nothing about whether adding ezetimibe on top of standard therapy provides any clinical benefit (or harm) above standard therapy alone.

In essence, enormous financial resources are put into trials whose main results clearly have much more value for increasing drug sales than for helping doctors learn the best ways to treat their patients. As a result, many billions of dollars are spent each year on unproven therapies, and millions of patients are exposed to drugs with unclear benefit. We can do better. We must.

P.S. For a succinct and thoughful commentary on the SHARP trial, click here.

2 comments:

ken covinsky said...

This study seems very concerning and raises serious questions about our obligations to research subjects. It seems this study design had clear advantages to the sponsor. If the study had shown a benefit from the drug, there would have been no way to know if patients should just get a statin or both ezetimide and statin. Most would have felt the need to give both in this circumstance. But it is quite obvious that the relevant question revolves around the comparison of the statin, both drugs, or placebo.

This seems to raise really important questions about the informed consent of research subjects. Is there an obligation to tell them that the study they are participating in will not address what most clinicians and experts view as the most important issues surrounding the study drug? Do they need to know that as a result of this, when the study is done, it is almost certain it will still not be known what the best treatment is? Do they also need to know that the optimal study is perfectly feasible but the sponsor has no interest in the learning the answer to the question posed by the optimal study?

Cyndi, RN, OCN, PCRN said...

I also wonder if the IRBs have a responsibility before approving to look at this aspect of trials. Maybe they need to consider if this the right trial to be doing? But that would take an expert in the topic field on each board (or maybe just consultant to each board?) to review the trial before approval.