Thursday, February 14, 2008

Lessons from the ENHANCE trial

Clinical trials form a very important part of "evidence based medicine" , which itself plays a very vital role in the position of "Western Medicine". Even negative trials can teach us a lot.

The ENHANCE trial is a study of 720 patients, undertaken by Merck, Sharpe and Dome in 2004 and completed in 2006. The trial was to compare simvastatin (a very established statin) against a simvastatin/ezetimide combination in a group of patients with familial heterozygous hypercholesterolemia. The primary end-point was carotid intimal thickness after 18 months. Although the study was completed in 2006, and all of us was expecting the results in early 2007, the results was not announced until January 2008, and that after the US congress had enquired why.

It is obvious that when clinical trial results are withheld, the trial must have been negative. In fact, the grape-vine told us that MSD was trying to ask the investigators to, first change the primary end-point, and two to take a re-look at the data. This certainly had all of us up in arms (so much for MSD's corporate transparency). With the US congress taking an interest, MSD released the results recently. It showed that although Vytorin (simvastatin+ezetimide) reduced LDL-C more than simvastatin alone, the simvastatin alone arm did show some carotid intimal plaque regression, whereas the Vytorin arm did not. In fact the Vytorin arm showed a non-significant increase in carotid intimal thickness.

This raises important issues. Firstly, MSD was very opaque, not honest, by withholding the results until pressured and by asking the investigators to massage the results. Secondly, and more importantly, how do we explain a fall in LDL-C without a reduction in Carotid intimal thickness (which is a surrogate of atherosclerosis in large to medium size arteries, which in turn is a surrogate for clinical events)? We know (and this we take almost as gospel truth) that statins lower LDL-C, regress plaques and reduce MACCE events. Vytorin reduces LDL-C, but does not reduce the surrogate of MACCE. Does it mean that statins are unique and that their MACCE reduction is not a function of LDL-C lowering? Or that "the lower LDL-C, the better" theory is inaccurate? Or that there are many forms of LDL-C and statins are able to reduce one form, oxidised-LDL-C, and Vytorin reduced the larger non oxidised LDL-C form? Interesting.

We now have more questions than answers. I do not know. I believe that Vytorin does reduce LDL-C but the less important (read clinical MACCE involved) type , whereas statins hit the important oxidised LDL-C type. Well we certainly need more imformation and I am told that there is a study undertaken "IMPROVE-IT" which we give us more information about the role of Vytorin. I also note that Vytorin is FDA approved for the last 4 years, without any large scale clinical data. USA pun boleh. You see, even a negative clinical trial can teach us so much, if properly done.

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