More, From Dr. Liu's Reply Letter -- in Circulation. . . .

To enter the long holiday weekend, I'll return, at least briefly, to the exchange of letters, set in this month's Circulation about the latest cholesterol management studies:

. . . .From the results of the Pravastatin or Atorvastatin Evaluation and Infection Therapy/Thrombolysis in Myocardial Infarction 22 (PROVE-IT/TIMI 22) and the Treating to New Targets (TNT) trials, it is clear that a greater reduction in LDL-C with either a more potent statin, a higher dose of statin, or both leads to a greater reduction in cardiovascular events. What is not known is whether there are any differences in cardiovascular outcomes depending on how you achieve the LDL-C goal. This will hopefully be addressed indirectly in the Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT), especially if the results turn out to be negative, because LDL-C levels will be lower in the Vytorin group. . . .

As pointed out by Westerink and Visseren, there are conflicting results from other studies with regard to statin monotherapy versus statin/ezetimibe combination therapy on endothelial function. One possibility is that some of these previous clinical studies lacked a control-placebo group to distinguish whether changes in flowmediated dilation (FMD) could have occurred by chance. Without a comparable placebo group, it is not possible to definitively conclude that the reduction in LDL-C and improvement in FMD are causal.

Furthermore, our findings are in agreement with the results of other studies showing that ezetimibe, either alone or in combination with statins, is less effective in improving endothelial function than statin monotherapy. . . .

The above is in response to a letter by Dr. Enrico Veltri -- yes, he of "tell him to f*ck off" fame -- who is still fighting the last (largely lost) war, in another of these letters:

. . . .The article in Circulation by Liu et al. claims that statin monotherapy provides greater “pleiotropic effects” than low-dose statin with ezetimibe due to the effects on Rho-kinase activity, which is postulated to play a role in flow-mediated dilation (FMD), a surrogate marker for endothelial function. We believe this article has significant limitations related to its design, presentation and conclusions.

Ezetimibe would not be expected to directly influence Rho-kinase activity, so the treatment group differences in Rho-kinase activity in this study are expected. However, the clinical significance of changes in Rho-kinase activity with respect to cardiovascular risk is entirely speculative. . . .

Pasternak and Tershakovec are employees of Merck, and they own stock and stock options in the company. Dr. Veltri is an employee of Schering-Plough Corporation and owns stock and stock options in the company. . . .

Sincere Hat Tip: Marilyn Mann, for the reprints!