RE: Studies in Circulation on etanercept (Enbrel)
I found the small study reported in Circulation to be intriguing, but preliminary. I noted that there was no change in ejection fraction in either the etanercept or the placebo group, whereas quality of life measures improved with the drug (but not with placebo). This would suggest to me that patients subjectively improved with etanercept, but casts doubt on whether long term outcome will be altered favorably. Left ventricular dysfunction is a very powerful predictor of morbidity and mortality, and ejection fraction is a good indication of left ventricular function. Since LVEF did not change with etanercept, long term outcome would not likely change. Nevertheless, improved quality of life is of no small value and should not be underestimated.
A second paper published in Circulation examined TNF alpha and TNF alpha converting enzyme (TACE) levels and activity in 30 heart failure patients and 5 controls. These investigators found that in myocardial biopsy specimens that TNF alpha mRNA was expressed in the heart failure patients, but not in control subjects; TACE mRNA expression was higher in heart failure patients than in controls; more advanced heart failure appeared to be associated with higher expression of TNF and TACE proteins and mRNAs.
TNF inhibition could ultimately be added to the pharmaceutical armamentarium useful in the treatment of heart failure, but I have some questions. Along these lines, it is useful to read the accompanying editorial by Gary S. Francis, MD. Although the overall tone of this editorial is cautiously hopeful, he points out that the numbers of patients are quite small, limited data is reported, inadequate comparisons with placebo are performed, and safest and most effective dosage levels are unknown. Also, the time course over which treatment should occur is not known, nor is it clear that the drug may not cause rebound hemodynamic deterioration after the drug is discontinued; the question of increased susceptibility to infection must be addressed; TNF clearly is a player in CHF, but the extent of it's role is not clear, and may be somewhat minor in relationship to other determinants of the syndrome. If so, TNF inhibition might not be of major importance in the treatment of CHF.
Hopefully, these and other questions will be addressed by the RENAISSANCE trial; I wonder if preliminary results from this trial may be ready in time for the American Heart Association Scientific Sessions in November. I'll keep an eye out.
My own impression is that it remains to be demonstrated compellingly that TNF metabolism significantly contributes to CHF; it could conceivably be primarily a result, rather than an important contributor to the pathology. On the other hand, I am taking these studies seriously because the market is huge (4.5 million in the U.S.; 15 million worldwide), and there is a need for more effective treatment. I suspect that TNF inhibition will be useful in some fraction of these ultimately. The size of this fraction remains to be determined, but will critically depend on the results of trials such as RENAISSANCE. However, if TNF inhibition takes a place alongside the standard first line therapies for CHF, the impact on IMNX will be huge, obviously.
Regards,
Walkingshadow
Disclosure: I am neither long nor short IMNX, but very interested and will probably take a long position at some point, the above notwithstanding.
WS |
