They were reminding physicians of the ups and downs of clinical drug development (Lancet, 355:1568-9, 2000), and the occasion was the appearance of paper #7. Five years ago a trial called ELITE had hinted—no more, and the investigators were well aware of the tentative nature of the finding—that a member of a new class of cardiovascular drug might have a real impact on mortality in patients with heart failure. Great news, if it stood up, but it did not. ELITE II basically compared the new drug, the angiotensin II receptor (ATIIR) antagonist losartan, with the well-established agent captopril, which is an angiotensin-converting enzyme inhibitor (ACEI).

The 46% lowering of mortality by losartan found as a secondary endpoint in the first trial disappeared when all-cause mortality was a primary endpoint in the second. There was no difference between the two groups. Patients on the new drug were less likely to discontinue treatment because of side effects. We learn from another paper (Qual. Life Res., 9:377-84, 2000) that health-related quality of life improved similarly in both groups.

There are lots of "-sartans," just as there are several "-prils." I know of no large head-to-head comparisons of one ATIIR antagonist against another but it is useful to consider the generalizability of the outcome of ELITE II. For example, last December the Valsartan Heart Failure Trial was published (see J.N. Cohn, G. Tognoni, et al., New Engl. J. Med., 345:1667-75, 2001). Here valsartan or a placebo was given in addition to conventional therapy (which almost always included an ACEI). No difference for overall mortality was found but if morbidity (e.g., hospital admission because of heart failure) was added there was an advantage for the active drug. By February of this year a Canadian group (P. Jong, et al., J. Am. Coll. Cardiol., 39:463-70, 2002) was able to include in a meta-analysis no fewer than 17 trials, in over 12,000 patients, in which an ATIIR antagonist had been compared with an ACEI or with placebo with no ACEI in the regimen. Placebo controls may be important pharmacologically, but for heart failure this cannot be the pressing question for physicians, so it seems fair to pick out the ATII versus ACEI conclusion. The newer drugs were not better at reducing mortality or admission to hospital with heart failure; however, an ATII antagonist "as monotherapy in the absence of ACEIs or as combination therapy with ACEIs appears promising."

ELITE lead author Bertram Pitt (Am. J. Hypertens., 15:22S-27S, 2002) feels that from the evidence of ELITE II and the valsartan trial Val-HeFt, "ACE inhibitors remain the current therapy of choice in treating heart failure." Science Watch contacted the Mario Negri Institute in Milan, Italy, and asked Gianni Tognoni, from Val-HeFT, where the ATIIR antagonist class stands in mid-2002, in the context of heart failure. He thinks that they are "a real contribution to the treatment of heart failure because they can be safely included in the combined pharmacological strategies which are required to manage this condition." But they are, he adds, "by no means a breakthrough." The upcoming CHARM and VALIANT trial results may clarify the position.