Nottingham, UK - A new analysis of the Prospective Pioglitazone Clinical Trial in Macrovascular Events (PROactive) suggests that pioglitazone is associated with a reduction in many different definitions of major adverse cardiovascular events (MACE), not just the one selected as the secondary end point of the study [1].

PROactive compared treatment with pioglitazone (Actos, Takeda/Lilly) vs placebo in patients with type 2 diabetes at high risk for macrovascular events. The main results, reported in 2005, showed a nonsignificant 10% reduction vs placebo in the study's primary end point of all macrovascular events (all-cause mortality, nonfatal MI [including silent infarction], stroke, ACS, cardiac intervention [CABG or PCI], leg revascularization, or amputation above the ankle). The secondary composite end point of all-cause death, MI, and stroke was reduced by a significant 16%. But the authors have previously attracted criticism for focusing on this one secondary end point when the primary end point of the study was not significant.

The current paper, published online January 21, 2008 in the American Heart Journal, was written by a group led by Dr Robert Wilcox (Queen's Medical Centre, Nottingham, UK).

Wilcox commented to heartwire: "Because there was some controversy about our secondary end point, we decided to apply the PROactive data to other definitions of MACE often used in major clinical trials to see whether the results still held irrespective of which components of the MACE end point were included. We found a consistent reduction in events with all definitions with pioglitazone. This shows that we haven't been scrabbling around for one end point that was positive and that whichever MACE end point we used, we would have gotten a similar result."

In the current analysis, Wilcox et al investigated the additional prespecified MACE end point of cardiovascular death, MI and stroke and six additional post hoc MACE composites that have been used in other large-scale studies. Results showed that the additional prespecified end point was significantly reduced with pioglitazone, as were five of the six post hoc composites.

The researchers conclude: "The approximate 20% reduction in time to the MACE end points in this study with pioglitazone over placebo is important from a clinical viewpoint, because it was independent of presenting vascular disease and was achieved on top of existing standard management with cardiovascular medication. The decrease observed is similar to that seen in lipid-altering-drug outcome studies with a similar end point and patient population."

But Wilcox said that more efforts should be made to standardize MACE end points in cardiovascular trials. "It would be a good idea if cardiovascular trialists could agree on what the most appropriate MACE end points were. At the moment, we can't even agree on whether we should use death or cardiovascular death. There would need to be some variation, of course, with regard to different populations studied, but there could be some standardization, which would help in the interpretation of trial results," he commented.

But none of the MACE end points investigated included heart failure, which is a known side effect of both pioglitazone and rosiglitazone (Avandia, GlaxoSmithKline). Addressing this, Wilcox said there had been two PROactive papers dedicated to heart failure, with the conclusion that the fluid retention associated with pioglitazone does fit the clinical definition of heart failure, but that this does not result in any increase in deaths due to heart failure. "This raises the issue of whether it is actually heart failure or just fluid retention," he added.

Wilcox highlighted the fact that the cardiovascular clinical-event data with pioglitazone appear to differ from those with rosiglitazone. "All the data on rosiglitazone seem to suggest an increase in events, whereas there seems to be a reduction with pioglitazone." He suggested that although the two drugs are members of the same class, they were chemically different, and that may give them different effects. "One of the first beta blockers to be developed—practolol—ran into terrible problems with side effects, but atenolol differs by the position of just one methyl group and has none of the same adverse effects, so just one trivial change can result in a marked change in clinical effect. This may also be the case for rosiglitazone and pioglitazone," he commented to heartwire, adding that maybe the only way to prove it will be to conduct a head-to-head study.