Dallas, TX - A retrospective look at a randomized trial that had found no overall survival benefit from the ACE inhibitor trandolapril among patients with stable CAD and preserved LV function suggests that mortality did fall among the subgroup with compromised renal function [1].

The published primary findings of the Prevention of Events with ACE Inhibition (PEACE) trial saw no such outcomes benefit even among its patients with a below-average creatinine clearance [2]. But the post hoc analysis showed there was a trandolapril-associated 27% reduction (p=0.05) in all-cause mortality among those with the poorest renal function compared with the best as measured by estimated glomerular filtration rate (eGFR), according to the authors, Dr Scott D Solomon (Brigham and Women's Hospital, Harvard Medical School, Boston, MA) and colleagues. Their report in Circulation appears online June 26, 2006 and is scheduled for the journal's July 4 issue.

The group's original finding of no overall survival benefit had lent greater perspective to the seemingly contrary results of two other major trials, HOPE [3] and EUROPA [4], both of which found that an ACE inhibitor seemed to reduce the risk of mortality and other clinical events in patients with chronic, stable CAD.

The authors are adding to the very interesting series of observations that indicate that blockers of the renin-angiotensin system might be particularly useful in people with impaired renal function. Why that is is not entirely clear.

In the placebo-controlled HOPE, ramipril for up to six years was associated with a highly significant 22% reduction in the composite rate of CV death, MI, or stroke among >9000 patients with CAD plus either vascular disease or diabetes and one other major heart-disease risk factor. Among the >12 000 patients in EUROPA's broader stable-CAD population, perindopril-randomized patients showed a 20% reduction in the end point of CV death, MI, or cardiac arrest over an average of four years.

That the clinical benefits in PEACE appear limited to those with a low GFR, they write, "may be related to the relatively low-risk PEACE population" compared with those in the other trials, according to Solomon et al. The HOPE, EUROPA, and PEACE trials have previously been extensively covered by heartwire.

Speaking with heartwire, Dr Michael Weber (State University of New York Downstate College of Medicine, Brooklyn) observed that patients in PEACE were seen as lower risk, at least in the short term, than those of HOPE and EUROPA—despite "their fair number of risk factors and even previous events"—because they were so well managed with statins, antiplatelets, and other interventions.

These results indicate that  . . . low eGFR defines a population most likely to benefit from ACE-inhibitor therapy for cardiovascular protection.

He added that the subanalysis results are "consistent with what we have seen in other studies in patients with reduced renal function—for example, in patients with diabetic nephropathy treated with angiotensin receptor blockers." Still, the authors "are adding to the very interesting series of observations that indicate that blockers of the renin-angiotensin system might be particularly useful in people with impaired renal function. Why that is is not entirely clear."

The PEACE trial had randomized 8290 patients with stable CAD and an LVEF >40% to receive trandolapril at up to 4 mg/day or placebo and followed them for an average of almost five years. According to the post hoc analysis of the 8280 patients for whom GFR could be estimated:

• The mean eGFR overall was 77.6 mL/min per 1.73 m², and 16.3% of the population had "reduced" renal function defined as an eGFR <60 mL/min.
• The hazard ratio (95% CI) for total mortality among trandolapril-treated patients with an eGFR <60 mL/min was 0.73 (0.54-1.00) and 0.94 (0.78-1.13) for the subgroup with "preserved" renal function (eGFR >60 mL/min) compared with an eGFR >75 mL/min.
• "Similar trends" were observed for CV mortality, but not for the PEACE primary composite end point of CV death, nonfatal MI, or revascularization, according to the authors.

An inverse relationship and a "significant interaction" (p<0.02) existed between eGFR and all-cause and CV mortality, they write. Whereas those risks climbed with sinking eGFR in the overall population, trandolapril attenuated the effect in multivariate analysis. Among control patients, each 10-unit reduction in eGFR independently raised CV and all-cause mortality by 7% (p=0.04). But the corresponding increase in those risks among trandolapril-treated patients reached only 1% (p=0.72).

Although they are merely hypothesis generating, write the authors, "these results indicate that ACE inhibition may be most effective at lowering the risk in patients with a low eGFR and that low eGFR defines a population most likely to benefit from ACE-inhibitor therapy for cardiovascular protection." The findings therefore suggest that "renal function should be evaluated and considered when considering which low-risk patients to treat with ACE inhibition."