DALLAS, TX -In a more detailed evaluation of hospitalized and fatal heart-failure events, ALLHAT researchers report a post-hoc analysis showing that during year one of follow-up, the diuretic chlorthalidone was superior to both the ACE inhibitor lisinopril and the calcium channel blocker amlodipine in preventing these events, but over subsequent follow-up, lisinopril pulled even with the diuretic [1]. The advantage of chlorthalidone over amlodipine on heart-failure prevention remained over the latter period, although the magnitude of that difference was reduced.

The new paper does not really contain new data, but the pattern of drug effects over time has not been published before, said lead author Dr Barry R Davis (University of Texas School of Public Health, Houston).

"This analysis is limited to a more strict definition of heart failure, hospitalized and fatal heart failure, and looks at it over time," Davis told heartwire. It was pointed out after the original publication that there seemed to be more heart-failure events at the beginning than at the end of follow-up, he explained. "So we looked at it this way, and there was this phenomenon."

The study was published online May 1, 2006 and appears in the May 9, 2006 issue of Circulation.

ALLHAT was a double-blind, randomized trial in 33 357 high-risk hypertensive patients that compared lisinopril or amlodipine with chlorthalidone [2]. The primary end point of the trial, fatal coronary heart disease or nonfatal MI, was almost identical between groups, but there were differences in some secondary end points that led the researchers to conclude that diuretics should be considered the first choice for antihypertensive therapy in these patients.

Among the secondary end points that showed a difference between the drugs was heart failure, which was lowest overall with chlorthalidone, even relative to lisinopril, a somewhat surprising finding, since ACE inhibitors have previously been shown in large trials to prevent and treat heart failure.

In this study, the ALLHAT researchers report these heart-failure events in more detail. Analysis using proportional hazards models showed that relative to chlorthalidone, the risk of hospitalized and fatal heart failure was higher among those taking lisinopril and amlodipine.

However, the proportional hazards assumption of a constant relative risk over time "was not valid," the authors write. When the data were examined using a "more appropriate model," they note, they found that during year one, chlorthalidone was superior to both other drugs in preventing heart failure, with a greater than 50% reduction in incidence. Thereafter, chlorthalidone use resulted in significantly less HF than with amlodipine but was equivalent to lisinopril.

"Prior use of specific antihypertensive medications, concomitant open-label BP drugs, and follow-up BP differences could not individually account for all the observed treatment differences," the authors conclude. "Thus, diuretics are clearly preferred over [calcium channel blockers] overall and over ACE inhibitors at least in the short term in preventing HF."

"We speculate that diuretics have a more immediate effect, whereas ACE inhibitors may have a more long-term effect," Davis said.

In an editorial that will accompany the print publication [3], Dr Salim Yusuf (McMaster University, Hamilton, ON)—principal investigator on some of the large ACE inhibitor trials like SOLVD and HOPE—points out that previous literature supports the finding that calcium channel blockers do not have the same effect on heart failure as diuretics or ACE inhibitors.

"By contrast, the slightly higher rate of heart failure in the lisinopril group compared with chlorthalidone (RR of 1.09, p=0.09) neither meets conventional or adjusted levels of statistical significance and is not supported by other similar trials," Yusuf writes. "The post hoc subdivision of the events by time (under one year vs later) is methodologically suspect and not supported by other data, so it is not particularly persuasive," Yusuf writes.

From a clinical practice perspective, though, more than one drug is often required to adequately control BP, he notes. "My preference is to use a combination of a diuretic and an ACE inhibitor in most patients, given the results of various trials of diuretics in hypertension and the special benefits of ACE inhibitors on patients with heart failure and post-MI and other high-risk patients with vascular disease or renal dysfunction," he writes. "Some may prefer the combination of an ACE inhibitor and amlodipine, and this too is a reasonable choice." Further, some individualization of therapy based on specific clinical situations, tolerability, and cost is "sensible," he notes.

Yusuf concludes, though, that overall risk reduction should be the focus, including use of lipid-lowering agents, weight reduction, and smoking cessation. "So while the benefits of BP-lowering therapies are immediate and important, they should be complemented by societal interventions that lower the entire BP distribution. Such a combined approach will lead to an important reduction in the burden of CVD at all ages in most societies."