Dallas, TX - Of the four types of initial antihypertensive drug therapy compared in the ALLHAT trial, the thiazide diuretic chlorthalidone appeared to reduce the risk of heart failure with preserved ejection fraction (HFPEF) better than the other tested agents, which included the ACE inhibitor lisinopril and the calcium-channel blocker amlodipine, according to an analysis based on patients hospitalized for heart failure in the landmark trial [1].

The diuretic offered about the same protection as the ACE inhibitor against the onset of systolic heart failure, and both provided better protection than the calcium-channel blocker, according to the ALLHAT spin-off, the Heart Failure Validation Study (HFVS), which defined reduced and preserved LVEF as <50% and >50%, respectively.

"This reinforces the original ALLHAT message," lead author Dr Barry R Davis (University of Texas Health Science Center School of Public Health, Houston) told heartwire. "Our recommendation was, if you're going to start with just one drug, you should really consider a diuretic. A lot of people need two drugs, so in [HFVS] we said that perhaps you might consider an ACE inhibitor as the second drug."

They were thinking of other things. We were talking about preventing the onset of heart failure, not the treating of heart failure.

The HFVS analysis, in which heart-failure events in ALLHAT, according to the trial's prespecified criteria, were prospectively and blindly adjudicated, was published online November 10, 2008 in Circulation. It was limited to the overall trial's 910 participants who had been hospitalized with heart failure and in whom LVEF was objectively measured.

As extensively covered by heartwire, ALLHAT had randomized >40 000 patients with hypertension and at least one other CV risk factor, but no heart failure, to initiate BP-lowering therapy using one of the three agents or the alpha-blocker doxazosin [2]. The doxazosin arm was later terminated early when it appeared the drug was raising the risk of CV events, especially new heart failure.

The remaining groups, in which therapy had led off with the diuretic, ACE inhibitor, or calcium-channel blocker, fared about equally well over an average of five years for the trial's primary end point of fatal CHD or nonfatal MI.

But the ALLHAT investigators gave the edge, controversially, to the diuretic as the preferred first-line approach, based largely on advantages seen in some secondary outcomes: the thiazide was associated with less new heart failure than amlodipine and with less heart failure and stroke than lisinopril.

"One of the remarkable things when the study was over and we showed the [secondary] heart-failure results was that people were very willing to accept that the diuretic was better than the calcium-channel blocker or the alpha blocker, but they didn't believe that somehow it could be better than the ACE inhibitor," according to Davis. "They were thinking of other things. We were talking about preventing the onset of heart failure, not the treating of heart failure."

And now, with the HFVS, he said, "we see that for heart failure with preserved ejection fraction, diuretics are better than the ACE inhibitor, but for systolic heart failure, they're equivalent."

Dr William C Little (Wake Forest University School of Medicine, Winston-Salem, NC) writes in an accompanying editorial [3] that patients treated for hypertension "may be subsequently hospitalized with heart failure with the entire range of left ventricular ejection fractions. Treating hypertension is effective in reducing the risk of developing heart failure." He adds: "Initiating therapy with a thiazide diuretic in patients with hypertension and a normal ejection fraction is further supported by this important analysis of the ALLHAT data."

That the thiazide and ACE inhibitor as initial antihypertensive agents were similarly effective at reducing the risk of systolic HF "is consistent with previous observations that using an ACE inhibitor in patients with an ejection fraction <0.35 reduces the risk of subsequently developing heart failure," according to Little. "Thus, an ACE inhibitor should be included in the initial therapy in patients with hypertension and clearly reduced ejection fraction."

When the ejection fraction is normal or isn't known, he writes, "we do not know if a patient with hypertension will subsequently develop HFPEF or systolic HF. In these patients, the initial use of a thiazide would be reasonable. Adding an ACE inhibitor as a second step, if needed, would be reasonable" and is supported by other data.