Published Online
on November 10, 2008

A more recent version of this article appeared on November 25, 2008

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Submitted on January 23, 2008
Accepted on September 3, 2008

Heart Failure With Preserved and Reduced Left Ventricular Ejection Fraction in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial

Barry R. Davis MD, PhD^*, John B. Kostis MD, Lara M. Simpson PhD, Henry R. Black MD, William C. Cushman MD, Paula T. Einhorn MD, Michael A. Farber MD, Charles E. Ford PhD, Daniel Levy MD, Barry M. Massie MD, Shah Nawaz MD, for the ALLHAT Collaborative Research Group

From the University of Texas Health Science Center School of Public Health, Houston (B.R.D., L.M.S., C.E.F.); UMDNJ–Robert Wood Johnson Medical School, New Brunswick, NJ (J.B.K.); New York University School of Medicine, New York, NY (H.R.B.); Memphis Veterans Affairs Medical Center, Memphis, Tenn (W.C.C.); Division of Prevention and Population Sciences, National Heart, Lung, and Blood Institute, Bethesda, Md (P.T.E.); Crozer Keystone Health Network, Upland, Pa (M.A.F.); Framingham Heart Study/National Heart, Lung, and Blood Institute, Framingham, Mass (D.L.); and San Francisco Veterans Affairs Medical Center, San Francisco, Calif (B.M.M.).

^* To whom correspondence should be addressed. E-mail: barry.r.davis{at}uth.tmc.edu.

Background—Heart failure (HF) developing in hypertensive patients may occur with preserved or reduced left ventricular ejection fraction (PEF [50%] or REF [<50%]). In the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), 42 418 high-risk hypertensive patients were randomized to chlorthalidone, amlodipine, lisinopril, or doxazosin, providing an opportunity to compare these treatments with regard to occurrence of hospitalized HFPEF or HFREF.

Methods and Results—HF diagnostic criteria were prespecified in the ALLHAT protocol. EF estimated by contrast ventriculography, echocardiography, or radionuclide study was available in 910 of 1367 patients (66.6%) with hospitalized events meeting ALLHAT criteria. Cox regression models adjusted for baseline characteristics were used to examine treatment differences for HF (overall and by PEF and REF). HF case fatality rates were examined. Of those with EF data, 44.4% had HFPEF and 55.6% had HFREF. Chlorthalidone reduced the risk of HFPEF compared with amlodipine, lisinopril, or doxazosin; the hazard ratios were 0.69 (95% confidence interval [CI], 0.53 to 0.91; P=0.009), 0.74 (95% CI, 0.56 to 0.97; P=0.032), and 0.53 (95% CI, 0.38 to 0.73; P<0.001), respectively. Chlorthalidone reduced the risk of HFREF compared with amlodipine or doxazosin; the hazard ratios were 0.74 (95% CI, 0.59 to 0.94; P=0.013) and 0.61 (95% CI, 0.47 to 0.79; P<0.001), respectively. Chlorthalidone was similar to lisinopril with regard to incidence of HFREF (hazard ratio, 1.07; 95% CI, 0.82 to 1.40; P=0.596). After HF onset, death occurred in 29.2% of participants (chlorthalidone/amlodipine/lisinopril) with new-onset HFPEF versus 41.9% in those with HFREF (P<0.001; median follow-up, 1.74 years); and in the chlorthalidone/doxazosin comparison that was terminated early, 20.0% of HFPEF and 26.0% of HFREF patients died (P=0.185; median follow-up, 1.55 years).

Conclusions—In ALLHAT, with adjudicated outcomes, chlorthalidone significantly reduced the occurrence of new-onset hospitalized HFPEF and HFREF compared with amlodipine and doxazosin. Chlorthalidone also reduced the incidence of new-onset HFPEF compared with lisinopril. Among high-risk hypertensive men and women, HFPEF has a better prognosis than HFREF.

Key words: angiotensin-converting enzyme inhibitors • antihypertensive agents • calcium channel blockers • diuretics • heart failure • hypertension • ventricular ejection fraction

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