Using national databases, we examined mortality in the 1761 participants who developed in-trial new-onset HF requiring hospitalization, and for whom mortality data were available (>99% of the cohort). Over three-quarters (77%) of the 1761 ALLHAT participants with initial HF events, fatal or requiring hospitalization, during the active, randomized phase of ALLHAT died over the extended follow-up period (mean follow-up time, 8.9 years). Mortality was high regardless of treatment group or EF category: all-cause 10-year mortality rates ranged from 83% in the chlorthalidone group to 87% in the lisinopril group. McCullough, et al., using administrative data sets exclusively, saw similar mortality rates among patients with heart failure in the community.21
In ALLHAT HF participants, mortality, whether attributed to any cause or limited to CVD or non-CVD causes, did not differ across randomized treatment comparisons; 10-year rates were 57%-66% for CVD and 55%-62% for non-CVD mortality. Among those with REF, 10-year mortality rates were similar across treatment groups (83%-87%); among those with PEF, mortality rates ranged from 81% in the chlorthalidone group to 89% in the lisinopril group.
The in-trial HF results of ALLHAT showed that the risk of HF defined as fatal, hospitalized or treated without hospitalization (ALLHAT prespecified endpoint) was higher in all comparator arms versus chlorthalidone (relative risk [RR]=1.38; 95% CI 1.25-1.52 and 1.19, 95% CI 1.07-1.31 for amlodipine and lisinopril, respectively, compared to chlorthalidone). For the amlodipine/chlorthalidone comparison for hospitalized or fatal HF, results were similar (RR=1.35; 95% CI 1.21-1.50); the lisinopril/chlorthalidone comparison showed no significant difference (RR=1.10, 95% CI 0.98-1.23).11, 12
These findings evoked questions as to diagnostic accuracy, relationship of HF to initial antihypertensive medications, and the eventual fate of the HF patients.22
Central adjudication validated the hospitalized HF diagnoses in the majority of patients (80% by Framingham criteria,23
71% by ALLHAT criteria, and 84% by reviewing cardiologists’ judgment), thus confirming results reported for the ALLHAT prespecified HF outcome (RR=1.46, 95% CI 1.27-1.68, P
<0.0001; and 1.18 [CI 1.02-1.28], P
=0.04, using ALLHAT diagnostic criteria for the amlodipine and lisinopril comparisons, respectively, with chlorthalidone).17
We have previously reported that the greatest benefit of thiazide-type diuretics in prevention of HF occurred during year 1 of follow-up.20
In seeking explanations for the early benefit, we explored whether discontinuation of medications at study entry could have contributed to the excess new-onset HF in the other drugs compared to chlorthalidone. A study of pre-ALLHAT medications taken by patients with incident in-trial HF showed no treatment group differences.24
We next sought to determine whether there were post-HF differences in survival (or, conversely, mortality) once patients were no longer subject to randomized medication assignments. The passive-follow-up of ALLHAT participants afforded us the opportunity to investigate long-term outcomes of the participants who developed their first hospitalized HF event during the active trial. It is clear from these data that, while randomized treatment groups did differ in HF incidence, mortality was similar and, as might be anticipated, high throughout.
New-onset HF is a common complication of hypertension and is associated with very high subsequent mortality, making prevention of HF an important goal of antihypertensive therapy.4, 23, 25
In ALLHAT, 6-year incidence rates of adjudicated hospitalized HF were comparable in magnitude to those of stroke (5.6%) and were about half those of CHD (CHD death or non-fatal MI; 11.4%).17
These data reiterate that, in spite of current treatments for HF, once it develops, the outcome is poor.26, 27
ALLHAT demonstrated that blood pressure control is an achievable goal in high-risk patients treated in diverse medical settings,16, 28
and that a regimen that includes a thiazide-type diuretic remains unsurpassed in the treatment of hypertension, especially in the prevention of HF within the population.
This study has several limitations. The high-risk hypertensive population of ALLHAT may not represent the general community, and outcomes may not be generalizable to a lower-risk population. Nonetheless, similar mortality rates among HF patients in the community have been reported.20
Lacking post-trial medication data on the HF participants, we cannot assess the impact of antihypertensive medications prescribed during the follow-up period. We do know that the majority of participants across the treatment groups were prescribed diuretics following the HF event. It is likely that many of the participants’ medications were altered as new events arose or new medications became available. Further, other post-trial management strategies, including revascularization, implantable devices, and medical therapy as directed by professional treatment guidelines, could modify biologic effects of prior treatment. However, during the in-trial phase, which included the incident HF event, the randomization process assured that, except for the randomized treatment, all other factors, including medications, should not have differed across treatment groups. As noted, in-trial hospitalized HF events were adjudicated via outside reviewers according to strict criteria.17
We did not, however, classify events according to ischemic vs. nonischemic HF. Finally, although the ALLHAT CTC Endpoints Department reviewed all in-trial events (through discharge/death summaries and death certificates), no such review or adjudication was possible for post-trial deaths, for which cause of death was derived from NDI-provided ICD codes. Patient identities associated with these documents were, however, vigorously confirmed through a complex algorithm, and so only specific causes of death may have been inconsistently reported.
In a national and international setting of increasing HF incidence and consequent high costs in lives lost and dollars, addressing modifiable risk factors must be a priority. In ALLHAT, treatment group differences in the risk of developing HF are clear; yet, once the HF develops, neither the type of HF as denoted by EF category nor initial antihypertensive treatment significantly impacts the very high subsequent mortality rates. Prevention of HF is a public health imperative, and a diuretic-based antihypertensive regimen remains a fundamental component of HF prevention.