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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
J Clin Hypertens (Greenwich). Author manuscript; available in PMC 2013 January 1.
Published in final edited form as:
PMCID: PMC3261592
NIHMSID: NIHMS334311

Mortality and Morbidity during and after the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial

William C. Cushman, MD,1 Barry R. Davis, MD, PhD,2 Sara L. Pressel, MS,2 Jeffrey A. Cutler, MD, MPH,3 Paula T. Einhorn, MD, MS,3 Charles E. Ford, PhD,2 Suzanne Oparil, MD,4 Jeffrey L. Probstfield, MD,5 Paul K. Whelton, MB, MD, MSc,6 Jackson T. Wright, Jr, MD, PhD,7 Michael H. Alderman, MD,8 Jan N. Basile, MD,9 Henry R. Black, MD,10 Richard H. Grimm, Jr, MD, PhD,11 Bruce P. Hamilton, MD,12 L. Julian Haywood, MD,13 Stephen T. Ong, MD, MPH,14 Linda B. Piller, MD, MPH,2 Lara M. Simpson, PhD,2 Carol Stanford, MD,15 Robert J. Weiss, MD,16 and for the ALLHAT Collaborative Research Group17

Abstract

A randomized, double-blind, active-controlled, multicenter trial assigned 32,804 participants aged ≥55 years with hypertension and ≥1 other coronary heart disease risk factors, to receive chlorthalidone (n=15,002); amlodipine (n=8898); or lisinopril (n=8904) for 4 to 8 years, when double-blind therapy was discontinued. Passive surveillance continued for a total follow-up of 8 to 13 years, using national administrative databases to ascertain deaths and hospitalizations. During the post-trial period, fatal outcomes and nonfatal outcomes were available for 98% and 65% of participants, respectively, due to lack of access to administrative databases for the remainder. This paper assesses whether mortality and morbidity differences persisted or new differences developed over the extended follow-up. Primary outcome was cardiovascular mortality; secondary outcomes were mortality, stroke, coronary heart disease, heart failure, cardiovascular disease, and end-stage renal disease. For the post-trial period, data are not available on medications or blood pressure levels.

No significant differences (p < .05) appeared in cardiovascular mortality for amlodipine (HR 1.00 [0.93–1.06]) or lisinopril (HR 0.97 [0.90–1.03]), each compared to chlorthalidone. The only significant differences in secondary outcomes were for heart failure, higher for amlodipine (HR 1.12 [1.02–1.22]), and stroke mortality, higher for lisinopril (HR 1.20 [1.01–1.41]), each compared to chlorthalidone. Similar to the previously reported in-trial result, there was a significant treatment by race interaction for cardiovascular disease for lisinopril versus chlorthalidone; Blacks had higher risk than non-Blacks on lisinopril compared with chlorthalidone.. After accounting for multiple comparisons, none of these results were significant. These findings suggest that neither calcium channel blockers nor angiotensin converting-enzyme inhibitors are superior to diuretic in long-term prevention of major cardiovascular complications of hypertension.

Keywords: antihypertensive therapy, clinical trials, hypertension—general, pharmacologic (drug) therapy, clinical management of high blood pressure

Introduction

The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) was a multi-center randomized double-blind, active-controlled clinical trial, designed to determine whether the primary endpoint of fatal coronary heart disease (CHD) or nonfatal myocardial infarction (MI) was reduced among high-risk hypertensive patients (n=42,418) treated initially with a calcium channel blocker (CCB), an angiotensin converting enzyme inhibitor (ACEI), or an α-blocker—each compared with patients treated initially with a thiazide-type diuretic.1, 2 Prespecified secondary endpoints included all-cause and cause-specific mortality, stroke, heart failure (HF), cardiovascular disease (CVD), and end-stage renal disease (ESRD).

Participants in the chlorthalidone (n=15,255), amlodipine (n=9,048), and lisinopril (n=9,054) treatment groups were followed for a mean of 4.9 years.3 Neither the primary outcome nor all-cause mortality differed among treatment groups. There was a 38% higher HF rate with amlodipine, and a 10%, 15% and 19% higher rate of CVD, stroke, and HF, respectively, with lisinopril, compared with chlorthalidone. For stroke, there was a statistically significant race-by-treatment interaction (40% higher stroke rate with lisinopril vs. chlorthalidone in Blacks). Participants in the doxazosin treatment group (n=9061) were followed for a mean of 3.2 years. This arm was terminated early due to a 25% higher incidence of CVD events, including a nearly two-fold higher risk of HF, accompanied by very low probability of reaching a statistically significant difference in the primary endpoint.4, 5 Therefore, in this paper we do not address outcomes in participants treated with doxazosin, who had a shorter in-trial follow-up due to early termination of the treatment arm

Reasons for post-trial follow-up in long-term clinical trials include assessing 1) whether in-trial trends diminish, remain constant or increase (a legacy effect) with time);6 2) whether new beneficial effects develop (another type of legacy effect);7 3) long-term safety issues; and 4) downstream consequences of in-trial events. Research questions can be formulated as a change or persistence of hazard ratios for treatment versus control. Many previous outcome trials have examined long-term follow-up of randomized treatment groups after the randomized interventions were discontinued,815 even though limited to no data on medication use or concomitant variables (blood pressure [BP], cholesterol, etc.) are available in the post-trial period. The Systolic Hypertension in the Elderly Program (SHEP),9 like ALLHAT, did not have any post-trial follow-up data on BP or medication use. When follow-up data have been available in trials, medication use and intervention variables became similar in randomized groups within a few years after removal from randomized interventions.8, 13, 14

The purpose of this paper is to report mortality and morbidity of ALLHAT participants during 8 to 13 years after randomization using in-trial data plus post-trial data from administrative data bases to assess long-term effects of first-step antihypertensive treatment with a thiazide-type diuretic, a CCB, or an ACEI.

Further, we report whether significant differences in clinical outcomes observed during the trial persisted or disappeared post-trial (e.g., HF), the latter suggesting a relationship to current treatment; and whether significant differences emerged over the entire follow-up period for outcomes that were not statistically different at the trial’s end (e.g., CHD), suggesting a lag until maximum effect. Such comparisons of effects of different regimens during various time-frames could inform the initial choice for clinicians interested in long-term benefits. The primary prespecified outcome for these analyses is CVD mortality, the major endpoint relevant to the tested treatments that includes the most randomized participants.

Methods

Details of the design and main results have been published.25 Post-trial follow-up of participants through 2006 was accomplished using the National Death Index (NDI), Social Security Administration (SSA), Center for Medicare and Medicaid Services (CMS), and the United States Renal Data System (USRDS) databases. All participants gave written informed consent, and all centers obtained institutional review board approval for the trial. The institutional review board (IRB) of The University of Texas Health Science Center at Houston approved the long-term follow-up study.

ALLHAT participants

Eligible participants were men and women ≥55 years of age with untreated or briefly (<2 months) treated systolic blood pressure (SBP) 140–180 mmHg, and/or diastolic blood pressure (DBP) 90–110 mmHg, or who took antihypertensive medication (<3 drugs) for at least 2 months with blood pressure (BP) ≤160/100 mmHg. Participants also needed to have a prior CVD event, known atherosclerotic CVD (ASCVD), or another risk factor for CHD.3

Double-blind treatment protocol

The objective of ALLHAT was to compare newer classes of drugs—CCBs represented by amlodipine and ACEIs by lisinopril—with an established thiazide-type diuretic represented by chlorthalidone, in a randomized, double-blind trial. To optimize statistical power for multiple comparisons, the randomization ratio was 1.7:1 for the thiazide versus each of the comparator drugs. Within the protocol-prescribed daily dose range (chlorthalidone 12.5–25 mg, amlodipine 2.5–10 mg, lisinopril 10–40 mg), the dose of each step 1 blinded medication was titrated in an attempt to achieve BP<140/90 mmHg. If BP could not be controlled using the maximum dose of step 1 medication, open-label step 2 (reserpine, clonidine, or atenolol) and step 3 (hydralazine) medications were available from the ALLHAT drug distribution center. After initial titration visits, participants were seen routinely every 3 months during year 1 and every 4 months thereafter.

Laboratory Tests During Active Phase

Baseline laboratory test results for glucose, lipids, creatinine, and potassium levels were obtained after an overnight fast. Central laboratory performed the analyses. At years 2, 4, and 6, fasting total cholesterol and glucose levels were evaluated. Serum potassium and creatinine levels were measured at 1 month and years 1, 2, 4, and 6.

Extended Follow-up Outcomes: Definitions and Determination

Mortality Only Endpoints

Mortality data were available during both in-trial and post-trial periods for the entire cohort except for Canadian participants (n= 553, due to lack of availability of necessary identifying information)(Figure 1). In-trial deaths were ascertained by investigators and confirmed by death certificates, and post-trial deaths, from NDI and SSA. In-trial causes of death were determined by investigators. When the cause of death was reported as unknown, we used the NDI Plus database, which also provided cause-specific mortality for the post-trial period. Data from NDI and SSA used Social Security number, name, date of birth, and sex (NDI only) as matching criteria.

Figure 1Figure 1
a. CONSORT Diagram for All-Cause Mortality

CVD mortality (death due to CHD, stroke, HF, or other CVD) was designated a priori as the primary endpoint. Total mortality and categories of death were prespecified and assessed as important secondary outcomes.1

A death identified through NDI or SSA was verified at the ALLHAT Clinical Trials Center (CTC) after receipt and review of a death certificate from the state or other jurisdiction. Of 6492 death certificates requested for the groups compared herein, 6488 (99.9%) were received, and 6367 (98.1% of those received) were determined to be for an ALLHAT participant. Death certificates were not obtainable for 4 deaths; these deaths and their reported causes were included in the main analyses, as the matching algorithm had been demonstrated to be highly reliable. Causes of death (ICD-10 coding) from NDI Plus were collapsed into 11 categories.1 These were initally provided under the International Classification of Diseases (ICD) 9th revision; for deaths occurring in 1999 forward, the ICD-10th revision. The World Health Organization (WHO)’s Two-way Translator for the Ninth and Tenth Revisions (1997) was used to convert ICD-10 codes to ICD-9.16

Fatal and Nonfatal Endpoints

Hospitalization data were available for both in-trial and post-trial periods for the majority of participants. During the in-trial period, events were ascertained and classified by investigators and confirmed by the ALLHAT CTC based on discharge summaries. Unlike previous reports from ALLHAT, in-trial ESRD events (chronic dialysis or kidney transplant) were ascertained from the United States Renal Data System (USRDS). During the post-trial period, nonfatal events were ascertained from the Centers for Medicare and Medicaid Services (CMS [formerly HCFA]) and the USRDS. Events identified through CMS data were classified using the provided ICD-9 codes from those sources.

During the post-trial period, nonfatal outcome data, except for ESRD, are only available for participants from non-VA U.S. clinical centers who have valid Medicare or Social Security numbers (65% of all participants), due to lack of access for administrative reasons. The following fatal/non-fatal composites were prespecified as secondary endpoints: CVD (CVD death or hospitalized non-fatal MI, stroke, or HF), CHD (CHD death or hospitalized non-fatal MI), stroke (fatal or non-fatal hospitalized), HF (fatal or non-fatal hospitalized), and ESRD.

Details on how the databases were used to identify events are noted in our online protocol.1 For the post-trial period, data are not available on medications, BP levels, outpatient morbidity, or laboratory values.

Statistical Analysis

To compare baseline characteristics of participants assigned to amlodipine (A) or lisinopril (L) versus chlorthalidone (C), contingency tables and z-tests were used. Intermediate outcomes of BP and laboratory measures are presented at baseline and year 4. Evaluations of the effect of assigned treatment on primary and secondary outcomes for the entire follow-up period were performed using Cox regression. Prespecified tests for interactions were conducted to determine whether the effects of the treatment intervention differ between subgroups, defined by age, race, sex, or diabetes status. Time-dependent Cox regression was used to estimate hazard ratios (HRs) associated with treatment assignment separately for in-trial and post-trial periods. Given the many multivariate, subgroup, and interaction analyses performed, statistical significance at the .05 level should be interpreted with caution. A Bonferroni step-down or Holm’s procedure17 was also utilized to give further perspective on the multiple analyses examined.

Estimated 10-year event rates for CVD mortality, total mortality, CHD, stroke, HF, CVD, and ESRD in the chlorthalidone group were calculated using a Weibull survival model of the observed results in the original study projected out to 10 years. Statistical power for each analysis was obtained using these rates and sample sizes within various treatment groups and subgroups of ALLHAT. For the primary outcome, for example, we estimated we had 90% power with an α=.017 to detect a reduction in risk of 11.0% (HR=0.89) for each group compared with the chlorthalidone group (10 year CVD mortality rate of 16%).1, 18 For other power estimations, see the extension protocol.1

Results

Patient Characteristics

Table 1 presents participant characteristics at baseline for all participants included in the analyses of extension mortality and ESRD data. Mean baseline age was 67 years; 47% were women, 36% were black, 16% were Hispanic, and 43% had diabetes. There were nearly identical distributions of baseline factors in the 3 treatment groups for those included in the post-trial analyses and for all trial participants.19

Table 1
Baseline Characteristics of the ALLHAT Antihypertensive Component Participants – Chlorthalidone, Amlodipine, and Lisinopril (Excluding Canadian Participants)

Follow-up Cohorts

Figure 1a shows the number of participants randomized and followed to the end of 2006 for all-cause mortality and ESRD. Mean length of follow-up including the post-trial period was 8.8 years. Maximum follow-up was 12.9 years. Figure 1b shows the number of participants randomized and followed up to the end of 2006 for fatal/nonfatal CVD.

Intermediate Outcomes

Intermediate outcome results were explored for the mortality cohort and the morbidity/mortality cohort defined for these extension analyses. Since the mortality cohort only excludes the 553 Canadian participants (1.7% of the total cohort), intermediate outcome results are very similar to those for the total cohort and are not presented or described here.5 Intermediate outcome data for the morbidity/mortality cohort are shown in Table 2. Four-year mean SBP was similar among participants randomized to amlodipine (+0.3 mmHg, P=.33) to that among participants randomized to chlorthalidone, and significantly higher among participants randomized to lisinopril (~2 mmHg, P<.001) than among participants randomized to chlorthalidone. At 4 years total cholesterol was slightly higher (~2 mg/dl), serum potassium levels were lower (~0.3–0.4 mEq/L), and fasting glucose levels were higher (~3–4 mg/dl) in the chlorthalidone group compared with amlodipine and lisinopril. Incident diabetes was higher in the chlorthalidone group compared with the amlodipine (~1%, NS) and lisinopril (~3%, P=.008) groups. Follow-up estimated glomerular filtration rate (eGFR) was lower among participants assigned to chlorthalidone compared with those assigned to amlodipine (P<.001) but similar to the lisinopril group.

Table 2
Blood Pressure and Biochemical Results at 4 Years (In-Trial) by Treatment Group for the Mortality/Morbidity Cohort

Primary and Secondary Outcomes

Study events by treatment group are provided in Tables 3 and and44 and Figures 2 and and33.

Figure 2
Kaplan- Meier Plots
Figure 3Figure 3
a. Subgroup Results Through the Extended Follow-up – Amlodipine vs. Chlorthalidone
Table 3
Outcomes Through the Extension Period by Antihypertensive Treatment Group
Table 4
In-Trial and Post-Trial Hazard Ratios

Amlodipine vs. Chlorthalidone

No significant differences were observed between amlodipine and chlorthalidone for CVD mortality (HR=1.00; 95% CI, 0.93–1.06) or for the secondary outcomes of all-cause mortality, non-CVD mortality, and cancer mortality (Table 3, Figure 2). Other cause-specific mortality rates were also similar for the two groups. Fatal/hospitalized HF was higher among participants randomized to amlodipine (HR=1.12; 95% CI, 1.02–1.22). No significant differences were observed for the other combined fatal/nonfatal endpoints. There was a significant interaction by race (P=.04) for HF with a significantly increased hazard for amlodipine versus chlorthalidone for Blacks (HR=1.26; 95% CI, 1.09–1.46) but not for non-Blacks (HR=1.04; 95% CI, 0.93–1.17) (Figure 3a). There were 2 other significant treatment interactions noted: stroke mortality (P=.01) for treatment by age (age <65: HR 1.53[1.06–2.21], P= .02; age 65+: HR 0.89[0.73–1.09, P= .26]; when analyzed using age as a continuous variable, interaction of age*treatment was not significant[P=.18]).; and cancer mortality (P=.01) for treatment by sex (female: HR 1.20[1.02–1.40, P= .02]; male: HR 0.93[0.82–1.05, P= .26]).

No significant differences were observed between amlodipine and chlorthalidone by time period for the primary outcome of CVD mortality or for stroke mortality (Table 4). For HF mortality, cancer mortality, and mortality due to accidents, suicides, and homicides there were significant treatment by time period interactions (P=.02–.04). Post-trial HRs for these were not significant, except for HF mortality (post-trial HR=0.71; 95% CI, 0.51–0.98). In-trial HRs for HF mortality, cancer mortality, and trauma mortality were 1.17 (95% CI, 0.89–1.54), 0.92 (95% CI, 0.80–1.06); and 0.51 (95% CI, 0.31–0.83), respectively. No significant differences were observed between amlodipine and chlorthalidone by time period for fatal/nonfatal CVD or stroke. For HF, there was a significant interaction (P<.001) with in-trial HR of 1.37 (95% CI, 1.20–1.55) and post-trial HR of 0.93 (95% CI, 0.82–1.06). There were no significant treatment-time period-race interactions (data not shown).

Lisinopril vs. Chlorthalidone

No significant differences were observed between lisinopril and chlorthalidone for CVD mortality (HR=0.97; 95% CI, 0.90–1.03) or for secondary outcomes of all-cause mortality, non-CVD mortality or cancer mortality (Table 3, Figure 2). Other cause-specific mortality rates were also similar in the 2 groups (Table 3) except the lisinopril group had a 20% higher risk for stroke mortality (P=.03) with no significant interaction by race. Rates of combined fatal/nonfatal events, including stroke, were similar in the lisinopril and chlorthalidone groups. There was a significant interaction (P=.04) by race for the CVD outcome but the HR estimates for lisinopril versus chlorthalidone included 1.0 for both Blacks (HR=1.07; 95% CI, 0.98–1.17) and non-Blacks (HR=0.95; 95% CI, 0.88–1.01). There was a significant interaction (P=.03) by race for the HF outcome but the HR estimates for lisinopril versus chlorthalidone included 1.0 both for Blacks (HR=1.14; 95% CI, 0.98–1.33), and non-Blacks (HR=0.92; 95% CI, 0.82–1.04) (Figure 3b).

No significant differences were observed between lisinopril and chlorthalidone by time period for CVD mortality, stroke mortality, or HF mortality (Table 4). For the CVD mortality/morbidity outcome, there was a significant interaction (P=.02) with in-trial HR of 1.05 (95% CI, 0.98–1.14) and post-trial HR of 0.92 (95% CI, 0.85–1.00). For HF, there was a significant interaction (P=.04) with in-trial HR of 1.11 (95% CI, 0.97–1.27) and post-trial HR of 0.91 (95% CI, 0.80–1.04). For stroke, there was a significant interaction (P=.03) with in-trial HR of 1.17 (95% CI, 1.02–1.35) and post-trial HR of 0.94 (95% CI, 0.82–1.07). There were no significant treatment-time period-race interactions (data not shown).

Using p <. 05, there were 6 significant interactions (Table 3, Figures 3a and 3b) out of 180 analyses on the entire follow-up (18 outcomes × 5 (overall + 4 subgroups) categories × 2 treatment comparisons) and 7 significant interactions (Table 4) out of 36 analyses (18 outcomes × 2 treatment comparisons across time periods). Using the Holm’s procedure, in either case, the only significant result was for the amlodipine versus chlorthalidone comparison for HF for the in-trial HR of 1.37 versus the post-trial HR of 0.93 (see above).

Secondary sensitivity analyses using data captured entirely from databases (as in the post-trial period) for both the in-trial and post-trial periods showed similar results (data not shown).

Discussion

Findings from the ALLHAT extension study show that over the entire follow-up period, the only major outcomes that were significantly different were a higher HF rate with amlodipine compared with chlorthalidone (HR=1.12, P=.01) and a higher stroke mortality rate with lisinopril compared with chlorthalidone (HR=1.20, P=.03). The former result was mostly attributable to the in-trial difference and the latter result was due to the addition of events post-trial which converted a not quite significant in-trial result (HR=1.25, P=.05) to a significant one. Thus neither for this nor any other outcome, such as CHD, was there evidence of any lagged (late emerging) effect. In the post-trial period, there were only two differences in major outcomes: a lower HF mortality rate in the amlodipine group compared with the chlorthalidone group (HR=0.71; 95% CI, 0.51–0.98, P=.02 for heterogeneity comparing in-trial with post-trial); and a lower CVD rate in the lisinopril group compared with the chlorthalidone group (HR=0.92; 95% CI, 0.85–1.00, P=.02 for heterogeneity comparing in-trial with post-trial). These results could be consistent with many other post-trial results wherein the medications used, including the use of diuretics, likely became more similar across the randomized groups or could be due to chance. There was no difference in HF mortality (HR=.94; 95% CI 0.77–1.17) or in CVD (HR=0.99; 95% CI, 0.94–1.05) over the entire follow-up period. Although the apparent persistence or emergence (a legacy effect) of post-trial differences may seem plausible (as discussed below), it must be noted that post-trial comparisons are no longer protected by blinded randomized therapy. Legacy effects for antihypertensive treatment due to prevention of nonfatal events, attenuation of left ventricular modeling or prevention or regression of pathological or functional changes caused by hypertension have been shown for mortality, but mainly where the comparator is placebo or usual care.6

In-trial results in this reduced cohort for all-cause mortality, stroke mortality, fatal and non-fatal CVD events, and renal outcomes were similar to what had been reported previously from the entire trial population. Notably, such similarities for lisinopril compared with chlorthalidone included higher HRs for stroke mortality (HR of 1.26 originally, 1.25 here), combined CVD (CVD plus revascularizations and hospitalized angina) (HR 1.07 originally and 1.05 as CVD was defined in this analysis), and HF (1.11 originally and 1.11 here), although the CVD and HF HR’s were not statistically significant in this smaller cohort. The similarities for amlodipine compared with chlorthalidone included the significantly higher HR for HF (1.35 originally vs. 1.37 here), significantly lower non-CV mortality (0.90 originally and 0.89 here), and significantly lower trauma mortality (0.49 originally and 0.51 here). These non-CV and trauma mortality differences disappeared post-trial, suggesting that they were related to randomized treatment, but we have no plausible explanation; these associations may merit further study.

The overall results suggest that observed in-trial differences dissipated over time as participants were taken off blinded study medications and put on open-label therapy. With the exception of the HF and stroke mortality results, there was no evidence of a legacy effect. Unfortunately, post-trial antihypertensive medications usage is unknown. It is likely that treatments became similar across randomized groups, which would cause post-trial HRs to be close to one. For the lisinopril-chlorthalidone comparison, another possibility is that participants may have received thiazide-type diuretics added to ACEIs—which could lead to decreases in CVD rates compared with those who were simply continued on a thiazide. If such altered regimens were more common among Black participants, this could explain the proportionately greater narrowing of differences for stroke, and perhaps for HF, in Black compared with non-Black participants. These sub-group results contrast with those in the amlodipine-chlorthalidone comparison, where lowered post-trial HRs for HF were proportionately similar in Black and non-Black participants.

An additional possibility is that the in-trial to post-trial difference for CVD suggests some delayed effects (or a legacy effect) for lisinopril that may make it (or any ACEI) a desirable adjunct in antihypertensive regimens.2023 ACEIs have shown beneficial CVD effects in some other trials, especially in combination with thiazide-type diuretics, in treating patients with hypertension, diabetes, high CVD risk, or after strokes.2326

Overall, these long-term results from passive follow-up suggest that differences in major CVD outcomes between regimens diminished once the clinical trial stopped and the antihypertensive regimens most likely became similar. In addition, for CVD and all-cause mortality, as well as most other secondary outcomes (except for stroke mortality for lisinopril versus chlorthalidone), there were no new differences that appeared as a net result of any possible intermediate effects observed or not recognized during the trial. For example, differences in effects on glucose, lipids, HF or stroke did not apparently result in overall net differences in CVD or all-cause mortality. Specific effects on post-trial outcomes will be reported further in separate papers addressing participants who developed diabetes or HF, or changes in glucose or renal function, within the ALLHAT trial; long-term renal outcomes from the United States Renal Data System (USRDS) will also be further reported.

The extended follow-up study had several strengths. ALLHAT was the largest antihypertensive randomized controlled outcome trial conducted to date, with 32,804 participants in the 3 arms. Also, ALLHAT was a double-blind, randomized, active-controlled clinical trial with well-documented procedures for outcome ascertainment, which were supplemented by national databases to capture outcomes for both post-trial and in-trial events.

The analyses of the extended data set had several limitations. Participants were taken off blinded therapies at the trial’s end, and information about medications participants used post-trial was not available. BP and laboratory data were not obtained post-trial. It should be noted that medication use and/or blood pressures in other major randomized trials with post-trial follow-up have tended to converge.8, 10 All participants were not included in the analyses, i.e., 533 Canadian participants were in neither the mortality nor combined mortality/morbidity analyses, and neither VA participants (n = 5558) nor those without a Medicare number (n=5623) were in the combined mortality/morbidity analyses except for ESRD outcomes. Event ascertainment, except for ESRD, was not the same in-trial and post-trial (but when analyses were done capturing information from databases for both in-trial and post-trial periods, results were remarkably similar). Finally, many analyses were performed and only one was significant by a strict multiple comparison standard. Given these limitations, it is noteworthy that the in-trial HRs were quite similar to those observed in the original analyses that included all the participants.

In conclusion, these long-term follow-up results from the ALLHAT trial show that significant cardiovascular outcome differences observed during the trial did not persist except for an excess of HF in the amlodipine group compared with the chlorthalidone group. No new significant differences were observed over the entire follow-up period that had not been present in-trial with the exception of a higher stroke mortality rate for lisinopril compared with chlorthalidone. Lastly, no new differences in major outcomes developed post-trial, except for slightly lower major CVD events in the lisinopril group compared with the chlorthalidone group. However, there was no difference in major CVD events or CVD mortality over the entire follow-up period. These findings, therefore, suggest that neither calcium channel blockers nor angiotensin converting-enzyme inhibitors are superior to diuretic in long-term prevention of major cardiovascular complications of hypertension.27, 28

Acknowledgments

Funding/Support: This study was supported by contract NO1-HC-35130 with the National Heart, Lung, and Blood Institute (NHLBI). ALLHAT investigators received contributions of study medications supplied by Pfizer (amlodipine besylate and doxazosin mesylate), AstraZeneca (atenolol and lisinopril), and Bristol-Myers Squibb (pravastatin), and financial support provided by Pfizer Inc.

Role of the Sponsors: The National Heart, Lung, and Blood Institute sponsored the study and was involved in all aspects other than direct operations of the study centers. This included collection, analysis, and interpretation of the data plus the decision to submit the manuscript for publication. Pfizer Inc, AstraZeneca, and Bristol-Myers Squibb had no role in the design and conduct of the study, the collection, analysis, and interpretation of the data; or the preparation or approval of the manuscript.

Footnotes

Financial Disclosures:

The authors report no conflicts of interest with regard to this paper.

Michael H. Alderman has consulted for Astra-Zeneca, Merck, and Sankyo; has received honoraria from Bristol-Myers-Squibb and Merck; has had grants/contracts with Sankyo; and has held a financial interest in Merck.

Jan N. Basile has consulted for Abbott Laboratories, Boeringer Ingelheim, Daichi Sankyo, Forest Laboratories, Forest Pharmaceuticals, Merck, Novartis, Reddy Pharmaceuticals, Sankyo, and SmithKline Beecham/Glaxo Wellcome; and has received honoraria from Abbott Laboratories, Astra-Zeneca, Boehringer Ingelheim, Daichi Sankyo. Forest Laboratories, Merck, Novartis, and Pfizer;

Henry R. Black has consulted for Abbot Laboratories, Astra-Zeneca, Aventis, Bayer Corporation, Biovail, Boehringer Ingelheim, Bristol-Meyers Squibb, CVRx, Daichi Sankyo, Forest Pharmaceuticals, Gilead, GlaxoSmithKline, Horizons Pharmaceuticals, Intercure, Merck, Novartis, Pfizer, Sankyo, Sanofi Aventis, Sanofi-Synthelabo, Servier, and Takeda; has received honoraria from Biovail, Boehringer Ingelheim, Bristol-Myers Squibb, CV Therapeutics, Forest Laboratories, Merck, Novartis, Pfizer, Sanofi-Synthelabo, and Servier; and has had grants/contracts with Pfizer.

William C. Cushman has consulted for Abbott Laboratories, Bristol-Myers Squibb, Calpis, Daichi Sankyo, Forest Pharmaceuticals, Gilead Colorado, Johnson and Johnson, King, Myogen, Novartis, Pfizer, Pharmacopeia, Reddy Pharmaceuticals, Roche, Sankyo, Sanofi Aventis, Sanofi-Synthelabo, Sciele, Takeda, and Theravance; has received honoraria from Abbott Laboratories, Astra-Zeneka, Boehringer Ingelheim, Bristol-Myers Squibb, Forest Pharmaceuticals, King, and Novartis and has had grants/contracts with Abbott Laboratories, Biovail, King, and Novartis.

Barry R. Davis has consulted for BioMarin, Forest Pharmaceuticals, GlaxoSmithKline, Merck, Proctor and Gamble, and Takeda; and has held a financial interest in Amgen.

Charles E. Ford has consulted for BioMarin.

Richard H. Grimm, Jr has consulted for Calpis, Merck, Merck/SP, Novartis, Pfizer, and Takeda; has received honoraria from Astra-Zeneca, Merck, Novartis, and Takeda; and has had grants/contracts with Merck, Novartis, and Pfizer.

Bruce P. Hamilton has had grants/contracts with GlaxoSmithKline.

L. Julian Haywood has held a financial interest in Pfizer.

Stephen T. Ong has received honoraria from Novartis; and has had grants/contracts with Abbott Laboratories, Arena, Daichi Sankyo, Ferring, Forest Pharmaceutical, Gilead Colorado, GlaxoSmithKline, Mylan Bertek, Novartis, Pharmacopeia, Roche, Sankyo, and Sanofi Aventis.

Suzanne Oparil has consulted for Boehringer Ingelheim, Daichi Sankyo, Eli Lilly, Encysive Pharm, Forest Pharmaceuticals, GlaxoSmithKline, Merck, NicOx, Novartis, Pfizer, Salt Institute, Sankyo, Sanofi Aventis, Schering Plough, and SmithKline Beecham/Glaxo Wellcome; has received honoraria from Boehringer Ingelheim, Bristol-Myers Squibb, and Encysive Pharm; has had grants/contracts with Daichi Sankyo, Eisai Medical Research, Encysive Pharm, Gilead, Novartis, Pfizer, Sankyo, and Takeda; and has held a financial interest in Encysive Pharm.

Jeffrey L. Probstfield has consulted for Boehringer Ingelheim, King, and King Pharmaceuticals/Monarch; has received honoraria from Boehringer Ingelheim; and has had grants/contracts with Boehringer Ingelheim, King, King Pharmaceuticals/Monarch, KOS, and Sanofi Aventis.

Carol Stanford has held a financial interest in Pfizer.

Robert J. Weiss has had grants/contracts with Forest, Novartis, and Takeda.

Jackson T. Wright, Jr. has consulted for Abbott Laboratories, Astra-Zeneca, and Bayer Coroporation; Biovail,, CV Therapeutics, CVRx, Daichi Sankyo, Forest Pharmaceuticals, GlaxcoSmithKline, Merck, NitroMed, Novartis, Pfizer, Reliant Pharm, Sankyo, Sanofi Aventis, Sanofi-Synthelabo, and SmithKline Beecham/Glaxo Wellcome; and has had grants/contracts with GlaxcoSmithKline and Novartis.

Jeffrey A. Cutler, Paula T. Einhorn, Linda B. Piller, Sara L. Pressel, Lara M. Simpson, and Paul K. Whelton have no financial conflicts of interest to report.

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