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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptNIH Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
Arch Intern Med. Author manuscript; available in PMC May 11, 2010.
Published in final edited form as:
PMCID: PMC2803011
NIHMSID: NIHMS163673
ALLHAT FINDINGS REVISITED IN THE CONTEXT OF SUBSEQUENT ANALYSES, OTHER TRIALS AND META-ANALYSES
Jackson T. Wright, Jr, MD, PhD,[1] Jeffrey L. Probstfield, MD,[2] William C. Cushman, MD,[3] Sara Pressel, MS,[4] Jeffrey A. Cutler, MD, MPH,[5] Barry R. Davis, MD, PhD,[4] Paula T. Einhorn, MD, MS,[5] Mahboob Rahman, MD,[1] Paul K. Whelton, MD, MSc,[6] Charles E. Ford, PhD,[4] L. Julian Haywood, MD,[7] Karen L. Margolis, MD, MPH,[8] Suzanne Oparil, MD,[9] Henry R. Black, MD,[10] and Michael H. Alderman, MD[11], for the ALLHAT Collaborative Research Group
[1] Case Western Reserve University, Cleveland, Ohio
[2] University of Washington Clinical Trials Service Unit, Seattle, Washington
[3] Veterans Affairs Medical Center, Memphis, Tennessee
[4] University of Texas Health Science Center at Houston School of Public Health, Houston, Texas
[5] National Heart, Lung, and Blood Institute, Bethesda, Maryland
[6] Loyola University Medical Center and Health System, Maywood, Illinois
[7] University of Southern California Medical Center, Los Angeles, California
[8] Health Partners Research Foundation, Minneapolis, MN
[9] University of Alabama at Birmingham, Birmingham, Alabama
[10] New York University School of Medicine, New York, New York
[11] Albert Einstein College of Medicine Department of Epidemiology and Social Medicine, Bronx, New York
Correspondence: Sara L. Pressel, M.S. Project Manager ALLHAT Clinical Trials Center University of Texas at Houston Health Science Center School of Public Health 1200 Herman Pressler, Houston, TX 77030 Telephone: (713) 500-9520 Fax: (713) 500-9530 ; Sara.L.Pressel/at/uth.tmc.edu
Background:
This paper re-evaluates the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) considering information from new clinical trials, meta-analyses, and recent ALLHAT analyses, especially those regarding heart failure and the association of drug treatment with new-onset diabetes (NOD) and its cardiovascular disease (CVD) consequences.
Methods:
Subgroup and explanatory analyses from a long-term 4-arm double-blind randomized antihypertensive treatment trial in diverse North American settings.
Results:
Chlorthalidone was superior to 1) doxazosin in preventing combined CVD (CCVD) (RR=1.20, 95% CI 1.13-1.27), especially HF (RR=1.80, CI 1.40-2.22) and stroke (RR=1.26, CI 1.10-1.46); 2) lisinopril, in preventing CCVD (RR=1.10, CI 1.05-1.16), including stroke (in Black persons only) and HF (RR=1.20, CI 1.09-1.34); and 3) amlodipine, in preventing HF, overall (by 28%) and in hospitalized/fatal cases (by 26%). Central independent blinded re-review of HF hospitalizations confirmed each comparison. Results were consistent by age, sex, race (except for stroke and CCVD), diabetic status, metabolic syndrome status, and renal function level. Neither amlodipine nor lisinopril was superior to chlorthalidone in preventing end-stage renal disease overall, by diabetes status or by renal function level. In the chorthalidone arm, NOD was not significantly associated with CCVD (RR=0.96, CI 0.88-2.42).
Conclusions:
Evidence from subsequent analyses of ALLHAT and other clinical outcome trials confirm that neither α-blockers, ACE-inhibitors nor calcium channel blockers surpass thiazide-type diuretics (at appropriate dosage) as initial therapy for reduction of cardiovascular or renal risk. Thiazides are superior in preventing heart failure, and new-onset diabetes associated with thiazides does not increase CVD outcomes.
The Antihypertensive and Lipid-Lowering Treatment to prevent Heart Attack Trial (ALLHAT), a clinical outcome trial in 42,418 high-risk hypertensive patients, compared four classes of antihypertensive agents as initial therapy of hypertension for their effect on cardiovascular (CVD) outcomes and published its main results in 2002. Some trial findings were unexpected and generated much discussion and several questions.(1-3). Despite the favorable metabolic effects of α-blocker and the angiotensin converting enzyme inhibitor (ACEI), and the demonstrated benefits of inhibitors of the renin-angiotensin-aldosterone system versus placebo in well-conducted outcome trials, these advantages did not translate into improvement for CVD or renal outcomes.(4-6) Since publication of the ALLHAT results, new clinical trials and meta-analyses have been reported, and ALLHAT data have been further analyzed.(6-16) Continuing attention to the issue of preferred antihypertensive drugs prompt a re-assessment of ALLHAT in light of the new information derived from these data,(17;18) with special emphasis on the heart failure findings and the association of drug use with new-onset diabetes and its CVD consequences.
ALLHAT Design and Main Results
ALLHAT was a randomized, double-blind, multicenter clinical trial, designed to determine whether incidence of major coronary heart disease (CHD) events (nonfatal MI and CHD death; primary endpoint) is reduced in high-risk (defined by age ≥ 55 years with at least one additional CVD risk factor [e.g. left ventricular hypertrophy, history of diabetes, current cigarette smoking, high density lipoprotein cholesterol < 35 mg/dl or < 0.91 mmoles/l, or documented history of atherosclerotic CVD]) hypertensive patients by a calcium-channel blocker (CCB; represented by amlodipine), an ACEI (represented by lisinopril), or an α-blocker (represented by doxazosin), each compared with diuretic (represented by chlorthalidone) as first-step therapy.(19). Overall findings of the trial, summarized in Figure 1, showed that CHD (fatal CHD plus nonfatal MI) risk was not improved for any of the 3 newer agents compared with chlorthalidone as first-step therapy.(1;2) However, diuretic-based therapy was superior to α-blocker, ACEI, and CCB-based therapies in preventing one or more major forms of CVD, including stroke and heart failure (HF).
Figure 1
Figure 1
Figure 1
Figure 1
Figure 1a. Blood pressure (BP) difference and relative risks (95% confidence intervals) for clinical outcomes for newer agents compared to chlorthalidone 12.5-25 mg/day in pre-specified subgroups – amlodipine vs. chlorthalidone. Coronary heart (more ...)
Chlorthalidone was superior to doxazosin in prevention of combined CVD, especially HF and stroke. Chlorthalidone was superior to lisinopril in preventing combined CVD, including stroke (in black persons only), HF, angina, and coronary revascularizations. Chlorthalidone was superior to amlodipine in preventing HF, overall (by 28%) and in hospitalized or fatal cases (26%). These results were consistent by age, sex, diabetic status and level of renal function for all outcomes, and by race, except for stroke and combined CVD (see below). Amlodipine and lisinopril were not superior to chlorthalidone in preventing end-stage renal disease (ESRD) overall, or when stratified by diabetes or baseline estimated glomerular filtration rate (GFR).(7;8)
Results in Subgroups (Figure 1)
ALLHAT, by design, recruited a very diverse patient population allowing important pre-specified subgroup analyses by gender, age, race and diabetic status. This was the most diverse experience to date for comparison of antihypertensive drug therapy in adults with diabetes mellitus (n=13,101) and impaired fasting glucose (n=1399).(2;9) There was no evidence of superiority for treatment with α-blocker, CCB or ACEI compared to diuretic in any glycemic stratum. In diabetic and non-diabetic ALLHAT participants, HF was significantly less frequent among participants assigned to diuretic than among those assigned other treatments.(2;9;10) Thus, compared to diuretic-based treatment, CCB and ACEI-based therapies failed to demonstrate superiority in the prevention of CVD or ESRD in diabetic participants.
ALLHAT was also the first large randomized controlled trial to provide a head-to-head comparison of major drug classes in a substantial number of Black participants (n=15,094) and persons 65 and older (n= 24,330).(1;8;11;20) In both subgroups, there was no evidence of significant superiority for primary or major secondary outcomes in those assigned to the α-blocker, CCB or ACEI versus the diuretic. Other apparent benefits of diuretic therapy included better reduction in BP (4 mmHg difference at four years), stroke incidence and CCVD compared to ACEI in Blacks. Also CCB was more effective than ACEI in this population for BP reduction and prevention of stroke.(21)
ALLHAT findings generated considerable discussion, and several questions about the results were raised. The remainder of this article addresses those issues in the context of newly available information.
Implications of the Blood Pressure Differences on Interpretation of ALLHAT Findings
Goal BP in ALLHAT was <140/90 mmHg in all four treatment groups. Intensification of therapy was required by protocol if BP was not controlled. During the trial, small but significant differences in achieved BP levels occurred among randomized treatment groups (Fig 1). SBP was higher in participants randomized to doxazosin (by 2-3 mmHg), lisinopril (by 2 mmHg [4 mmHg in Blacks]), and amlodipine (by <1 mmHg) than in those on chlorthalidone. BP differences in Blacks accounted for the major BP difference between treatment arms, particularly between the ACEI and diuretic arms. However, non-Black participants made up 2/3rd of the study population. Despite negligible BP differences between treatment arms in the non-Black group, newer agents did not offer an advantage over diuretic.(8;11)
ALLHAT was not the only clinical trial to report differences in achieved BP levels across randomized treatment groups. Perfect comparability in achieved BP is unlikely in a double-blind randomized practice-based trial due to differences in intrinsic BP-lowering efficacy of agents and/or synergistic efficacy with available add-on therapies.(5;12;22) Serial median matching has been used in some studies to account for the observed differences in achieved BP levels.(22;23) This approach leaves out substantial amounts of participant information, is susceptible to bias, disturbs randomized comparison (may interject bias), and favors the drug less effective in lowering BP. ALLHAT has reported analyses using achieved BP levels as time-dependent covariates in a Cox proportional hazard regression model showing that after adjustment for BP, the differences in risk of stroke and HF between treatment arms remain statistically significant, with only slight reduction in the RR.(1;2;13;24) However, the Blood Pressure Lowering Treatment Trialists' Collaboration (BPLTTC) meta-analysis reported that differences in achieved BP reduction between randomized groups accounted for the observed difference in risk for every outcome except HF.(6) Therefore, BP differences may account for some but not all of the advantages seen with chlorthalidone.
Do Chlorthalidone Findings Generalize to Other Thiazide-type Diuretics?
Since chlorthalidone is not widely used in practice, clinicians have questioned why it was chosen as the comparator agent. Previous NHLBI-sponsored trials (HDFP(25), SHEP(26), and MRFIT in post-hoc subgroup analyses(27) showed beneficial effects on clinical outcomes with this agent. Comparison of doses of chlorthalidone used with standard thiazides is a subject of considerable discussion. Recent data suggest a 1 ½-2 fold greater antihypertensive potency for chlorthalidone in comparison to HCTZ.(28) A meta-analysis of trials using other thiazide-type agents reported similar clinical cardiovascular outcomes across the class.(29) However, these studies used higher doses of these agents than the 12.5-25 mg/day dose of HCTZ currently used in clinical practice and one recent outcome trial (see below). Thus, at doses equivalent to that used in ALLHAT (chlorthalidone, average of 20 mg/day),(30) it is likely that attributes of chlorthalidone extend to others in the class.
Validity of the Heart Failure Results in ALLHAT
In ALLHAT, HF was a pre-specified outcome encompassing fatal and non-fatal treated HF whether participants required hospitalization or not. It was defined in the Manual of Operations as a combination of symptoms and signs/test findings, similar to methods used in other studies.(14;31) Individuals with a history of symptomatic HF and/or known ejection fraction<35% were not eligible for randomization. When the initial publications from ALLHAT reported that chlorthalidone-based treatment was superior to each of the three other agents in preventing new-onset HF,(1;2) some found these results unexpected and raised questions about their validity.(3) Given the public health importance of HF among older individuals, extensive steps to validate these findings were undertaken. The ALLHAT Heart Failure Validation Study rigorously evaluated all hospitalized HF events, using independent blinded-to-treatment-assignment reviewers.(14) Source documentation for HF hospitalizations (n=2778 in 1935 patients) was centrally reviewed using pre-specified algorithms (based on SHEP/ALLHAT and Framingham criteria) and reviewers' global clinical judgment. This review confirmed site-physicians' diagnoses in the majority of patients (71%, 80%, and 84% respectively using ALLHAT, Framingham and reviewer diagnoses). More importantly, the originally reported higher risk of HF associated with first-step therapy using amlodipine, lisinopril or doxazosin compared with chlorthalidone was confirmed by RRs calculated when applying various validation criteria. RRs across criteria sets ranged as follows: 1.41-1.46 for amlodipine, 1.12-1.21 for lisinopril, and 1.71- 1.80 for doxazosin, each compared with chlorthalidone. Results of other active drug comparison trials are mixed, but overall consistent with the ALLHAT findings.(6;12;32) Mortality risk subsequent to hospitalized HF (over 50% at 5 years) underscores the importance of preventing new-onset HF in high-risk patients, and provides an indirect validation of the diagnosis. Thus, thiazide-type diuretics would appear to provide better protection against new-onset HF (particularly HF with preserved ejection fraction) in high-risk patients with hypertension,(14;33) though treatment of patients with established HF should follow appropriate guidelines.(34;35)
Implications of Diuretic-Associated Diabetes on Long-Term CVD Risk
An important ALLHAT rationale was to determine whether newer drugs with more favorable effects on glucose and other metabolic parameters would result in a lower incidence of major clinical outcomes, especially coronary events, compared with diuretics. As anticipated from previous studies, diuretic treatment resulted in 4-6 mg/dl higher fasting plasma glucose levels compared with other agents. Among non-diabetic participants (baseline fasting glucose level<126 mg/dl), mean baseline fasting glucose level was approximately 94 mg/dl in all groups.(15) Fasting glucose levels increased in all treatment groups, with the largest increase in the chlorthalidone group to 104 mg/dl at 4 years. The increase was intermediate in the amlodipine arm (to 102 mg/dl at 4 years) and smallest in the lisinopril (to 100 mg/dl at 4 years) and doxazosin arms (to 99 mg/dl at 4 years).
The proportion of participants who developed levels of fasting glucose consistent with diabetes (>125 mg/dl) after 4 years was 11.6% in the chlorthalidone group, compared to 9.8% in the amlodipine (p=0.01) and 7.8% in the lisinopril (p<0.001) groups. In the doxazosin arm, the comparison with chlorthalidone was 8.8% vs. 10.6%, although (due to early termination of the doxazosin arm) values are available for less than 10% of participants at 4 years. Assuming that CCBs are metabolically neutral, comparison of 4-year rates of incident diabetes in the amlodipine versus chlorthalidone arms (9.8% versus 11.6%), suggests that only 17% of new-onset diabetes associated with thiazide use in studies like ALLHAT is likely due to the diuretic (diuretic-induced as opposed to diuretic-associated changes).(36)
Despite showing that diuretics were at least as effective as newer agents in preventing major clinical outcomes, ALLHAT results seemed to heighten rather than lessen the interest in diuretic-induced dysglycemia. However, focus changed from speculations regarding significance of the absolute increase in glucose levels to a focus on increases in incident diabetes. This focus suggested that the risk of CVD events in diuretic-treated patients is more dependent on crossing the threshold for diabetes than on the magnitude of glucose elevation (i.e. that risk of diabetic complications in a patient with a fasting glucose of 121 mg/dl following a 5 mg/dl increase in glucose is determined more by crossing the 126 mg/dl threshold than by the 5 mg/dl increase). However, regression analysis of ALLHAT data (15) showed that while incident diabetes during the first two years was associated with a subsequent 64% higher risk of CHD, as much as a 10 mg/dl increase in glucose during that two year period resulted in no subsequent significant increase in CVD (Table 1). Importantly, the increase in aggregate clinical CVD associated with both incident diabetes and a 10 mg/dl increase in glucose was lowest in the chlorthalidone arm and highest in the lisinopril arm, with the CCB arm intermediate or similar (Table 1).
Table 1
Table 1
Hazard Ratios for Clinical Outcomes Associated with Glucose Abnormalities in ALLHAT
These recent analyses from ALLHAT are consistent with other data evaluating the link between diuretic-induced increases in glucose and adverse clinical outcomes. Lack of congruence between these effects was demonstrated in many comparative trials and confirmed by recent prospective meta-analyses involving >26,000 patients, with almost 4,000 CVD events, nearly 1900 coronary events, and in both diabetic and non-diabetic hypertensive individuals.(6;37) In addition, recent reports provide data on diuretic-induced glucose elevations and long term CVD risk.(15;38;39) While one study reported a nearly 3-fold higher (2.92 95% CI 1.33-6.41) CVD risk after up to 16 years of follow-up in treated hypertensives (54% treated with diuretics) who developed new-onset diabetes, no relationship was seen between diuretic usage and CVD events. Analysis of the 14.3 year follow-up from the SHEP revealed that incident diabetes during the trial among subjects on placebo was associated with a more than 50% increase in CV mortality (adjusted HR 1.56, 95% CI 1.12-2.18) but not in those randomized to the diuretic (adjusted HR 1.04, 95% CI 0.75-1.46).(38) Thus, diuretic-induced glucose changes may underlie the lesser prognostic significance.
Implications of ALLHAT in Patients with the Metabolic Syndrome
Hypertensive patients meeting criteria for metabolic syndrome (MetS) represent a population with or at high risk for diabetes mellitus and for CVD and renal events.(40-42) Use of antihypertensive drugs with favorable metabolic profiles has been advocated over those with less favorable profiles (e.g., beta-blockers and thiazide-type diuretics).(43-46) In ALLHAT, almost 55% of participants met criteria for MetS. This permitted the first test of this issue based on clinical outcomes.(8;47) Participants with MetS randomized to α-blocker experienced lower plasma glucose and total cholesterol (by 10 mg/dl and 9 mg/dl respectively) compared to diuretic, and those randomized to ACEI experienced reductions of 6 mg/dl and 2 mg/dl respectively. HDL-cholesterol was 0.9 mg/dl higher on α-blocker vs. diuretic. Despite these differences there was no evidence of benefit from newer agents on CVD outcomes. As seen in Table 2, no CVD or renal outcome was significantly reduced by the α-blocker or ACEI compared to the diuretic in ALLHAT participants with MetS, including in those without diabetes.(47) In Black ALLHAT participants with MetS, α-blocker and ACEI treatment provided considerably less protection compared to the diuretic for stroke (RR=1.49 (1.09-2.03) and 1.37 (1.07-1.76) respectively), HF (RR=1.88 (1.42-2.47) and 1.49 (1.17-1.90) respectively), combined CVD (RR=1.37 (1.19-1.58) and 1.24 (1.09-1.40) respectively) and ESRD (RR=1.17 (0.62-2.22) and 1.70 (1.13-2.55) respectively).(8)
Table 2
Table 2
ALLHAT Findings in Participants with the Metabolic Syndrome
ALLHAT Findings versus Those from Other Studies
Differences in Trial Design
ALLHAT was an active-controlled trial comparing effects of antihypertensive treatments on clinical outcomes. There are several design possibilities for active-controlled outcome trials. The randomized, double-blind design used in ALLHAT is the most rigorous. While prospective, randomized, open-label, blinded end point (PROBE) design, used in trials such as ANBP-2 and ASCOT, should lead to comparable groups at baseline, the presence of bias in applying the randomized treatment assignments cannot be determined (e.g. 15-16% of ANBP2 participants did not start their assigned treatment).(48) Additionally, although outcomes are evaluated in a blinded fashion, they are not ascertained that way. Thus, there could be bias in event reporting, especially for events or side effects that might have been “expected” to be lower in one arm versus another.
Recent Trials – What do they imply for ALLHAT?
Recent antihypertensive trials have compared initial therapy between different drugs representing various antihypertensive classes. Several trials utilized a “standard therapy” regimen or investigator's choice of either a thiazide-type diuretic or a ⎕-blocker, although these classes have different mechanisms of action and differences in CVD outcomes.(49-52) Thus, the relative contributions of the diuretic and ⎕-blocker cannot be interpreted, since allocation to therapies is not randomized.
Aside from ALLHAT, only one outcome trial in hypertension (ANBP-2) directly compared a diuretic with an ACEI as initial therapy.(1;48) The combined incidence of first and recurrent CVD events was significantly reduced by an ACEI-based regimen compared with one based on thiazide-type diuretic (only in men). However, there was no significant difference for time to first CVD event, the primary outcome used in most trials (though usually requiring a significantly larger sample size).
There were substantial differences between ANBP2 and ALLHAT. ANBP2 had approximately ¼ the participants (6,083 versus 24,309 in ALLHAT for thiazide and ACEI arms) and 1/5 to 1/10 the CVD endpoints as ALLHAT. ANBP2 also had an open-label design. Only 83% of subjects in ANBP2 ever received assigned treatment, and only 58% of subjects randomly assigned to ACEI and 62% of those assigned to diuretic were still receiving assigned treatment at the end of the study (83% and 89% in ALLHAT). Drug dosing in ANBP2 was left to the investigator, and doses administered during the trial have not been reported.(32)
Only two large CVD outcome hypertension trials other than ALLHAT have compared initial treatment with CCB versus one with thiazide-type diuretic, INSIGHT (n=6,321) and the diuretic arm of CONVINCE (n=16,602). Both used a double-blind design.(1;53) Neither trial reported a significant difference in composite CVD primary outcomes. However, as in ALLHAT, fatal and non fatal HF events were significantly higher in the CCB arm in INSIGHT (RR=2.20 [95% CI 1.07–4.49], p=0.028) and CONVINCE (RR=1.30 [95% CI 1.00–1.69], p=0.05), compared with a RR=1.38 (CI 1.25-1.52, p=0.001 in ALLHAT.
The ASCOT trial randomized participants to initial treatment with either amlodipine or atenolol but is frequently portrayed as providing contradictory results to ALLHAT.(12) Although there were amlodipine-based arms in both trials, ALLHAT used atenolol as add-on therapy for all treatment groups. In ASCOT an ACEI was added, if needed, to amlodipine and a thiazide diuretic was added, if needed, to atenolol. Since these second drugs were not allocated randomly or consistently, a definitive comparison cannot be made between second drugs, while ALLHAT was designed to directly compare thiazide diuretic with ACEI, CCB and α-blocker arms. In addition, the dose of thiazide diuretic, bendroflumethiazide 1.25-2.5 mg/d, was 1/4 to 1/2 of the dose of bendroflumethiazide or other thiazide-type diuretics used in previous relevant antihypertensive trials.(29)
The recently completed Avoiding Cardiovascular events through COMbination therapy in Patients LIving with Systolic Hypertension (ACCOMPLISH) trial appears to be inconsistent with ALLHAT findings.(16) The study was stopped early when the difference in primary endpoint between the two arms crossed a pre-specified endpoint favoring CCB/ACEI combination (RR 0.81, CI 0.72-0.90; p=0.0002). A randomized double-blind study (n=11,462), it compared effects of two single-pill combination antihypertensive regimens, an ACEI–diuretic combination (benzapril/hydrochlorothiazide force titrated to 40/12.5 mg), and ACEI-CCB combination (benazapril/amlodipine besylate force titrated to 40/5 mg), on a composite outcome of CVD mortality and morbidity (CHD and stroke but not HF). The doses could be further titrated to 40/25 mg and 40/10 mg respectively, and other classes of drugs added for BP control. While the dose of amlodipine (5-10 mg/day) in ACCOMPLISH was similar to that demonstrating favorable outcomes in other outcome trials,(1;12;22) dose range for HCTZ (12.5-25 mg) was lower than dose ranges (25-50 mg/day, or equivalent dose of other thiazide-type diuretic) used in trials demonstrating benefits on CVD of thiazide-type diuretics.(6;54-56) A significant though small BP difference was reported between arms favoring the ACEI/CCB arm. Dosage details of supplementary drugs are not available; however, recommended supplementary drugs were BBs and alpha blockers, whose effects on clinical outcomes are inferior.(2;17) Results of ACCOMPLISH trial may suggest that doses of thiazide-type diuretics equivalent to ≤ 25 mg/day of HCTZ may be less effective in preventing CVD outcomes than full doses of amlodipine or doses of diuretics used in previous trials.
Meta-Analyses
The largest meta-analyses of randomized outcome trials of antihypertensive treatment conducted since 2002(6;37;57-61) were conducted by the BPLTTC. (6;37;57;58) These meta-analyses were designed to include trials selected prospectively (62) based on study design before their results were available. The most comprehensive of these analyses included 29 trials (including ALLHAT) that collectively enrolled 162,341 patients, and concluded that treatment based on main drug classes reduced major CVD events, with most of the benefits being attributable to BP lowering.(6) However, CCBs were reported less effective in preventing HF than ACEIs or diuretics and/or beta-blockers (D/BB): pooled relative risk for CCB versus D/BB was 1.33 (95% CI, 1.21-1.47). In contrast, results for stroke were suggestive but not significantly in favor of CCB: the relative risk of 0.93 (0.86-1.00), based on 9 trials, also virtually identical to that from ALLHAT alone.
BPLTTC results comparing D/BB with ACEI regimens were less clear with a trend toward differences favoring D/BB.(6) These may have been influenced by a 2 mmHg advantage for D/BB arms, especially with regard to stroke, where the RR (ACEI vs. D/BB), based on 5 trials, was 1.09 (1.00-1.18). For HF, findings were also similar to ALLHAT, RR=1.07 (0.96-1.19). BPLTTC analyses merged treatment arms with regimens based on thiazide diuretics, BBs, or either (according to local investigator choice). One report from BPLTTC suggested a modest BP-independent benefit of ACEI (not ARB) compared to D/BB for CHD but not stroke or HF.(58) This finding was not supported in a network meta-analysis that was able to assess the effect of diuretics on CV outcomes separate from that of the beta blockers.(59) Aggregate trial evidence for patients with and without diabetes have also been reported from BPLTTC.(37) Based on a total of 6 trials (including ALLHAT) with 47,430 participants randomized to either ACEI or diuretic/BB, no difference was seen in rates of major CV events including CHD, nor any specific CV outcome between arms for either non-diabetic or diabetic patients.
In summary, more complete ALLHAT analyses, subsequent trial and meta-analytic data are consistent in confirming initial ALLHAT findings that (despite more favorable effects on glucose, lipid, and other surrogate variables) neither the α-blocker, ACEI nor the CCB surpasses the thiazide-type diuretic as initial therapy for control of BP or reduction of cardiovascular or renal clinical outcomes (when compared at appropriate dosage). Although initial unveiling of ALLHAT findings met with a number of questions and some controversy, further analyses of ALLHAT data and findings from subsequent trials continue to support the original findings. In conclusion, extensive further analyses from ALLHAT and data from other sources underscore the original conclusions from ALLHAT that thiazide-type diuretics remain the preferred first-step therapy in most patients with hypertension. Passive follow-up of ALLHAT participants for morbidity and mortality using administrative databases continues, and this nearly ten years of experience should provide additional insights.
Acknowledgments
This study was supported by contract N01-HC-35130 from the National Heart, Lung, and Blood Institute. The Institute's role included involvement in design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, and approval of the manuscript. The ALLHAT investigators acknowledge contributions of study medications supplied by Pfizer, Inc., (amlodipine and doxazosin), AstraZeneca (atenolol and lisinopril), and Bristol-Myers Squibb (pravastatin) and financial support provided by Pfizer,Inc.
Dr. Davis had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
1. The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHATThe ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group) JAMA. 2002;288(23):2981–2997. [PubMed]
2. Diuretic versus alpha-blocker as first-step antihypertensive therapy: final results from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) Hypertension. 2003;42(3):239–246. [PubMed]
3. Davis BR, Furberg CD, Wright JT, Jr., Cutler JA, Whelton P. ALLHAT: setting the record straight. Ann Intern Med. 2004;141(1):39–46. [PubMed]
4. Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. The SOLVD Investigators. N Engl J Med. 1992;327(10):685–691. [PubMed]
5. Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med. 2000;342(3):145–153. [PubMed]
6. Turnbull F. Effects of different blood-pressure-lowering regimens on major cardiovascular events: results of prospectively-designed overviews of randomised trials. Lancet. 2003;362(9395):1527–1535. [PubMed]
7. Rahman M, Pressel S, Davis BR, Nwachuku C, Wright JT, Jr., Whelton PK, et al. Renal outcomes in high-risk hypertensive patients treated with an angiotensin-converting enzyme inhibitor or a calcium channel blocker vs a diuretic: a report from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) Arch Intern Med. 2005;165(8):936–946. [PubMed]
8. Wright JT, Jr., Harris-Haywood S, Pressel S, Barzilay J, Baimbridge C, Bareis CJ, et al. Clinical Outcomes by Race in Hypertensive Patients with and without the Metabolic Syndrome in ALLHAT. Arch Intern Med. 2008;168:1–11. [PMC free article] [PubMed]
9. Whelton PK, Barzilay J, Cushman WC, Davis BR, Iiamathi E, Kostis JB, et al. Clinical outcomes in antihypertensive treatment of type 2 diabetes, impaired fasting glucose concentration, and normoglycemia: Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) Arch Intern Med. 2005;165(12):1401–1409. [PubMed]
10. Barzilay JI, Davis BR, Bettencourt J, Margolis KL, Goff DC, Jr., Black H, et al. Cardiovascular outcomes using doxazosin vs. chlorthalidone for the treatment of hypertension in older adults with and without glucose disorders: a report from the ALLHAT study. J Clin Hypertens (Greenwich) 2004;6(3):116–125. [PubMed]
11. Wright JT, Jr., Dunn JK, Cutler JA, Davis BR, Cushman WC, Ford CE, et al. Outcomes in hypertensive black and nonblack patients treated with chlorthalidone, amlodipine, and lisinopril. JAMA. 2005;293(13):1595–1608. [PubMed]
12. Dahlof B, Sever PS, Poulter NR, Wedel H, Beevers DG, Caulfield M, et al. Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomised controlled trial. Lancet. 2005;366(9489):895–906. [PubMed]
13. Davis BR, Piller LB, Cutler JA, Furberg C, Dunn K, Franklin S, et al. Role of diuretics in the prevention of heart failure: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. Circulation. 2006;113(18):2201–2210. [PubMed]
14. Einhorn PT, Davis BR, Massie BM, Cushman WC, Piller LB, Simpson LM, et al. The Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) Heart Failure Validation Study: diagnosis and prognosis. Am Heart J. 2007;153(1):42–53. [PubMed]
15. Barzilay JI, Davis BR, Cutler JA, Pressel SL, Whelton PK, Basile J, et al. Fasting glucose levels and incident diabetes mellitus in older nondiabetic adults randomized to receive 3 different classes of antihypertensive treatment: a report from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) Arch Intern Med. 2006;166(20):2191–2201. [PubMed]
16. ACCOMPLISH: ACE Inhibitor Plus Calcium-Channel Blocker Best for Reducing Clinical Events in Hypertensive Patients. 2008. http://www.medscape.com/viewarticle/572304.
17. Cutler JA, Davis BR. Thiazide-type diuretics and beta-adrenergic blockers as first-line treatments for hypertension. Circulation. 2008 In Press. [PMC free article] [PubMed]
18. Messerli FH, Bangalore S, Julius S. Risk/benefit assessment of beta-blockers and diuretics precludes their use for first-line therapy in hypertension. Circulation. 2008;117(20):2706–2715. [PubMed]
19. Davis BR, Cutler JA, Gordon DJ, Furberg CD, Wright JT, Jr., Cushman WC, et al. Rationale and design for the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). ALLHAT Research Group. Am J Hypertens. 1996;9(4 Pt 1):342–360. [PubMed]
20. Grimm RH, Jr., Margolis KL, Papademetriou V,V, Cushman WC, Ford CE, Bettencourt J, et al. Baseline Characteristics of Participants in the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) Hypertension. 2001;37(1):19–27. [PubMed]
21. Leenen FH, Nwachuku CE, Black HR, Cushman WC, Davis BR, Simpson LM, et al. Clinical events in high-risk hypertensive patients randomly assigned to calcium channel blocker versus angiotensin-converting enzyme inhibitor in the antihypertensive and lipid-lowering treatment to prevent heart attack trial. Hypertension. 2006;48(3):374–384. [PubMed]
22. Julius S, Kjeldsen SE, Weber M, Brunner HR, Ekman S, Hansson L, et al. Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomised trial. Lancet. 2004;363(9426):2022–2031. [PubMed]
23. Poulter NR, Wedel H, Dahlof B, Sever PS, Beevers DG, Caulfield M, et al. Role of blood pressure and other variables in the differential cardiovascular event rates noted in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA) Lancet. 2005;366(9489):907–913. [PubMed]
24. Davis BR, Cutler JA, Furberg CD, Wright JT, Farber MA, Felicetta JV, et al. Relationship of antihypertensive treatment regimens and change in blood pressure to risk for heart failure in hypertensive patients randomly assigned to doxazosin or chlorthalidone: further analyses from the Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial. Ann Intern Med. 2002;137(5 Part 1):313–320. [PubMed]
25. Five-year findings of the hypertension detection and follow-up program. I. Reduction in mortality of persons with high blood pressure, including mild hypertension. Hypertension Detection and Follow-up Program Cooperative Group. JAMA. 1979;242(23):2562–2571. [PubMed]
26. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. Final results of the Systolic Hypertension in the Elderly Program (SHEP). SHEP Cooperative Research Group. JAMA. 1991;265(24):3255–3264. [PubMed]
27. Mortality after 10 1/2 years for hypertensive participants in the Multiple Risk Factor Intervention Trial. Circulation. 1990;82(5):1616–1628. [PubMed]
28. Ernst ME, Carter BL, Goerdt CJ, Steffensmeier JJ, Phillips BB, Zimmerman MB, et al. Comparative antihypertensive effects of hydrochlorothiazide and chlorthalidone on ambulatory and office blood pressure. Hypertension. 2006;47(3):352–358. [PubMed]
29. Psaty BM, Lumley T, Furberg CD. Meta-analysis of health outcomes of chlorthalidone-based vs nonchlorthalidone-based low-dose diuretic therapies. JAMA. 2004;292(1):43–44. [PubMed]
30. Cushman WC, Ford CE, Einhorn PT, Wright JT, Jr., Preston RA, Davis BR, et al. Blood pressure control by drug group in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT. J Clin Hypertens (Greenwich) 2008;10:751–760. [PMC free article] [PubMed]
31. Kostis JB, Davis BR, Cutler J, Grimm RH, Jr., Berge KG, Cohen JD, et al. Prevention of heart failure by antihypertensive drug treatment in older persons with isolated systolic hypertension. SHEP Cooperative Research Group. JAMA. 1997;278(3):212–216. [PubMed]
32. Cutler JA. The ANBP2 and ALLHAT: conflicting or consistent? J Clin Hypertens (Greenwich) 2003;5(3):192–195. [PubMed]
33. Davis BR, Kostis JB, Simpson LM, Black HR, Cushman WC, Einhorn PT, et al. Heart Failure With Preserved and Reduced Left Ventricular Ejection Fraction in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. Circulation. 2008;118(22):2259–2267. [PMC free article] [PubMed]
34. Hunt SA, Abraham WT, Chin MH, Feldman AM, Francis GS, Ganiats TG, et al. ACC/AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure): developed in collaboration with the American College of Chest Physicians and the International Society for Heart and Lung Transplantation: endorsed by the Heart Rhythm Society. Circulation. 2005;112(12):e154–e235. [PubMed]
35. Executive summary: HFSA 2006 Comprehensive Heart Failure Practice Guideline. J Card Fail. 2006;12(1):10–38. [PubMed]
36. Cutler JA. Thiazide-associated glucose abnormalities: prognosis, etiology, and prevention: is potassium balance the key? Hypertension. 2006;48(2):198–200. [PubMed]
37. Turnbull F, Neal B, Algert C, Chalmers J, Chapman N, Cutler J, et al. Effects of different blood pressure-lowering regimens on major cardiovascular events in individuals with and without diabetes mellitus: results of prospectively designed overviews of randomized trials. Arch Intern Med. 2005;165(12):1410–1419. [PubMed]
38. Verdecchia P, Reboldi G, Angeli F, Borgioni C, Gattobigio R, Filippucci L, et al. Adverse prognostic significance of new diabetes in treated hypertensive subjects. Hypertension. 2004;43(5):963–969. [PubMed]
39. Kostis JB, Wilson AC, Freudenberger RS, Cosgrove NM, Pressel SL, Davis BR. Long-term effect of diuretic-based therapy on fatal outcomes in subjects with isolated systolic hypertension with and without diabetes. Am J Cardiol. 2005;95(1):29–35. [PubMed]
40. Hall WD, Clark LT, Wenger NK, Wright JT, Jr., Kumanyika SK, Watson K, et al. The Metabolic Syndrome in African Americans: a review. Ethn Dis. 2003;13(4):414–428. [PubMed]
41. Grundy SM, Brewer HB, Jr., Cleeman JI, Smith SC, Jr., Lenfant C. Definition of metabolic syndrome: Report of the National Heart, Lung, and Blood Institute/American Heart Association conference on scientific issues related to definition. Circulation. 2004;109(3):433–438. [PubMed]
42. Eckel RH, Kahn R, Robertson RM, Rizza RA. Preventing cardiovascular disease and diabetes: a call to action from the American Diabetes Association and the American Heart Association. Circulation. 2006;113(25):2943–2946. [PubMed]
43. Mykkanen L, Kuusisto J, Pyorala K, Laakso M, Haffner SM. Increased risk of non-insulin-dependent diabetes mellitus in elderly hypertensive subjects. J Hypertens. 1994;12(12):1425–1432. [PubMed]
44. Giles TD, Sander GE. Pathophysiologic, diagnostic, and therapeutic aspects of the metabolic syndrome. J Clin Hypertens (Greenwich) 2005;7(11):669–678. [PubMed]
45. Mancia G. The association of hypertension and diabetes: prevalence, cardiovascular risk and protection by blood pressure reduction. Acta Diabetol. 2005;42(Suppl 1):S17–S25. [PubMed]
46. Wagh A, Stone NJ. Treatment of metabolic syndrome. Expert Rev Cardiovasc Ther. 2004;2(2):213–228. [PubMed]
47. Black HR, Davis BR, Barzilay J, Nwachuku C, Baimbridge C, Duffy D, et al. Clinical outcomes in non-diabetic individuals with the metabolic syndrom assigned to chlorthalidone, amlodipine, or lisinopril as initial hypertension therapy: A report from the ALLHAT Study. Diabetes Care. 2007;31:353–360. [PubMed]
48. Wing LM, Reid CM, Ryan P, Beilin LJ, Brown MA, Jennings GL, et al. A comparison of outcomes with angiotensin-converting--enzyme inhibitors and diuretics for hypertension in the elderly. N Engl J Med. 2003;348(7):583–592. [PubMed]
49. Hansson L, Lindholm LH, Niskanen L, Lanke J, Hedner T, Niklason A, et al. Effect of angiotensin-converting-enzyme inhibition compared with conventional therapy on cardiovascular morbidity and mortality in hypertension: the Captopril Prevention Project (CAPPP) randomised trial. Lancet. 1999;353(9153):611–616. [PubMed]
50. Hansson L, Lindholm LH, Ekbom T, Dahlof B, Lanke J, Schersten B, et al. Randomised trial of old and new antihypertensive drugs in elderly patients: cardiovascular mortality and morbidity the Swedish Trial in Old Patients with Hypertension-2 study. Lancet. 1999;354(9192):1751–1756. [PubMed]
51. Black HR, Elliott WJ, Grandits G, Grambsch P, Lucente T, White WB, et al. Principal results of the Controlled Onset Verapamil Investigation of Cardiovascular End Points (CONVINCE) trial. JAMA. 2003;289(16):2073–2082. [PubMed]
52. Hansson L, Hedner T, Lund-Johansen P, Kjeldsen SE, Lindholm LH, Syvertsen JO, et al. Randomised trial of effects of calcium antagonists compared with diuretics and beta-blockers on cardiovascular morbidity and mortality in hypertension: the Nordic Diltiazem (NORDIL) study. Lancet. 2000;356(9227):359–365. [PubMed]
53. Brown MJ, Palmer CR, Castaigne A, de Leeuw PW, Mancia G, Rosenthal T, et al. Morbidity and mortality in patients randomised to double-blind treatment with a long-acting calcium-channel blocker or diuretic in the International Nifedipine GITS study: Intervention as a Goal in Hypertension Treatment (INSIGHT) Lancet. 2000;356(9227):366–372. [PubMed]
54. Amery A, Birkenhager W, Brixko P, Bulpitt C, Clement D, Deruyttere M, et al. Mortality and morbidity results from the European Working Party on High Blood Pressure in the Elderly trial. Lancet. 1985;1(8442):1349–1354. [PubMed]
55. Anonymous. Medical Research Council trial of treatment of hypertension in older adults: principal results. MRC Working Party. BMJ. 1992;304(6824):405–412. [PMC free article] [PubMed]
56. Psaty BM, Smith NL, Siscovick DS, Koepsell TD, Weiss NS, Heckbert SR, et al. Health outcomes associated with antihypertensive therapies used as first-line agents. A systematic review and meta-analysis. JAMA. 1997;277(9):739–745. [PubMed]
57. Neal B, MacMahon S, Chapman N. Effects of ACE inhibitors, calcium antagonists, and other blood- pressure-lowering drugs: results of prospectively designed overviews of randomised trials. Blood Pressure Lowering Treatment Trialists' Collaboration. Lancet. 2000;356(9246):1955–1964. [PubMed]
58. Turnbull F, Neal B, Pfeffer M, Kostis J, Algert C, Woodward M, et al. Blood pressure-dependent and independent effects of agents that inhibit the renin-angiotensin system. J Hypertens. 2007;25(5):951–958. [PubMed]
59. Psaty BM, Lumley T, Furberg CD, Schellenbaum G, Pahor M, Alderman MH, et al. Health outcomes associated with various antihypertensive therapies used as first-line agents: a network meta-analysis. JAMA. 2003;289(19):2534–2544. [PubMed]
60. Staessen JA, Wang JG, Thijs L. Cardiovascular prevention and blood pressure reduction: a quantitative overview updated until 1 March 2003. J Hypertens. 2003;21(6):1055–1076. [PubMed]
61. Staessen JA, Li Y, Thijs L, Wang JG. Blood pressure reduction and cardiovascular prevention: an update including the 2003-2004 secondary prevention trials. Hypertens Res. 2005;28(5):385–407. [PubMed]
62. Protocol for prospective collaborative overviews of major randomized trials of blood-pressure-lowering treatments. World Health Organization-International Society of Hypertension Blood Pressure Lowering Treatment Trialists' Collaboration. J Hypertens. 1998;16(2):127–137. [PubMed]