The Journal of Informed Pharmacotherapy 2000;2:200-202.
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Reviewer: Nancy Cherry, B.Sc.(Pharm)
Reviewer's email address: email@example.com
Reviewer's profession/specialty: Hospital Pharmacy Resident
ALLHAT Collaborative Research Group.Major Cardiovascular Events in Hypertensive Patients Randomized to Doxazosin versus Chlorthalidone - The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) JAMA 2000;283:1967-75. PubMed Cit
The Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) is a double-blind, randomized, practice-based clinical trial involving over 40,000 high-risk hypertensive patients aged 55 years and older. Sponsored by the National Heart, Lung and Blood Institute and the U.S. Department of Veterans' Affairs, this trial has two components; the antihypertensive agent assessment and the lipid-lowering agent assessment. The objective of the antihypertensive component of ALLHAT was to determine whether the combined incidence of fatal coronary heart disease (CHD) and nonfatal myocardial infarction differs between persons randomized to diuretic (chlorthalidone) treatment and each of three alternative treatments - a calcium antagonist (amlodipine), an angiotensin converting enzyme inhibitor (lisinopril), and an alpha-adrenergic blocker (doxazosin). The results of the prematurely-terminated doxazosin arm of the trial are presented here.
1. Was assignment of patients randomized?
Yes. The results presented in this study are only representative of the doxazosin arm of ALLHAT. The study investigators randomized participants using a computer-generated schedule to one of four treatments: chlorthalidone, amlodipine, lisinopril, or doxazosin, in a ratio of 1.7:1:1:1, respectively. Randomization was stratified by center and blocked over time to maintain the ratio. The ALLHAT Clinical Trials Center held the randomization code.
Yes. The large sample size and randomization process resulted in similar baseline characteristics across the chlorthalidone and doxazosin treatment groups.
Yes. All patients were followed every three months during the first year of enrollment and every four months thereafter.
1. How large was the treatment effect?
The primary outcome for the hypertension component of ALLHAT was the composite of fatal CHD and nonfatal MI. No significant difference was found between the chlorthalidone and doxazosin treatment groups with regards to the primary outcome. Fatal CHD or non-fatal MI: RR=1.03, P=0.71. Secondary outcomes included all-cause mortality, combined CHD, stroke and combined cardiovascular disease (CVD). No significant difference was observed for all-cause mortality (RR=1.03, P=0.56). However, significant differences were observed with the three other secondary endpoints: combined CHD (RR=1.1, P=0.05, 95% CI= 1.00-1.12), stroke (RR=1.19, P<0.001, 95% CI= 1.01-1.40) and combined CVD (RR=1.25, P=0.04, 95% CI= 1.17-1.33). Results for combined CVD were further broken down to reveal significant differences between the two treatment groups for congestive heart failure (CHF) (RR=2.04, P<0.001, 95% CI= 1.79-2.32), coronary revascularization (RR=1.15, P=0.05, 95% CI=1.00-1.32), and angina (RR=1.16, P<0.00.1, 95% CI= 1.05-1.27). No significant difference was observed in peripheral artery disease (RR=1.07, P=0.50, 95% CI=0.88-1.30).
2. How precise was the estimate of the treatment effect?The only significant difference observed was with the secondary outcome of combined CVD. The 95% CI were narrow (RR=1.25, 95% CI= 1.17-1.33).
2. Were all clinically important outcomes considered?
This study shows that when compared with doxazosin, chlorthalidone therapy appears to yield an essentially equal risk of CHD death/nonfatal MI (primary outcome), but significantly reduces the risk of combined CVD events. This was particularly evident for CHF in high-risk hypertensive patients. However, it is important to recognize that no difference was observed in the primary outcome, only in one of four secondary outcomes. Another limitation of this study is that it does not address the issue of class effect and whether or not all alpha-blockers should be avoided in the treatment of hypertension. The US-JNC, CMA, WHO and the British Hypertension Society all consider alpha-blockers as equally efficacious as angiotensin-converting enzyme inhibitors, angiotensin receptor blockers and calcium channel blockers when used for antihypertensive effects. If the results of this study are adopted, these guidelines will need to be amended.
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