Doxazosin versus chlorthalidone

What can we learn from the early results of the ALLHAT trial?

Original Citation

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)

Overall Study Question

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.

Are the Results of the Study Valid?

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.

Were all patients who entered the trial properly accounted for and attributed at its conclusion?

Yes.  42,448 patients met the inclusion criteria and were randomized to one of the four treatment groups. Of the 15,268 patients who received chlorthalidone, 501 were lost to follow-up, 851 died (633 non-CHD deaths and 218 CHD deaths) and the remaining patients are still being followed as part of the ongoing ALLHAT.  Of the 9,067 patients who received doxazosin, 338 were lost to follow-up and 514 died (384 non-CHD deaths and 130 CHD deaths).  Patients who were also enrolled in the lipid-lowering trial component of ALLHAT continue to be followed.

Were patients, their clinicians, and study personnel ‘blind’ to treatment?

Yes. Initially, all parties were blinded; however, once a patient reached the maximum dose and did not meet the BP goal, an open-label Step 2 agent (atenolol, reserpine or clonidine) or an open-label Step 3 agent (hydralazine) was added.

Were the groups similar at the start of the trial?

Yes.  The large sample size and randomization process resulted in similar baseline characteristics across the chlorthalidone and doxazosin treatment groups.

Aside from the experimental intervention, were the groups treated equally?

Yes.  All patients were followed every three months during the first year of enrollment and every four months thereafter.

Overall, are the results of the study valid?

Yes.

What were the Results?

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).

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).

Will the Results Help Me in Caring for My Patients?

Can the results be applied to my patient care?

Yes.  The inclusion criteria were very broad and the results of this trial can be applied to a wide range of patients who have hypertension.  The inclusion criteria included both men and women aged 55 years and older who had systolic blood pressure (SBP) of at least 140mmHg and/or diastolic blood pressure (DBP) of at least 90mmHg, or took medication for hypertension and had at least one additional risk factor for CHD. These risk factors included previous MI or stroke, left ventricular hypertrophy by electrocardiogram or echocardiogram, history of type 2 diabetes, current cigarette smoking, and low high-density lipoprotein cholesterol level. Exclusion criteria included symptomatic MI or stroke within the past six months, symptomatic CHF or ejection fraction<35%, angina pectoris within the past six months, requirements for any of the study treatment drugs for any reason other than hypertension, current requirement for more than two antihypertensive medications, and SBP>180mmHg or DBP>110mmHg on two separate readings.

Were all clinically important outcomes considered?

Yes. All major cardiac endpoints were considered including fatal CHD and non-fatal MI, all-cause mortality, combined CHD, stroke , CHF, coronary revascularization, angina and peripheral vascular disease.

Are the likely treatment benefits worth the potential harms and costs?

Yes. It appears that doxazosin is associated with a greater risk of combined cardiovascular events, particularly CHF in high-risk hypertensive patients compared to chlorthalidone. However, it is important to note that these differences were observed in a secondary outcome while no difference was observed in the primary outcome, namely fatal CHD or non-fatal MI. No difference was observed in any other secondary outcome or all-cause mortality.

Commentary

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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