Outcomes with Angiotensin-Converting Enzyme Inhibitors and Diuretics for Hypertension in the Elderly

Abstract & Commentary

Synopsis: Initiation of antihypertensive treatment involving ACE inhibitors in older subjects, particularly men, appears to lead to better outcomes than treatment with diuretic agents, despite similar reductions of blood pressure.

Source: Wing LMH, et al. N Engl J Med. 2003;348:538-592.

This is a prospective, randomized, open-labeled study that compared enalapril (ENAL) to hydrochlorothiazide (HCTZ) in the treatment of hypertension (HTN). Analysis was by intention to treat. The study was conducted in family practice offices in Australia with randomization beginning in 1995. Eligibility criteria were: aged 65-84 years; average systolic blood pressure (SBP) = 160 or average SBP = 140 and average diastolic blood pressure (DBP) = 90; and no cardiovascular events in the last 6 months. Subjects were excluded if they suffered from a life-threatening disease; had a contraindication to either of the study drugs; had a plasma creatinine = 2.5 mg/dL; had malignant HTN; or were demented.

Treatment goals were a reduction in SBP = 20 to < 160 and DBP = 10 to < 90. If patients could tolerate it, further reduction of SBP to < 140 and DBP to < 80 was encouraged. The physicians could use other antihypertensives (beta-blockers, calcium-channel blockers, and alpha-blockers) to achieve goal. The primary study end point was all cardiovascular events or death from any cause. Cardiovascular events included: myocardial infarction, sudden or rapid cardiac death, therapeutic coronary artery procedures, heart failure, acute occlusion of any major artery (except coronary or cerebral), dissecting or ruptured aortic aneurysm, stroke, and transient ischemic attacks. From a pool of 54,288 patients screened for eligibility, 6083 underwent randomization.

A total of 3044 were assigned to the ENAL group and 3039 to the HCTZ group. The 2 groups were well matched at baseline in regard to gender (50% vs 48% male), age (average, 72.0 vs 71.9 years old), blood pressure (average, SBP 167 vs 168 and average DBP 91 in both groups), previous antihypertensive therapy (62% in both groups), body mass index (average 27 in both groups, tobacco use (7% current smokers in both groups), alcohol use (74% vs 72%), physical activity (78% vs 76%), coronary heart disease (8% in both groups), cerebrovascular disease (5% vs 4%), diabetes mellitus (8% vs 7%), hypercholesterolemia (38% vs 36%), and treatment with lipid-lowering drugs (13% in both groups). Fully 95% of the participants were white. The patients’ physicians had the option of not starting therapy immediately; 83% of patients in both groups started with the drug to which they had been assigned.

At study’s end, 58% of the ENAL group was still taking ENAL vs 62% of the HCTZ group. ENAL was the only antihypertensive used by 65% in that group; HCTZ was monotherapy in 67% in its group. The percentage receiving 3 or more antihypertensives was 6% vs 5%, respectively. At the end of the first year, both drugs had achieved nearly identical reductions in BP (20/9 vs 22/9) and this reduction persisted until the study’s end after 5 years (26/12 in both groups). However, the ENAL group had 695 primary end point events compared to the HCTZ group, which had 736. This represents a hazard ratio (HR) of 0.89 (95% confidence interval [CI], 0.79-1.00) favoring ENAL when the survival curves were compared. The HR for fatal stroke was 1.91 (CI, 1.04-3.50) favoring HCTZ. The HR for nonfatal myocardial infarction was 0.68 (CI, 0.47-0.99). When men and women were analyzed separately, the HR for all primary end point events was 0.83 (CI, 0.71-0.97) for men favoring ENAL and 1.00 (CI, 0.83-1.21) for women. The result for women is not statistically significant.

Comment by Allan J. Wilke, MD

You are probably scratching your head right now, thinking, "Didn’t I just read that the ALLHAT study showed that a diuretic beat out an ACE-inhibitor and a calcium-channel blocker for the treatment of hypertension?" Yes, you did. So what gives? The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) results were published late last year1 and reviewed recently in this publication.2 It compared chlorthalidone, lisinopril, and amlodipine, and indeed, chlorthalidone was better than amlodipine in preventing heart failure and better than lisinopril in preventing stroke, angina, heart failure, myocardial infarction, and revascularization procedures. The apparent contradictory results can probably be explained by carefully comparing the 2 studies, especially the study populations. The current study enrolled 6083 overwhelmingly white Australians. ALLHAT enrolled 33,357 North Americans; more than than one third were black. At the start of the study, the "average" ALLHAT participant was younger (66.9 years vs 71.9), more overweight (BMI 29.7 vs 27.0), less hypertensive (146/84 vs 167/91), more likely diabetic (36% vs 8%), more likely smoking (21.9% vs 7%), and more likely to have pre-existing coronary heart disease (25% vs 8%). On the face of it, the Australian group was more active and much healthier. In his editorial in the same issue, Frohlich also reminds us that while the drugs are from the same classes, diuretics and ACE-inhibitors, they are not equivalent. Perhaps the drugs have different effects beyond their ability to lower blood pressure.

In the end, what are we to do? I think that the current study demonstrates a slightly better outcome for older, hypertensive males who are treated with enalapril. I do not see my approach to drug therapy for hypertension radically changing, however. I will continue to tailor treatment to the patient in front of me who may be diabetic (think ACE-inhibitor), in heart failure (think diuretic and/or ACE-inhibitor), or a survivor of a heart attack (think beta-blocker or ACE-inhibitor), and so forth. More importantly, with an estimated one-quarter of Americans with high blood pressure and one-third of them unaware they have it, I will continue to work to identify patients with the disease.

Dr. Wilke is Assistant Professor of Family Medicine at the Medical College of Ohio, Toledo, OH.


1. JAMA. 2002;288:2981-2997.

2. Phillips BA. Internal Medicine Alert. 2003;25:9-10.

3. Frohlich ED. N Engl J Med. 2003;348:639-641.