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Editorial
Edward D. Frohlich, M.D. Not infrequently, on release of the results of major multicenter trials, the lay press promulgates an immediate response before physicians have had time to assess the peer-reviewed paper. By the next morning, physicians are greeted by a multitude of messages containing frantic questions from patients about how the reported results relate to their particular problems. When the report deals with a common disease (such as hypertension), the magnitude of the public's anxieties is intensified. Moreover, when results appear to conflict with those of a previous study, not infrequently described as "landmark," there is potential for mass confusion and loss of confidence in individual health care providers, exacerbated by media reports that pose this rhetorical question: "Just what are we to believe?" In this issue of the Journal, Wing et al.1 report the results of a major trial comparing the effects of angiotensin-converting�enzyme (ACE) inhibitors with the effects of diuretics on the rate of cardiovascular events in elderly hypertensive patients. The investigation, the Second Australian National Blood Pressure Study (ANBP2), involved 6083 patients who were followed by 1594 family practitioners for a median of 4.1 years. Numbers of patients and the design and conduct of the study appear reliable, but some of the results contradict those of another major trial, the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT).2 ALLHAT was designed to compare the diuretic chlorthalidone with agents representing each of three other classes of antihypertensive drugs (ACE inhibitors, calcium antagonists, and alpha-adrenergic�receptor inhibitors) and involved more than 42,000 patients from the United States and Canada. The trials should therefore be comparable. But ANBP2 indicates that ACE inhibitors have an outcome advantage over diuretics (particularly among older men), whereas ALLHAT concluded that diuretics were more effective for blood-pressure control, as well as in terms of outcomes. So what are we to believe? First, we should consider the sources. Both trials were sponsored and supervised by national health research institutions with academic participation and without commercial influence. A second issue might be whether the drugs studied in each class were equivalent. The honest answer is that we do not really know. ANBP2 used hydrochlorothiazide as the diuretic, whereas ALLHAT used chlorthalidone. Hydrochlorothiazide has an excellent track record and was used as the diuretic in most early trials of antihypertensive therapy; chlorthalidone is equally well accepted. However, there have been no head-to-head trials comparing the efficacy of and outcomes with these two diuretics. In addition, ANBP2 used enalapril as the ACE inhibitor, whereas ALLHAT used lisinopril. Again, questions may be raised, since it is possible that one agent may have a greater effect not only on blood pressure, but also on local renin�angiotensin systems that may affect disease outcomes.3 There have not been (nor are there likely to be) head-to-head comparisons of the long-term efficacy of and outcomes with the two ACE inhibitors. We may also ask whether these were the only drugs used to control blood pressure in these trials. The answer to this question is equivocal. In both trials, other antihypertensive medications were frequently required to achieve blood-pressure goals, and the use of these additional agents also compounds the complexities of any comparison between the trials. All of these are straightforward questions whose answers could explain the differences between the conclusions. There are also some more complex questions. Which agent controlled blood pressure better? The ANBP2 report indicates that there were similar reductions in blood pressure in the two treatment groups, whereas in ALLHAT, the diuretic-based regimen was more efficacious (as indicated both by the blood pressures and by the percentage of patients in whom the blood-pressure goal was achieved). We may well ask why there was a difference in blood pressure if the participating physicians were allowed to achieve the goal with the addition of the other classes of antihypertensive drugs. What about clinical outcomes? Again, we must equivocate, because the trials used vastly different definitions of primary and secondary outcomes. The primary outcome in ANBP2 was the total number of fatal and nonfatal cardiovascular events, which favored enalapril. In ALLHAT, the treatment groups were similar in terms of the primary outcome of death from coronary causes or nonfatal myocardial infarction, but when combined with the secondary cardiovascular events, outcomes favored chlorthalidone. Perhaps comparison of the demographic and clinical characteristics of the subjects in the two trials can help. Age, sex, and body-mass index were similar. Ninety-five percent of the subjects in ANBP2 were white, whereas 35 percent of the subjects in ALLHAT were black. In ANBP2, the pretreatment blood pressures were higher. Could the differential in achieved blood pressure between the chlorthalidone group and the lisinopril group in ALLHAT have affected its results? The percentages of patients with diabetes, smokers, and patients with coronary heart disease or cerebrovascular disease in ANBP2 were lower. These characteristics could also have an effect on outcomes.4,5 In order to obtain firm answers to these questions for ourselves and our patients, medical leaders and responsible health care providers should assume more direct oversight of the interpretation of such studies. Whereas epidemiologists focus on responses at the population level in order to develop therapeutic guidelines, health care providers must deal with the specific relationship between the physician and the patient. This relationship is where the therapeutic tire meets the road, and there is no place for absolute or categorical answers. Population-based studies of therapies help to point the way but are not analogous to the care of individual patients. Elsewhere in this issue of the Journal, there is an informative article by August6 that describes an exceedingly common clinical problem faced by all primary care physicians: the initial treatment of patients with less severe essential hypertension. Although such hypertension was formerly considered to be "mild," we must recognize that all hypertension is severe in that it is associated with an increased risk of premature illness and death. August outlines the importance of a comprehensive evaluation and the necessity for prompt recognition and treatment of hypertension. Now we can develop specific resolutions to the apparent dilemma presented by the results of ANBP2 and ALLHAT. For patients with essential hypertension but without complications, it makes sense for the prescribing physician to choose a diuretic in a dose that does not cause potassium wasting, precipitate gout, or have other unwanted effects. In ANBP2 and ALLHAT, it was frequently necessary to prescribe a second or third medication in order to control blood pressure. In such a circumstance, the addition of an ACE inhibitor makes sense. Furthermore, a diuretic alone is not sufficient for the achievement of blood-pressure goals in some patients with hypertension, and both ACE inhibitors and diuretics are valuable and currently available as generic compounds. One should not lose sight of the fact that both diuretics and ACE inhibitors are extremely effective in improving clinical outcomes.7,8,9 However, patients with hypertension � particularly elderly patients � frequently have associated coexisting conditions. If a patient has diabetes, it would certainly be wise to initiate therapy with an ACE inhibitor, as long-term studies have clearly demonstrated.10,11,12 If a patient has cardiac failure, one might use both a diuretic and an ACE inhibitor. If there is a history of myocardial infarction, an ACE inhibitor diminishes the risks of future cardiac failure, a second infarction, and subsequent death13,14,15; a beta-blocker is also indicated for such a patient.7 If the patient has angina pectoris, whether from atherosclerotic epicardial coronary artery disease or from hypertensive arteriolar disease, it may also be wise to use a calcium antagonist. Dihydropyridine calcium antagonists not only relieve chest pain, but also help to prevent strokes.7,16 The answer to our question about what we are to believe has now become apparent. First, measure blood pressure in all patients. Second, if blood pressure remains elevated, control it with medication so as to achieve the blood-pressure goal (systolic blood pressure of less than 140 mm Hg and diastolic blood pressure of less than 90 mm Hg). In selecting appropriate therapy, choose a drug or a combination of drugs for which there is strong evidence of effectiveness in persons with the type of problem found in the patient. Finally, we must not join the clamor of media and industry, allowing newscasts to declare immediately which class of drugs is best. Treatment of the individual patient with hypertension is complicated, requiring time and judgment. In choosing between a diuretic and an ACE inhibitor, the physician can make a reasonable selection by reviewing the patient's history and course. We must remember that trials describe population averages for the purposes of developing guidelines, whereas physicians must focus on the individual patient's clinical responses. Dr. Frohlich reports having consulted and lectured for Merck.
From the Ochsner Clinic Foundation, New Orleans. References
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