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The meaning of ALLHAT

2003; Lippincott Williams & Wilkins; Volume: 21; Issue: 2 Linguagem: Inglês

10.1097/00004872-200302000-00004

1473-5598

Norman M. Kaplan,

Renin-Angiotensin System Studies

The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) is the largest and, in most ways, among the best-conducted outcome trials in the treatment of hypertension [1]. The results largely confirm the findings of other comparative trials but, because of the size and heterogeneity of the study population, they clarify the position of four major classes of antihypertensive drugs. The three primary conclusions are: (i) a low-dose diuretic is the preferred initial drug for virtually all hypertensive patients; (ii) there are none of the widely trumpeted dangers from dihydropyridine calcium channel blockers (CCBs); and (iii) angiotensin-converting enzyme (ACE) inhibitors may not be as protective as previously thought. Diuretic as initial choice As to the use of a low-dose diuretic for initial therapy, ALLHAT confirms the conclusions from multiple placebo-controlled trials that such low doses provide protection from coronary disease, a protection that may not be seen with higher doses of diuretic [2]. Again, as noted in previous comparative trials, a low-dose diuretic was equal to either a CCB or an ACE inhibitor in protection from coronary disease [3]. Compared to the CCB, the diuretic-based regimen provided a 38% significantly greater protection from heart failure but a statistically insignificant 7% higher rate of stroke. On the other hand, the diuretic provided a 15% lesser rate of stroke than did the ACE inhibitor, as well as a surprisingly 20% lesser rate of heart failure. This latter finding partially reflects the 2–3 mmHg higher systolic blood pressure in those on the ACE inhibitor as well as the requirement that a beta-blocker or a sympathetic blocker be the second drug rather than a diuretic as typically provided in clinical practice. In addition, the diagnosis of heart failure was based largely on clinical grounds and pedal oedema, one of the criteria, would be expected to be less with a diuretic than with an ACE inhibitor and even more so than with a CCB. The difference between chlorthalidone and lisinopril for 'hospitalized/fatal heart failure' fell to statistical insignificance so that there remains a question about the data on congestive heart failure. Chlorthalidone was the diuretic used in ALLHAT whereas hydrochlorothiazide is by far the most widely used thiazide, at least in the USA. Evidence-based purists may insist that ALLHAT only proves the efficacy of chlorthalidone, but it seems very likely that the benefits will be obtained with any sustained diuretic action. Only 41% of those started on chlorthalidone were taking a second or third drug by the fifth year. The lower level of pre-treatment blood pressure, averaging 156/89 mmHg, in the previously untreated ALLHAT participants likely explains the lesser need for additional drugs as seen among patients with higher levels of pressure in studies such as the Hypertension Optimal Treatment trial [4]. Nonetheless, the ALLHAT participants were, if anything, a higher risk population than is seen in typical clinical practice. All had at least one other major cardiovascular risk factor: 36% were diabetic; 16% had left ventricular hypertrophy by electrocardiogram; and 52% had pre-existing atherosclerotic cardiovascular disease. Thus, a low-dose diuretic alone may be adequate for a larger portion of the total hypertensive population than previously assumed [5]. Nonetheless, biochemical changes were more severe with the diuretic, in particular hypokalemia, which was seen in 12.7% at 2 years compared to 2.6% of the CCB and 1.5% of the ACE inhibitor. Fasting hyperglycemia in the non-diabetics increased to 11.6% at 4 years in those on the diuretic compared to 9.8% on the CCB and 8.1% on the ACE inhibitor. Safety of calcium channel blockers It seems almost providential that one of the most vociferous critics of the safety of CCBs was the principal investigator of the ALLHAT trial [6]. The concerns expressed by Dr Furberg and others can now be put to rest. As noted in their comments: 'A body of literature based on observational studies and secondary CHD prevention trials on short-acting CCBs has suggested that CCBs, especially DHP-CCBs, may increase the risk of cancer, gastrointestinal bleeding, and all-cause mortality. The results of ALLHAT do not support these findings. In fact, the mortality from non-cardiovascular causes was significantly lower in the CCB group'. Those who have been concerned about putative lesser degrees of renal protection with CCBs than with other classes should also be reassured. As stated: 'There were no significant differences in the incidence of ESRD between chlorthalidone and amlodipine … Comparison of the reciprocal serum creatinine slopes suggested a slower decline in kidney function in the amlodipine group'. The special effects of ACE inhibitors As noted, the higher rate of heart failure in those on lisinopril than in those on chlorthalidone may be explained by the higher blood pressures in the ACE inhibitor group and the nature of the step-wise addition of drugs. Regardless, the inferences from studies suggesting special benefits of ACE inhibitors in systolic dysfunction and heart failure [7], as well as in patients with pre-existing coronary disease [8], may need to be reconsidered. Their ability to lower blood pressure may be the predominant reason that ACE inhibitors are so effective in these conditions. Nonetheless, agents which inhibit the renin–angiotensin system will continue to be preferred in the treatment of proteinuric nephropathies [9], and in patients with an abnormally activated renin–angiotensin system. The higher rate of stroke in those on an ACE inhibitor than in those on a diuretic was largely related to a 40% greater stroke rate in Blacks. Drugs which inhibit the renin system as monotherapy do not lower blood pressure as much in Blacks, as do either diuretics or CCBs. Therefore, if an ACE inhibitor is used in a Black individual, a diuretic should be used concomitantly. ACE inhibitors have also been widely recommended as being especially beneficial to diabetic patients. However, as stated [1], 'For the important diabetic population, lisinopril appeared to have no special advantage (and amlodipine no particular detrimental effect) for most CVD and renal outcomes when compared with chlorthalidone'. Conclusions ALLHAT does not answer all issues about the initial drugs for the treatment of hypertension. The trial did not include a beta-blocker or an angiotensin II-receptor blocker (ARB) because previously published trials showed lesser benefits with beta-blockers, and because ARBs were not available when the study was started. Obviously, questions remain but ALLHAT should settle the issue as to the most appropriate initial drug for almost all hypertensive patients. Unless a low-dose diuretic is contra-indicated, it should be the foundation of therapy. Patients who do not achieve adequate blood pressure control, or who have compelling indications for other agents, should remain on the diuretic along with whatever other drugs they need.