Even well-conducted randomized controlled trials can only reduce uncertainty, not eliminate it. The trials presented in this article all have gaps, and like many studies, some raise more questions than answers. A summary of the current trials, however, can be presented as follows. For patients with
essential hypertension who are at high risk for
cardiovascular disease, the use of
diuretic therapy (excluding simultaneous use of ACE or CCB) resulted in outcomes at least equivalent to the use of either ACE or CCB without
diuretics. Naturally, the dilemma for clinicians is that these drugs are most often used in combination with
thiazide diuretics, as indicated by the RENAAL trial where 80% of ARB were used with
diuretics in patients with type II diabetes and known nephropathy. The increased risk of
heart failure observed with ACE and CCB in that trial may be relevant only to patients in whom
diuretics were not also used. The study does raise important awareness, however, that ACE or CCB use without
diuretic therapy is no better than
diuretic therapy, and may be associated with higher risk of certain outcomes. A substantial number of patients with
essential hypertension might achieve adequate blood pressure control with
diuretic monotherapy. If so, that certainly has important implications for the cost of medical care in this country. For African Americans with
essential hypertension, ACE may have advantages as a component of
therapy in comparison with CCBs or beta-blockers, although
diuretics should probably be the cornerstone of
therapy for them and supported by the Seventh Joint National Committee. For patients with proteinuric renal disease, whether associated with diabetes or
hypertension, it should be considered inappropriate to use DHP CCB as monotherapy in any setting, whether as part of a clinical trial or in clinical practice. These drugs should not be considered as ethical placebo arms in trials, most especially in
diabetic nephropathy, nor should they be used without an ACE or ARB in patients with proteinuric renal disease in the absence of documented
contraindications or intolerance to ACE, ARB, or non-DHP CCB (which are now considered second-line agents for proteinuric renal disease, and are acceptable placebo or comparison arms in clinical trials). For patients with type I diabetes, ACE remain the cornerstone of
therapy. Because of recent RENAAL and IDNT trial results, the greatest benefit for slowing progression of renal disease in type II
diabetic nephropathy now belongs to ARBs. In contrast, however, the HOPE trial showed that ACE, specifically
ramipril, had the greatest evidence for prevention of cardiovascular outcomes in patients with
renal insufficiency, regardless of diabetic status. Cardiovascular outcomes were secondary end points in the RENAAL and IDNT trials, and with the exception of
heart failure for
losartan, no benefits on cardiovascular outcomes were statistically significant. Progression of renal disease has only been studied in a relatively small cohort of Israeli patients comparing
enalapril with
nifedipine. These gaps lead to a classic dilemma in medical decision-making. Because evidence has shown that patients with elevated serum
creatinine (greater than or equal to 1.4 mg/dL) are just as likely to die from
cardiovascular disease as they are to reach
end-stage renal disease, which outcome should be the focus for clinicians, or for researchers? Using a strictly evidence-based approach, this question can only be answered by yet another large, long, randomized, controlled trial. Given the similarity of actions between the ARB and ACE, it is likely there is considerable overlap of both benefits and side-effects between the two, although ARB may have a lower incidence of
cough and
hyperkalemia. The decision of which
antihypertensive agents to use will have to be tailored carefully to the needs of the patient and careful consideration of both medical and economic factors. Regardless of the choice between an ACE or ARB, however, post hoc analysis of clinical trials [21,47] and observational data clearly indicate that patients with
chronic kidney disease, even if considered mild (ie, serum
creatinine greater than or equal to 1.4 mg/dL) are at significantly greater risk of cardiovascular morbidity and mortality compared with those with better kidney function. As stated in a recent review by the authors of the HOPE trial [50], "the frequent practice of withholding ACE [or ARB] in patients with mild
renal insufficiency is unwarranted," because not only are these patients precisely those who might benefit most from their use, but safety and tolerability are generally excellent. Based on the results of the AASK trial, the authors add the same for the use of
ACE inhibitors in African Americans.