Franz Volhard Clinic at the Max Delbrück Center for Molecular Medicine, Medical Faculty of the Charité, Humboldt University of Berlin, Berlin, Germany
Correspondence and offprint requests to: Friedrich C. Luft, MD, Charité Campus-Buch, Franz Volhard Clinic, Wiltberg Str. 50, D-13125 Berlin, Germany.
Blood pressure lowering with medication has had a major effect on mortality and morbidity of cardiovascular disease. This achievement is one of the major medical highlights of the past 50 years. Inhibiting angiotensin converting enzyme (ACE) has proved a highly worthwhile clinical strategy that lowers blood pressure, but also has substantial effects on inhibiting the progression of heart failure, chronic renal disease, and perhaps the course of diabetes mellitus. Three recent clinical trials shed new information on ACE inhibitors in terms of blood pressure and cardiovascular risk reduction, as well as risk reduction in patients with cardiovascular risk factors in general. The information from these trials is important enough to warrant editorial comments.
The captopril prevention project (CAPPP) study was performed to test the hypothesis that blood pressure reduction with the ACE inhibitor captopril would result in a better outcome than blood pressure reduction with diuretics and beta blockers [1]. Over 10000 patients with diastolic blood pressures 100 mmHg were randomized. The regimens were similar in terms of lowering blood pressure. In the intention-to-treat analysis the overall cardiovascular morbidity and mortality, as well as the rate of myocardial infarction and heart failure, were similar. Disturbingly, the relative risk of stroke was higher with captopril than with diuretics and beta blockers (RR=1.25, P=0.04). An analysis of actual treatment made things worse rather than better (RR=1.43, P=0.004). Diabetes mellitus developed at a lesser rate in the captopril group, compared to the conventionally treated group. In the subgroup of 572 patients with diabetes mellitus at baseline, the overall cardiovascular event incidence was significantly decreased with captopril, as well as the number of myocardial infarctions. The incidence of strokes was the same in this subgroup analysis. These results were somewhat disappointing if not disquieting, since they raised the possibility that captopril might be less effective at reducing stroke risk compared to standard therapy. Fournier et al. [2] have recently discussed the foibles of this study in detail. One problem was that some subjects in the ACE inhibitor group received captopril only once daily. The pharmacokinetics and pharmacodynamics of captopril are such that the drug is not suitable for once-a-day therapy. However, clearly the CAPPP study did not prove to be the death knell for conventional antihypertensive treatment that many believed it might.
An additional Scandinavian effort to turn the tables on standard antihypertensive treatment is the Swedish Trial in Old Patients with Hypertension (STOP-Hypertension)-2 trial [3]. In STOP-2, 6628 hypertensive men and women (systolic 180 mmHg, diastolic
105 mmHg or both) were randomized to thiazide diuretics (plus amiloride), beta blockers, ACE inhibitors or longer-acting calcium antagonists. When goal blood pressure was not achieved, the diuretic group could receive a beta blocker, the ACE inhibitor group could receive a diuretic, or the calcium antagonist group could receive a beta blocker. About half the patients required a second drug. STOP-2 showed that standard care and `newer' agents did not differ in terms of preventing stroke, myocardial infarction, or all major cardiovascular events. The frequency of heart failure was marginally (P=0.095) better in the ACE inhibitor group. When the ACE inhibitor group was compared to the calcium antagonist group, ACE inhibitors were significantly better at preventing myocardial infarction and heart failure. Oddly, the protection from diabetes offered by ACE inhibitors observed in CAPPP was not present in STOP-2. STOP-2 provides valuable treatment guidelines. Again is underscored the important message that blood pressure reduction per se is of major importance for the prevention of cardiovascular events. Other theoretical considerations are secondary.
The final word on ACE inhibitor therapy, at least until the next study results are available, is the Heart Outcomes Prevention Evaluation (HOPE) study [4]. The trial was not primarily directed at patients with hypertension. In HOPE, 9297 men and women 55 years old were eligible if they had a history of coronary disease, stroke, peripheral vascular disease, or diabetes mellitus, plus at least one other cardiovascular risk factor (smoking, hypertension, hyperlipidaemia, or microalbuminuria). The eligible patients were randomized to either ramipril 10 mg daily or matching placebo. Exclusion criteria were low ejection fraction (<0.40), concurrent ACE inhibitor therapy, uncontrolled hypertension, renal failure (creatinine >2.3 mg/dl), a recent myocardial infarction or a recent stroke. A vitamin E randomization was an additional HOPE hypothesis that need not concern us here. A follow-up of 5 years was planned, however, the study was discontinued earlier than planned because of clear benefits in the ramipril group.
Blood pressures were similar in the ramipril and placebo groups (137/76 mmHg compared with 139/77 mmHg). Less patients died of myocardial infarction in the ramipril group, compared to the placebo group (RR=0.78, P<0.001). Death from all cardiovascular causes was similarly reduced by ramipril. The occurrence of myocardial infarction was reduced (RR=0.80, P<0.001), as were stroke (RR=0.69, P<0.001), and death from any cause (RR=0.75, P=0.006). Secondary hypotheses included a decrease in the appearance of heart failure (RR=0.77, P<0.001) and complications related to diabetes mellitus (R=0.84, P=0.03). The benefits were independent of age, gender, or pre-existing cardiovascular disease.
The HOPE results must be interpreted in the context that HOPE was not a blood pressure-lowering study. Nevertheless, the fact that ramipril protected from stroke is reassuring to those whose minds were crossed with the idea that ACE inhibitor treatment might be permissive for stroke. The conclusion that ramipril significantly reduces the rates of death from myocardial infarction, and stroke in a broad range of high-risk patients who do not have low ejection fraction or heart failure, seems inescapable.
There appear to be two important messages from these studies. The first is that in patients with hypertension, the single most important service we can provide is to lower blood pressure with medications to a range suggested from trials such as the HOT study [5]. By so doing, we will maximally lower their blood pressure-related cardiovascular risk. The second is that ACE inhibition renders a remarkable service, independent of its blood pressure-lowering effects. The trials in patients with heart failure and decreased renal function, with or without diabetes mellitus, are compelling. The HOPE study extends the cardiac benefits to high cardiovascular risk persons who still have ventricular function in the normal range. How ACE inhibitors provide this benefit is not clear. Inhibition of angiotensin (Ang) II formation would not appear to be the sole mechanism, since Ang II levels do not remain low with ACE inhibitor treatment. Perhaps the answer does indeed lie in kinin generation. A recent report showed that mice with targeted disruption of the bradykinin-2 receptor develop elevated blood pressure with cardiomyopathy [6]. ACE inhibitors provide for increased bradykinin-dependent signalling because ACE is responsible for the degradation of bradykinin. Thus, ACE inhibitors have earned their high place in the saddle. Since the ELITE 2 study (unpublished) was not able to confirm the preliminary data from the initial ELITE study in which captopril and losartan were compared in older patients with heart failure [7], it is likely that they will remain there for a bit longer.
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