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ACE Inhibition and Vascular Protection in Hypertension

Dosing of ACE Inhibitors in Left Ventricular Dysfunction: Does Current Clinical Dosing Provide Optimal Benefit?

Pinto, Yigal M.; van Geel, Peter Paul; Alkfaji, H.; van Veldhuisen, Dirk-Jan; van Gilst, Wiek H.

Editor(s): Lüscher, Thomas F.

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Journal of Cardiovascular Pharmacology: August 1999 - Volume 34 - Issue - p S13-S17
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Abstract

Until the advent of angiotensin converting enzyme (ACE) inhibitors, left ventricular dysfunction had often been approached with symptomatic treatment, without clear evidence that this would alter prognosis. However, improved understanding of the complex mechanism behind the ultimately fatal progression from left ventricular dysfunction to heart failure has paved the way to intervene successfully, thereby improving not only symptoms, but also prognosis. The remaining issue is to translate experiences from clinical trials into day-to-day practice.

ACE INHIBITION IS A WELL ESTABLISHED TREATMENT IN LEFT VENTRICULAR DYSFUNCTION

ACE inhibitors have become one of the cornerstones of heart failure treatment. ACE inhibitors reduce after-load, preload, and increase cardiac output. Moreover, several large, prospective, randomized, placebo-controlled trials have established that ACE inhibitors reduce overall mortality in patients with congestive heart failure (references shown in Table 2); ACE inhibition is even effective in asymptomatic left ventricular dysfunction. This reduction in mortality results primarily from a reduction in progression of congestive heart failure, although the incidence of sudden death and myocardial infarction may also decrease.

Table 2
Table 2:
Overview of different dosages used in clinical trials

The role of ACE inhibition during acute myocardial infarction remains unclear; it is not common practice to commence ACE inhibition during an acute myocardial infarction, although some studies did suggest beneficial effects (1). However, it is highly probable that only the patients prone to develop left ventricular dysfunction will benefit from this very acute start of ACE inhibitors. In the acute phase of myocardial infarction it is difficult to predict which patients will benefit, so that many patients are unnecessarily subjected to treatment.

THE MECHANISM BY WHICH ACE INHIBITION EXERTS ITS BENEFICIAL ACTIONS REMAINS ELUSIVE

In-vitro studies suggest that the presence of the sulfhydryl group may confer free-radical scavenging properties and effects on prostaglandins (2). However, ACE inhibitors from all three classes are clinically efficacious, so that there does not seem to be a particular advantage to one of the different types of ACE inhibitors (Table 1); indeed, a direct experimental comparison between ACE inhibitor with or without a sulfhydryl group has not demonstrated differences in efficacy (3).

Table 1
Table 1:
Classification of angiotensin-converting enzyme (ACE) inhibitors according to the chemical structure of their active moiety

Captopril differs from other ACE inhibitors because of its short half-life. With the exception of fosinopril, trandolapril, and spirapril, ACE inhibitors are cleared predominantly by the kidney. For this reason, dose reductions are required in the setting of impaired renal function. The majority of ACE inhibitors are administered as prodrugs that remain inactive until esterified in the liver. These prodrugs have enhanced oral bioavailability compared with their active drugs. ACE is present in plasma as well as in tissues, and there are differences in the relative tissue affinity of ACE inhibitors. Recent experimental evidence suggests that issue ACE is functionally more important than free, unbound circulating ACE (4). In this study, the phenotype of the complete ACE knock-out mice was mimicked by a knock-out of the membrane bound part of ACE, leaving only testicular and circulating ACE intact. This suggests a physiological impairment in ACE activity when tissue-bound ACE is disrupted, even when circulating ACE is left intact.

Several investigators have shown that the effects of ACE inhibitors on blood pressure correlate better with tissue ACE levels than with circulating ACE (5), but the clinical significance of differences in tissue binding has not been established. However, differences in binding to tissue ACE between different ACE inhibitors is better established. For example, Fabris et al. (6) examined the binding of various ACE inhibitors to heart homogenates (Fig. 1).

FIG. 1
FIG. 1:
Depiction of the binding-affinity of various angiotensin converting enzyme inhibitors to heart homogenates. Data from (5).

The effects of ACE inhibitors on the renin-angiotensin system (RAS) in humans is well documented. ACE inhibitors block the pressor response to intravenous angiotensin I but not angiotensin II. When ACE inhibitors are given in the short-term, endogenous levels of angiotensin II and aldosterone decrease, whereas plasma renin activity (PRA) and angiotensin I increase, at least in part because of loss of feedback inhibition. The resulting increase in angiotensin I levels may result in degradation of angiotensin I to angiotensin 1-7, a vasodilator, or in the formation of angiotensin II via non-ACE-mediated pathways (7,8), although the role of these alternative degradation products in humans is still controversial (9). Interestingly, with chronic ACE inhibition, angiotensin II and aldosterone levels tend to return toward pretreatment levels (10-12).

Having described on one hand the beneficial effects of some ACE inhibitors in patients with left ventricular dysfunction but on the other hand that different ACE inhibitors vary greatly with regard to half-life and binding of tissue ACE, one may question whether each dose of any given ACE inhibitor can be expected to yield optimal results in patients with left ventricular dysfunction. There is evidence to suggest the contrary.

SOME PATIENTS MAY BE RESISTANT TO ACE INHIBITION

It is unclear whether all patients are similarly sensitive to ACE inhibition. A deletion/insertion (D/I) polymorphism is associated with higher plasma and cardiac ACE activity (13,14). Some preliminary studies reported that the ACE polymorphism can modify the efficacy of ACE inhibition therapy. Ueda et al. (15) showed that the effect of enalaprilat was significantly greater and lasted longer in normotensive men homozygous for the II ACE genotype. In patients with coronary artery disease, the efficacy of quinapril to improve endothelium-dependent flow-mediated coronary vasodilatation was related to ACE genotype so that a significant improvement was seen only in patients with the I allele but not in DD patients (16). That exogenous factors can also influence the efficacy of ACE inhibition treatment in patients with the ACE DD genotype was reported by van der Kleij et al. (17). They found, in patients with stable non-diabetic proteinuria, that the sodium status accounted for the efficacy of ACE inhibition on proteinuria and blood pressure in patients with the DD genotype but not in II and ID patients. These studies indicate that knowledge of ACE genotype may be of value in determining the likely impact of ACE inhibitor treatment and possibly explain the well known individual heterogeneity in the response to antihypertensive drugs.

CLINICAL TRIALS USE HIGHER DOSES THAN IN NORMAL PRAXIS

An important difference between clinical trials and current daily practice is that the target dose in clinical trials is higher than that often given in daily practice: enalapril was always given twice daily in the trials, while it is often used only once daily in clinical practice, the mean dose of enalapril being close to 20 mg daily. Captopril was used at doses of 75-150 mg daily, either twice or three times daily. This level of ACE inhibitor dose is often not achieved in clinical practice, as a recent evaluation demonstrated (18). Most patients enrolled in the Prospective Randomized Study of Ibopamine (PRIME) with heart failure used an ACE inhibitor at a dose at the discretion of the treating physician. When a high dose was defined as 75 mg captopril or higher, or higher than 20 mg enalapril, it was shown that only about 25% of the patients were using the 'high' dose of ACE inhibitor (18). Given these differences, it is important to evaluate whether higher doses of an ACE inhibitor would yield better clinical results. Indeed, in a recent study we conducted it is suggested that higher dosages are more efficacious (19). Here, 244 patients suffering from mild-to-moderate heart failure were randomized to receive either placebo, or the long-acting ACE inhibitor imidapril 2.5 mg, 5 mg or 10 mg once daily. Although all three doses suppressed plasma ACE activity to a similar extent, only the highest dose (10 mg) was associated with a significant increase in exercise time. This suggests not only that higher doses of an ACE inhibitor may be more efficacious, but also that this effect is unrelated to the degree to which plasma ACE activity is inhibited. Therefore, this concurs with the notion obtained from experimental data that plasma ACE activity is less relevant than tissue-bound ACE (20). In the Assessment of Treatment with Lisinopril and Survival (ATLAS) study, 3164 patients were randomized to receive either low-dose lisinopril (2.5 or 5 mg) or high-dose lisinopril (32.5 or 35 mg) for 4 years (21). The high-dose lisinopril compared to low-dose reduced all-cause mortality (the primary end-point), but this was not statistically significant. However, high-dose lisinopril significantly reduced the secondary end-point of combined all-cause mortality and hospitalization (−12%). Therefore, this trial at least suggests that chronic high-dose ACE inhibition may be more beneficial than low-dose. However, there are also arguments against. Firstly, the NETWORK trial assessed the effects of 10 mg, 5 mg or 2.5 mg enalapril twice daily on mortality and hospitalizations in 1532 patients with heart failure (22). At 6-months follow-up there were no differences between the higher and lower dosage groups. However, one could argue that the follow-up period is rather short, particularly since the protective effects of ACE inhibition usually only become apparent after a longer period. Another important limitation is the fact that the installation of a high dose of ACE inhibition may simply reflect that a patient is able to tolerate this higher dose better, and that this in itself is associated with a better prognosis.

Taking the above together, it is clear that a minority of patients with heart failure are treated with the dose of ACE inhibition for which efficacy was proven in the large randomized trials. Although it is still unsettled, two recent trials suggest that a higher dose of an ACE inhibitor may improve outcome as compared to a lower dose. Therefore, it seems reasonable to install a higher dose in the patients that tolerate that, until data become available to suggest otherwise.

ACE ACTIVITY INCREASES DURING ACE INHIBITOR THERAPY

Experimental studies clearly show that, during ACE inhibitor treatment, there is a counter-regulatory increase in ACE expression (23) and that this can lead to an increase in ACE activity after the last dose. This is not only seen with circulating unbound ACE, but also with tissue-bound ACE. It is therefore important that each subsequent dose is adequately timed and of sufficient amount to counteract this increase in ACE protein. This again underlines the previous point; it is conceivable that dosing of an ACE inhibitor lower than given in the above trials (e.g., enalapril 10 mg once daily, or captopril 12.5 mg twice daily) is inefficient in blocking the counter-regulatory increase in ACE production and hence ACE activity, which results in a lack of functional ACE inhibition. Similarly, one could argue that, for a few ACE inhibitors, a once-daily regimen has been proved to be efficacious; this has been shown for lisinopril and trandolapril (Table 2) and may apply to the newer agent fosinopril (24). The long half-life of ACE inhibitors such as spirapril, lisinopril or others may be helpful to prevent an increase of ACE activity during s drug-free interval. It is important to note that a drug such as enalapril is often used in daily practice once daily, whereas its efficacy has been investigated and proved only with twice daily dosing.

CONCLUSION

This brief review has discussed ACE inhibition in patients with left ventricular dysfunction. Although their efficacy is clearly proven in large prospective trials, some questions have remained in the translation of ACE inhibitor treatment to daily practice.

Firstly, it is still to be determined whether a genetic predisposition such as the ACE deletion type gene may confer decreased ACE inhibitor efficacy. Secondly, in general higher doses, such as used in the large clinical trials, seem more effective than lower doses that are (too) often used in daily practice; for example, often enalapril is administered once daily, whereas its efficacy in left ventricular dysfunction has been proved solely with twice-daily administration. It is conceivable that doses that are too low, and timed too far apart, may fail to block the increased production and activity of ACE that is known to occur during ACE inhibition.

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Section Description

A Spirapril symposium held in Vienna, Austria, August 25, 1998

The symposium and the publication of this supplement were supported by an educational grant from ASTA Medica AG, Frankfurt am Main, Germany.

Keywords:

ACE inhibitors; Left ventricular dysfunction; Clinical trials; Genetics; Treatment

© 1999 Lippincott Williams & Wilkins, Inc.