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J Am Coll Cardiol, 1998; 32:1811-1818 © 1998 by the American College of Cardiology Foundation |
a Department of Cardiology/Thoraxcenter, University Hospital Groningen, Groningen, The Netherlands
* the II. Medical Clinic, Johannes Gutenberg-University Clinic, Mainz, Germany
COEUR/Department of Internal Medicine I, University Hospital Dijkzigt, Rotterdam, The Netherlands
Clinical Research, Merck KGaA, Darmstadt, Germany
|| the Institute of Clinical Pharmacology, University of Groningen, Groningen, The Netherlands
the Department of Cardiology, Academic Medical Center, Amsterdam, The Netherlands
Manuscript received May 5, 1998; revised manuscript received July 13, 1998, accepted August 6, 1998.
Address for correspondence: Dr. D.J. van Veldhuisen, Department of Cardiology/Thoraxcenter, University Hospital Groningen, PO Box 30 001, 9700 RB Groningen, The Netherlands
d.j.van.veldhuisen{at}thorax.azg.nl
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Abstract |
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Background. The ACE inhibitors have become a cornerstone in the treatment of CHF, but whether high doses are more effective than low doses has not been fully elucidated, nor have the mechanisms involved in such a dose-related effect.
Methods. In a parallel group comparison, the effects of three doses of imidapril were examined. We studied 244 patients with mild to moderate CHF (New York Heart Association class II–III: ±80%/20%), who were stable on digoxin and diuretics. Patients were treated for 12 weeks, and the main end points were exercise capacity and plasma neurohormones.
Results. At baseline, the four treatment groups were well-matched for demographic variables. Of the 244 patients, 25 dropped out: 3 patients died, and 9 developed progressive CHF (3/182 patients on imidapril vs. 6/62 patients on placebo, p < 0.05). Exercise time increased 45 s in the 10-mg group (p = 0.02 vs. placebo), but it did not significantly change in the 5-mg (+16 s), and 2.5-mg (+11 s) imidapril group, compared to placebo (+3 s). Physical working capacity also increased in a dose-related manner. Plasma brain and atrial natriuretic peptide decreased (p < 0.05 for linear trend), while (nor)epinephrine, aldosterone and endothelin were not significantly affected. Renin increased in a dose-related manner, but plasma ACE activity was suppressed similarly (±60%) on all three doses.
Conclusions. Already within 3 months after treatment initiation, high-dose ACE inhibition (with imidapril) is superior to low-dose. This is reflected by a more pronounced effect on exercise capacity and some of the neurohormones, but it does not appear to be related to the extent of suppression of plasma ACE.
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Imidapril hydrochloride is a long-acting, orally active, nonsulphydryl-containing ACE inhibitor that has been used in hypertension, CHF and after myocardial infarction (7–12). Imidapril is a pro-drug that is converted by the liver to its active metabolite imidaprilat. It has a potent hypotensive effect, and the inhibition of ACE lasts significantly longer in tissue than in plasma. In hypertensive patients, blood pressure was still decreased 24 h after imidapril administration in a dose-dependent manner; plasma ACE was still 60% suppressed at this time (8). Maximal reduction in blood pressure and plasma ACE was achieved with 10 mg imidapril once daily (8,9), and with increasing doses no additional effect was found (8). When administered to patients with acute myocardial infarction, imidapril was found to improve left ventricular ejection fraction and to reduce plasma brain natriuretic peptide (BNP) levels (11). In patients with CHF (New York Heart Association [NYHA] functional class II–III), 2.5 mg and 5 mg imidapril lowered plasma ACE to a similar extent, whereas the effect on blood pressure was more pronounced on 5 mg imidapril (12).
In the present study, we examined the dose-related clinical and neurohormonal effects of three doses (2.5 mg, 5 mg and 10 mg) of imidapril during 12 weeks of treatment, compared to placebo in patients with stable mild to moderate CHF, who were treated with digoxin and diuretics.
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Methods |
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Patients. Subjects were eligible if they met the following criteria: 1) signs and symptoms of mild to moderate CHF (NYHA class II–III); 2) aged 21 to 75 years (females were postmenopausal, or taking contraceptive medication); 3) a left ventricular ejection fraction <0.45; and 4) a minimal exercise duration >2 min, and a maximal exercise duration of 12 and 10 min, respectively, for men and women <46 years, of 10 and 8 min for subjects 46 to 60 years, and 8 and 6 min for subjects >60 years. A 20% difference in exercise was allowed between the two baseline tests (the shorter exercise duration serving as the 100% value), and both tests were limited by dyspnea and/or fatigue.
Patients were excluded from participation if they had hemodynamically significant valvular disease, active myocarditis, thyroid disease or hypertrophic cardiomyopathy, a history of myocardial infarction or open heart surgery <3 months, severe hypertension (requiring treatment other than diuretics) or hypotension (supine systolic blood pressure <100 mm Hg), angina pectoris (limiting exercise capacity as well as unstable complaints), atrial fibrillation (requiring other than digitalis therapy), supraventricular or ventricular arrhythmias requiring treatment (antiarrhythmic drugs and pacemakers not allowed), right-sided CHF, significant electrolyte abnormalities, any other relevant disease (including anemia) and significant over- or underweight from normal. Patients with known or suspicion of bilateral renal artery stenosis, and those with significant impaired renal function (serum creatinine >1.8 mg/dl or >160 µmol/liter) or renal transplantation were also excluded. Patients who had a history of substance abuse were also not included. The following drugs were not allowed: vasodilators (including calcium channel blockers) except for nitrates, ß-blockers, potassium-retaining diuretics, lithium, allopurinol, cytostatic or immunosuppressive agents, neuroleptics, imipramine, and nonsteroidal anti-inflammatory drugs except aspirin. Also, ACE inhibitor therapy was not allowed within 4 weeks prior to the start of the study (=6 weeks prior to randomization), and patients with known intolerance were also excluded.
Exercise protocol. During the run-in phase, exercise testing was performed twice (see above), and it was repeated after 8 and 12 weeks of double-blind treatment. Exercise testing was performed in the morning between 9 and 10 AM, before intake of study medication; it was intended that this test was carried out 24 ± 4 h after intake of the previous study medication, and 2 to 4 h after a light breakfast, without coffee or tea. Exercise testing was carried out in the sitting position, using an electrically braked bicycle ergometer. The protocol started with a workload of 50 W, and was increased with steps of 10 W; each step was maintained for 1 min. Heart rate and blood pressure were measured before and throughout the test, and the electrocardiogram was monitored continuously.
Exercise tolerance was assessed by determining total exercise time and physical (or pulse) working capacity (PWC) determined at 110 beats/min during exercise (PWC110). The PWC allows us to measure submaximal exercise tolerance and is not dependent on patients’ motivation (13–15). The PWC is determined by examining the relationship between heart rate and power output (in watts). By using PWC, one gets information on how many watts (W) can be reached at a certain heart rate. Because of the limited maximal pulse reached by CHF patients during exercise testing, we (prospectively) chose 110 beats/min, but in healthy subjects higher heart rates are often used (13). The PWC110 is calculated as follows:
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The PWC110 was only determined in patients with sinus rhythm, as the chronotropic response to exercise in atrial fibrillation and CHF is markedly enhanced and difficult to quantify (16).
Plasma neurohormones. Measurements were determined in a subset of patients and performed at three core laboratories (see Appendix). All samples were taken from an indwelling venous canula, after >30 min of supine rest, and at peak exercise. Samples were taken at baseline and at the end of the study. Plasma norepinephrine (normal value in our laboratory: 100 to 500 pg/ml) and epinephrine (normal: 10 to 70 pg/ml) were determined by high performance liquid chromatography with electrochemical detection (17). Active plasma renin (normal: 5 to 50 µU/ml) was determined with immunoradiometric assay (Nichols Institute, Bad Nauheim, Germany) (18). Plasma aldosterone (normal: 50 to 250 pg/ml) was determined by radioimmunoassay (Coat-a-Count, Diagnostic Products, Los Angeles, California) (19). Plasma endothelin concentrations (normal: 1 to 5 pg/ml) were measured by using radioimmunoassay (Amersham Buchler, Braunschweig, Germany) (20). Plasma ACE (normal: 18 to 55 U/I) was determined radiometrically by using (phenyl-4-3H)-hippuryl-glycyl-glycine as a substrate (21,22). Plasma atrial natriuretic peptide (ANP; normal: 50 to 110 pg/ml) and BNP (normal: 25 to 55 pg/ml) were measured (after SepPak extraction) with kits from the Nichols Institute, Nijmegen, The Netherlands, and Peninsula Laboratories, Belmont, California, respectively (23,24).
Statistical analysis.
The primary end point of the study was change in maximal exercise time after 12 weeks. Secondary end points were changes in submaximal exercise tolerance using PWC110, CHF symptomatology, progression of CHF and neurohormones. In addition, various safety parameters were assessed. It was estimated that 60 patients per group would be sufficient to detect a true difference between the medication groups, with a probability of 90% at an 
= 0.05 significance level (2-sided, normal distribution).
The primary analysis was performed with the intention-to-treat population, to ensure that all patients were included in the analysis, and to avoid bias from missing data, as previously described (19). In short, we used a nonparametric approach in which all patients who dropped out were assigned lowest rank, and missing values were substituted by the lowest exercise results of that particular group (worst-case analysis). In addition, only patients who completed the protocol were analyzed (per protocol population).
Distribution of the baseline variables was compared with analysis of variance (ANOVA) and the t test (for continuous variables) and chi-square test (for categoric variables). Differences among groups after randomization were analyzed at each scheduled follow-up visit by comparing the mean change from baseline with use of the ANOVA and the t test. Use of this procedure avoided any bias that would have been caused by including baseline data from patients who were subsequently withdrawn from the study. Values are mean ±SD unless indicated otherwise. All p values reported are for two-tailed test, and a two-tailed alpha of <0.05 was considered statistically significant.
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Plasma neurohormones. These were available in 82 patients (placebo n = 19, imidapril 2.5/5/10 mg, n = 22/17/24, respectively). This subgroup was not different from the total study group, and the four groups were also well balanced. At baseline, only plasma ANP and BNP were elevated; other neurohormones were within the normal range (Table 2).
Plasma norepinephrine concentrations at rest were not affected by imidapril; during exercise they appeared to be slightly attenuated (p = NS) (Fig. 2A). Epinephrine was also not affected. Plasma renin at rest slightly increased on all three doses of imidapril (only significant for 10 mg), but during exercise this increase was more pronounced (p < 0.05 for all doses) (Fig. 2B). Furthermore, a dose-response relation by linear trend was observed both at rest (p = 0.011) and during exercise (p < 0.001). Plasma aldosterone and plasma endothelin were not affected, neither at rest nor during exercise. Plasma ACE (Fig. 2C) was suppressed by ±60% on all three doses (all p < 0.001). Plasma ANP at rest was not significantly affected by imidapril, although a trend was observed: –36 pmol/liter on 10 mg imidapril, p = 0.1 vs. placebo. During exercise, all three imidapril doses decreased ANP, which was dose dependent (p = 0.02 for linear trend). Plasma BNP decreased in the 5-mg and 10-mg imidapril group at rest (both p < 0.05), and in the 10-mg group during exercise (p < 0.05) (Fig. 2D). This effect was dose dependent, at rest and during exercise (p < 0.05).
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Potential explanations. Given the dose-related decrease of both BNP and ANP during imidapril treatment in this study, unloading of the heart appears to play an important role. Natriuretic peptides are released in response to an increase in intracardiac volume or pressure, both in the atria (ANP) and in the ventricles (BNP) (25). Furthermore, natriuretic peptides are related to the severity of CHF and prognosis, and a decrease could thus be interpreted as a favorable response (6). An important effect of ACE inhibitors in CHF is unloading of the heart, thereby preventing cardiac dilatation, and improving diastolic function (26). The latter was also found to correlate significantly with a reduction in ANP levels, which is therefore compatible with the observed (dose-related) effect in the present study.
A second explanation may be the dose-related improvement in PWC110, which indicates that at a heart rate of 110 beats/min, more work is accomplished, or a lower heart rate is "required." While both resting and peak exercise heart rates were not affected by imidapril, submaximal heart rate was lower. In CHF, cardiac output during exercise depends on chronotropic mechanisms, and the present findings would support a dose-dependent effect of imidapril. Furthermore, while resting heart rate may be similar in CHF patients of different severity, during the early stages of exercise it increases more in advanced CHF than in mild CHF (27). This blunted response of heart rate in mild CHF may be explained by a reduced sympathetic drive during exercise (28), which was also observed in the present study.
Several other mechanisms may have played a role in the observed effects of ACE inhibition in the present study. Chronic heart failure is accompanied by a decreased skeletal muscle blood flow, which is an important contributing factor responsible in the exercise intolerance in these patients. The ACE inhibitors improve skeletal muscle blood flow (29), and the present findings may also be related to this. Furthermore, ACE inhibitors inhibit the degradation of bradykinin and potentiate its actions, which may also explain part of its beneficial effects, and in animal studies this effect was also dose-related (30). Although it may be speculated that both mechanisms might also have been affected in a dose-related manner by imidapril, they were not investigated in the present study.
Previous studies. In two earlier studies with quinapril in patients with mild CHF, a dose-dependent improvement in exercise time (31) and hemodynamics (22) was observed. In advanced CHF, high-dose enalapril was superior to low-dose for symptomatology, but no difference was observed in exercise capacity and hemodynamics (32). Recently, the NETWORK was published, in which 1,532 patients with CHF NYHA class II–IV were randomized to 2.5, 5 or 10 mg enalapril twice daily (33). After 6 months, no differences were observed with regard to mortality or hospitalizations for CHF. Even more recently, results of the Assessment of Treatment with Lisinopril and Survival (ATLAS) study have also become available (34). In that study, 3,164 patients with NYHA class II–IV CHF were randomized to either low-dose (2.5 or 5 mg) or high-dose (32.5 or 35 mg) lisinopril, and they were followed for almost 4 years. Although results of the ATLAS study have not yet been fully published, the data show that, compared to low-dose ACE inhibition, high-dose lisinopril does not cause a statistically significant reduction in all-cause mortality, but it is associated with a significant reduction (–12%) in the combined end point of all-cause mortality and hospitalization. A third large-scale trial of comparable size (ACHIEVE) is currently still underway (6).
Regarding the neurohormonal effects, Nussberger et al. (22) showed a dose-dependent decrease in angiotensin II after quinapril, while renin increased. A similar effect was also found after short-term lisinopril treatment in patients with mild CHF (24), but in severe CHF (32), neurohormones were not affected in a dose-dependent manner by enalapril. In the present study, only ANP and BNP were increased at baseline, which supports their value in mild CHF (35), and confirms that these neurohormones may also be very useful in the assessment of drug-induced changes in mild CHF (6).
Inhibition of the renin-angiotensin system. Plasma renin increased during imidapril treatment in a dose-related manner, but plasma ACE was suppressed to a similar extent, which suggests that plasma ACE activity poorly reflects the degree to which the renin-angiotensin system is suppressed. This is supported by a recent experimental study in which the degree of plasma ACE inhibition underestimated local angiotensin I conversion (36). Furthermore, in a clinical study there was no correlation between the clinical effects and the degree of plasma ACE inhibition (37). Therefore, plasma renin (particularly during exercise) may be a better parameter to judge dose-related suppression of the renin-angiotensin system. Plasma renin increases in response to ACE-inhibition both at rest and during exercise; the latter effect is probably due to an acute release from the juxtaglomerular cells in the kidney, which is susceptible to sympathetic blockade (38). Thus, the higher exercise-related increase in renin with higher doses of imidapril may reflect larger stores of renin in the kidney, which suggests a more effective decrease of local angiotensin II, and confirms the importance of tissue inhibition (39).
Study limitations. Given the rather small patient population and the short follow-up, the present results are clearly not definitive, for they do not provide data on mortality and (long-term) morbidity. However, this study was designed to examine whether high-dose ACE inhibition would be superior to low-dose, with regard to exercise capacity and neurohormones, and in this respect the data may be complementary to larger survival studies such as ATLAS. A study period of 3 months was chosen because it was deemed unethical to refrain patients from ACE inhibition any longer at that time. Given this short follow-up, however, it can also not be excluded that low-dose imidapril might also have been effective during prolonged treatment, and in more advanced CHF. In addition, these data obtained with imidapril should not automatically be extrapolated to other ACE-inhibitors, as these compounds may differ—for instance, with regard to tissue penetration (40). Furthermore, the observed superiority of high-dose ACE inhibition in mild CHF may not be similar in advanced CHF (32), which might be due to differences in sensitivity to ACE inhibition.
Clinical implications. The present study shows that already within the first 3 months of initiating ACE inhibitor treatment with imidapril, high-dose treatment is more effective than low dose treatment, which is reflected by a preservation of exercise capacity, and a more pronounced decrease in the atrial peptides (ANP and BNP). Although the present study provides insight into underlying mechanisms of dose-related effects, further data from larger survival trials will be needed to confirm a dose-dependent effect on prognosis.
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Appendix |
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TopAbstractMethodsResultsDiscussionAppendixReferences |
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Maria Ziekenhuis, Tilburg, H.A.M. van Kesteren; St. Jans Gasthuis Weert, H.J.A.M. Penn; University Hospital Groningen, D.J. van Veldhuisen; St. Elisabeth Ziekenhuis, Tilburg, W.H. Pasteuning; Ziekenhuis Hilversum, K.L. Liem; Refaja Ziekenhuis, Stadskanaal, L.M. van Wijk; Reinier de Graaf Ziekenhuis, Delft, A.J.A.M. Withagen; St. Gemini Ziekenhuis, Den Helder, J.G.M. Tans; Twenteborg Ziekenhuis Almelo, J.L. Darmanata; Het Nieuwe Spittaal, Zutphen, A.C. Tans.
Belgium
Ziekenhuis Genk, W. Van Mieghem.
Germany
Städtisches Krankenhaus, Bietigheim-Bissingen, D. Hey; Klinikum Südstadt, Rostock, G. Naumann; Johannes-Gutenberg-Universität Medizinische Klinik, Mainz, H. Darius; Krankenhaus Pfungstadt, K.H. Baumgartl; Stadtkrankenhaus Neuwied, W. Mansury; Stadtkrankenhaus Worms, P. Limbourg; Krankenhaus Rosenheim, R. Rackwitz; Medizinische Akademie, Erfurt, I. Assmann; Krankenhaus Kaarst, D. Maring; Krankenhaus Bellheim, R. Philipp; Krankenhaus Berlin, R. Bohm; Krankenhaus Darmstadt, D. Gengnagel; Katharinen-Krankenhaus, Frankfurt/Main, H.J. Gilfrich; Medizinische Universitätsklinik, Tübingen, R. Haasis.
Core Laboratories for Plasma Neurohumoral Determinations
Plasma (nor)epinephrine, renin, aldosterone, and ACE activities were determined at Bioscientia, Ingelheim/Rhein, Germany (Dr. A. Schmitt). Plasma endothelin was determined at Merck KGaA Clinical Research, Darmstadt, Germany (Dr. A. Klieber), and ANP and BNP were determined at the University Hospital Dijkzigt, Rotterdam, The Netherlands (Dr. F. Boomsma).
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1 Dr. Van Veldhuisen is a Clinical Scientific Investigator of the Dutch Heart Foundation. 
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