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Clinical and neurohumoral differences between spirapril and captopril in mild to moderate chronic congestive heart failure
Journal of Cardiac Failure Vol. 3 No. 3 1997
Clinical Investigations Clinical and Neurohumoral Differences Between Spirapril and Captopril in Mild to Moderate Chronic Congestive Heart Failure STAN A. J. VAN DEN BROEK, MD,* PIETER A. DE GRAEFF, MD,t DIRK J. VAN VELDHUISEN, MD, FACC,* WIEK H. VAN GILST, PhD,t HANS HILLEGE, MD,* HARRY WESSELING, MD,t KONG I. LIE, MD* Groningen, The Netherlands
ABSTRACT Background: This study was done to determine whether the difference in duration of action of the long-acting angiotensin-converting enzyme (ACE) inhibitor spirapril compared with the short-acting ACE inhibitor captopril affects clinical efficacy in patients with congestive heart failure. Methods and Results: The effects on exercise capacity, neurohumoral status, and quality of life were studied in 20 patients with mild to moderate congestive heart failure in a doubleblind, randomized, comparative study in parallel groups with a duration of 12 weeks. All assessments during the study were performed in the morning, before intake of the study medication, to avoid the expected peak effect of the ACE inhibitors used. Mean peak oxygen consumption (peak Vo2) was 17.4 mL/min/kg (range, 14.2-19.9 mL/min/kg) and mean left ventricular ejection fraction was 28% (range, 13-40%). Exercise duration in tile captopril group showed a significant increase after 12 weeks (P < .05) of treatment compared with the spirapril group. Peak oxygen consumption tended only to increase in the captopril-treated patients compared with the spirapril-treated patients. Serum ACE activity was significantly different between the two treatment groups during treatment (P < .0001) and showed only a significant decrease in the spirapril group. There was no difference in improvement of quality of life between the two treatment groups. Conclusions: This study showed that the effects of the ACE inhibitors spirapril and captopril on exercise capacity are not related to the degree of inhibition of serum ACE activity. Key words: angiotensin-converting enzyme inhibitor, exercise capacity, serum angiotensinconverting enzyme activity.
Angiotensin-converting enzyme (ACE) inhibitors have become a cornerstone in the treatment of conges-
tive heart failure (CHF). They have been shown to improve not only haemodynamics, clinical status, and exercise performance (1,2), but survival as well (3,4). Although both long- and short-acting ACE inhibitors are effective in patients with C H F (5-8), the question remains whether all ACE inhibitors are equal or do differences in duration of fiction affect clinical efficacy (9). It has been suggested that prolonged ACE inhibition may be required if exercise improvement is expected throughout the day (10). Therefore, we compared spirapril, a rather new ACE inhibitor, with a prolonged dura-
From the *Department of Cardiology/Thoraxcenter and "?Department of Pharmacology~Clinical Pharmacology, University Hospital of Groningen, Groningen, The Netherlands.
Supported by a grant from Sandoz Pharma, Basel, Switzerland. Manuscript received August 30, 1996; revised manuscript received March 31, 1997; revised manuscript accepted May 21, 1997. Reprint requests: Dirk J. van Veldhuisen, MD, Thoraxcenter/Departmerit of Cardiology, University Hospital Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands. ©1997 Churchill Livingstone Inc.
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tion of action, with captopril, the only currently used ACE inhibitor with a short duration of action. Spirapril is a nonsulfydryl-containing ACE inhibitor that has demonstrated beneficial hemodynamic and neurohumoral effects in patients with moderate to severe CHF (11). The therapeutic efficacy of spirapril as compared with other ACE inhibitors in CHF has not been studied yet. Because of the different durations of action of the two ACE inhibitors, all clinical and neurohumoral examinations were performed in the morning before intake of the morning dose of the study drug. This design was deliberately chosen to avoid the possibility of bias from the "peak" drug effect and to determine whether the longer duration of inhibition of serum ACE activity of spirapril affects the clinical outcome.
Materials and Methods Patients Patients were eligible for the study if they met the following entry criteria: (1) chronic CHF class II-III according to the New York Heart Association classification, (2) left ventricular ejection fraction _<40%, and (3) peak oxygen consumption (peak Vo2) < 20 mL/min/kg. Patients with acute myocardial infarction or coronary bypass surgery less than 3 months prior to the study, patients with unstable angina pectoris, and those with a systolic blood pressure less than 100 mmHg and/or diastolic pressure less than 60 mmHg were excluded from the study. Patients in whom angina pectoris, chronic obstructive pulmonary disease, or claudication limited their exercise tolerance were also excluded.
Study Design This was a double-blind, randomized, comparative study in parallel groups with a duration of 12 weeks after a single blind placebo run-in period of 1 week. Patients were evaluated in the screening period, the placebo period, and at the end of weeks 1, 3, 6, and 12. The protocol was performed in accordance with the guidelines established in the Declaration of Helsinki and approved by the ethical committee of the University Hospital Groningen. Written informed consent was obtained from each patient prior to entry into the study.
chloride-restricted diet of 3-5 g sodium daily. At the end of the placebo period, patients received a first dose of either spirapril (3.0 rag) or captopril (6.25 mg). If the first dose was tolerated well, the patients continued with spirapril 6 mg once daily + 2 placebos or captopril 12.5 mg three times daily. At the end of 3 and 6 weeks, the dosage could be doubled if an insufficient clinical response and no adverse effects had occurred at the lower drug dose.
Cardiopulmonary Exercise Test Exercise testing on a treadmill with respiratory gas exchange measurements was conducted as previously described (12). It was performed during the screening period, during the placebo run-in period, and at the end of weeks 6 and 12. All tests were performed in the morning, before intake of the study medication. The first exercise test was used for screening as well as to familiarize the patient with the test. All patients terminated the test because of dyspnea or fatigue. In all patients the gas exchange anaerobic threshold was reached (the point at which carbon dioxide production increases disproportionately in relation to oxygen consumption). Peak Vo2 was defined as oxygen consumption (mL/min/kg) at peak exercise calculated as the mean of values during the last minute of exercise. Both peak Vo2 and exercise time were considered as endpoints for exercise capacity.
Neurohumoral Parameters Blood samples were drawn from an indwelling catheter in the brachial vein after 30 minutes of supine rest to analyze serum ACE activity, plasma renin activity, and plasma norepinephrine and aldosterone levels in the placebo run-in period and at the end of weeks 1, 6, and 12. Established techniques were used to determine serum ACE activity, plasma renin activity and plasma norepinephrine and aldosterone levels (13-16). Blood samples for routine blood chemistry were obtained at each visit. All blood samples were drawn in the morning, before intake of the study medication (thus, approximately 24 hours after the last dosage of spirapril and approximately 12 hours after the last dosage of captopril).
Quality of Life Medication Diuretics and/or digoxin were allowed as concomitant medication, but the dosage was kept constant during the study. Long-acting nitrates, calcium antagonists, or other vasodilators, as well as inotropic agents (except digitalis), if used, had to be discontinued, before entry in the placebo period. No patient had previously been treated with an ACE inhibitor. All patients were on a sodium
To assess the quality of life, the Minnesota Living With Heart Failure Questionnaire was used (17,18). This self-administered test of 21 questions specifically assesses the limitations commonly associated with CHE A low score indicates a better quality of life than a high score. The questionnaire was filled in by the patient at each visit, after a brief set of standardized instructions.
Spirapril/Captopril Differences in CHF
Radionuclide Ventriculography and Chest Radiography Left ventricular ejection fraction was determined by means of multiple-gated cardiac blood pool imaging with 350 M B q technetium-99m in the screening period, the placebo period, and at the end of week 12. A standard posteroanterior roentgenogram of the chest, in upright position at full inspiration, was obtained in the placebo period and at the end of week 12 to measure the cardiothoracic ratio.
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Table 1. Baseline Clinical Characteristics of the Patients in the Spirapril and Captopril Groups Who Completed the Study Spirapril (n = 9)
Captopril (n = 9)
Sex 7M, 2F Etiology 8 CAD, 1 IDC New York Heart Associationclass 7 II, 2 III Age 55 + 12 Cardiothoracicratio 0.51 +0.06 Left-ventricularejection fraction (%) 30 + 6 Mean arterial pressure (mm Hg) 96 + 11
5M, 4F 8 CAD, 1 IDC 7 lI, 2 III 62 + 7 0.51 +0.05 26 + 9 91 + 7
Exercise parameters
Exercise duration (s) Voz rest (mL/min) VO2 exercise (mL/min) Peak Vo2 (mL/min/kg)
Statistical A n a l y s i s
Qualitive differences between the two treatment groups were compared by the chi-square statistic. Quantitative differences were tested with analysis of variance and Student's t-test, paired for within-group differences, unpaired for between group differences. Multiple analysis of variance for repeated measurements was used to compare changes in time in response to drug treatment. Data are expressed as means + SD. Differences were considered statistically significant at the 5% level, two-sided.
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1117 + 185 331 _+66 1498 _+356 18.2 + 1.8
1008 + 103 290 + 64 1236 + 170 16.9 + 1.7
31 _+15
27 + 6
2.6 + 2.3 3.0 _+1.2 0.5 + 0.2
5.1 + 8.9 3.8 + 2.0 0.6 + 0.4
Neurohumoral parameters
Angiotensin-converting enzyme (U/L) Plasma renin activity(nmol/L/h) Norepinephrine(nmol/L) Aldosterone(nmol/L)
Values expressed as means + SD. There were no significant differences between the two groups. CAD, coronary artery disease; CTR, cardiothoracic ratio; IDC, idiopathic dilated cardiomyopathy; peak Vo2, peak oxygen consumption; Voa exercise, oxygen consumption at maximal exercise; Vo2 rest, oxygen consumption at rest.
Results Patients
A total of 20 patients entered the study. They were all in sinus rhythm and had a history of C H F of more than 3 months. There were 14 men and 6 women ranging in'age from 39 to 73 years. Congestive heart failure was cansed by coronary artery disease in 18 patients and by idiopathic dilated cardiomyopathy in 2. Mean peak Vo2 was 17.4 mL/min/kg (range, 14.2-19.9 mL/min/kg) and mean left ventricular ejection fraction was 28% (range, 13-40%). Patients were randomized to receive either spirapril (n = 9) or captopril (n = 11). Eighteen patients completed the study; 2 patients in the captopril group were withdrawn after 3 weeks of treatment because o f adverse events (1 patient complained of increasing dizziness, 1 patient had gastrointestinal complaints). The average daily doses at the end of the study were 9.3 mg (range, 6 - 1 2 rag) and 50 mg (range, 37.5-75 rag) for spirapril and captopril, respectively. At baseline, there were no statistically significant differences in clinical characteristics between the patients in both groups who completed the study (Table 1).
Exercise Data The effects on exercise capacity between the spirapril and captopril are shown in Figures 1 and 2. There was no significant change in peak Vo2 between the spirapril and captopril groups after 6 and 12 weeks of treatment, although peak Vo2 showed a tendency to increase in the
captopfil group. Within the captopril group the increase was significant at week 6, 18.8 _+2.4 mL/min/kg (P < .05), but not at week 12, 19.2 + 3.6 (P = .11), compared with baseline. Exercise duration was significantly increased after 12 weeks of treatment in the captopriI group compared with the spirapril group (P < .05).
Peak oxygen consumption Change in peak V02 (ml/min/kg) 8
NS r - - ]
NS I
E
6 4 2 0 -2
--2-
i
-4 I
I
Week 6
Week 12
[ ] zplmpdl [ ] oeptoprll Fig. 1. Change in peak VO2 (mL/min/kg) between the spirapril- and captopril-treated patients at weeks 6 and 12. Values are expressed as mean change + SD.
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Serum ACE activity
Exercise time ACE
Change In exercise time (see) NS
(u/i) s0
p < 0.05
I
F--I 40
300 30~ 200 20 100 10 0 0
-1 O0
Week 6
Week 12
[ ] splraprll [ ] captoprll
q
I
E
I
Baseline
Week 1
Week 6
Week 12
Fig. 3. Serum angiotensin-converting enzyme (ACE) activity during treatment with either spirapril or captopril. Values are expressed as means + SD. *P < .0001 between the groups.
Fig. 2. Change in exercise time (seconds) between the spirapril- and captopril-treated patients at weeks 6 and 12. Values are expressed as mean change + SD. show significant changes in serum creatinine, urea, potassium, and sodium levels during the study.
Neurohumoral Changes
Quality of Life
Serum ACE activity was significantly different between the two treatment groups at the end of weeks 1, 6, and 12 (P < .0001). In the spirapril group, serum ACE activity decreased significantly at the end of weeks 1, 6, and 12 compared with the end of the placebo period. In the captopril group, there was no significant change in serum ACE activity at the end of week 1 when compared with the end of the placebo period; however, there was a significant increase in serum ACE activity at the end of week 6 (P < .01) and week 12 (P < .01) (Fig. 3). There were no significant changes in plasma levels of aldosterone, renin activity, or norepinephrine between the spirapril and captopril groups (Table 2). In none of the two treatment groups did routine blood chemistry
The changes in quality of life as determined by the Minnesota Living With Heart Failure Questionnaire are summarized in Figure 4. There were no significant differences between the spirapril- and captopril-treated patients. New York Heart Association class improved in four patients receiving spirapril and in five patients receiving captopril. In none of the patients who completed the study did New York Heart Association class or quality of life deteriorate.
Noninvasive Hemodynamic Measurements During therapy, mean arterial pressure, measured before intake of the morning dose, decreased both in the
Table 2. Plasma Renin Activity and Plasma Norepinephrine and Aldosterone Levels at the End of Placebo, Week 1, Week 6, and Week 12 in the Patients Who Completed the Study Plasma Renin Activity (nmol/L/h)
Spirapril (n =
Placebo Week 1 Week 6 Week 12
Plasma Aldosterone (nmol/L)
9)
Placebo Week 1 Week 6 Week 12
Captopril (n =
Plasma Norepinephrine (nmol/L)
2.6 7.7 4.9 6.7
_+ 2.3 + 10.2 -+ 3.5 + 7.6
3.0 3.5 2.7 3.0
_+ 1.2 + 1.0 + 0.8 -+ 1.2
5.1 3.1 7.4 4.7
-+ 8.9 + 1.2 _+7.9 -+ 5.1
3.8 + 2.0 3.4_+ 1.6 2.9 + 1.5 3.1 _+ 1.5
0.46 0.36 0.38 0.37
_+0.15 _+0.25 _+0.15 -+ 0.14
9) 0.62 + 0.41 0.39+0.17 0.44 +- 0.22 0.54 _+ 0.46
Values are expressed as means _+ SD. There were no significant changes between or within the groups.
Spirapril/Captopril Differences in CHF Change In Minnesota CHF questionnaire 0 -5
.10 .15 .20 .25
[
1
I
NS
.30 Spirepril
Captopril
[ ] Week 1 [ ] Week 3 [ ] Week 6 [ ] Week 12
Fig. 4. Changes from baseline in quality of life as determined by the Minnesota Living With Heart Failure Questionnaire. Values are expressed as mean change + SD. No significant difference between the groups at weeks 1, 3, 6, and 12.
patients receiving spirapril and in the patients receiving captopril; however, this decrease was significant only in the spirapril group at week 6, 96 + 11 mmHg, versus 90 + 12 mmHg at baseline (P < .05). There were no significant differences between the two treatment groups with respect to mean arterial pressure, left ventricular ejection fraction, and cardiothoracic ratio. Adverse Events
In the spirapril group, one patient experienced temporary loss of appetite. In the captopril group, two patients were withdrawn at the end of week 3: one patient because of increasing complaints of dizziness, one patient because of abdominal pain. Furthermore, one patient in the captopril group developed a stomatitis, and one patient a psoriatiform skin lesion. Both patients completed the study, and the complaints disappeared after the study medication was stopped at 12 weeks. No serious adverse events occurred.
Discussion This study compared the new long-acting ACE inhibitor spirapril with captopril, the only short-acting ACE inhibitor currently in use for the treatment of CHF. The main finding of this study is that spirapril, in contrast to captopril, did not increase exercise capacity despite a significant decrease in serum ACE activity when compared with captopril. Both peak Vo2 and exercise duration were considered endpoints for exercise
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capacity, because from the trials with ACE inhibitors it has not been shown that determination of peak Vo2 is superior to exercise duration alone (19). Differences in structure and pharmacologic properties of ACE inhibitors may lead to differences in action. Captopril is an active drug in its ingested form, with a plasma peak concentration within 1 hour of drug intake in patients with CHF. Its peak effect on hemodynamic response occurs 1 to 2 hours after administration of the drug, and the hemodynamic effects return to resting levels within 8 hours (5,20). During long-term treatment it has been suggested that on a three-times-daily dosage regimen, maximal inhibition of the renin-angiotensin system was not maintained throughout the dosage interval (20). Unlike captopril, spirapril is administered as a prodrng that is rapidly metabolized to the diacid form spiraprilate. This pharmacologically active metabolite reaches its peak plasma level concentration 4 hours after drug intake in patients with CHE In a dose-ranging study we showed that maximal hemodynamic effects occur approximately 4 to 6 hours after drug administration, with inhibition of serum ACE activity even after 24 hours (11). It has been suggested that prolonged ACE inhibition may be required when exercise improvement is expected throughout the day (10). To avoid the expected "peak" effect, we performed measurements of exercise capacity and neurohumoral parameters in the morning, before intake of the study medication, that is, approximately 12 and 24 hours after the last dose intake of captopril and spirapril, respectively. Our results show that at this time point, inhibition of serum ACE activity was still present in the spirapril-treated patients but not in those in the captopril group; however, exercise capacity failed to increase in the spirapril group. In fact, only in the captopril group did exercise capacity increase significantly compared with the spirapril group. This suggests that constant suppression of serum ACE activity is not necessary for, and does not lead to enhancement of exercise capacity. This may be attributed to the fact that intermittent ACE inhibition with short-acting ACE inhibitors has less pronounced blood pressure-lowering effects compromising systemic perfusion and organ function than sustained ACE inhibition with long-acting ACE inhibitors (21). The inhibition of plasma ACE does not fully explain the effects of ACE inhibitors. Several studies have demonstrated a duration and magnitude of blood pressure reduction in response to ACE inhibitors that appeared to correlate better with the inhibition of vascular or tissue ACE than with the inhibition of serum ACE activity (22-24). As a consequence, ACE inhibitors may differ with respect to different degrees of penetration into tissues and different binding characteristics of ACE. Although at present data on clinical
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consequences of these differences are lacking and vascular or tissue ACE in our study was not measured, one can speculate that the effect of captopril on exercise capacity in our study, despite the absence of inhibition of serum ACE activity, may be related to interference with a vascular or tissue renin-angiotensin system. ACE, however, is not only a key enzyme in the renin-angiotensin system, but also acts on a variety of other peptides such as bradykinin. Augmentation of the dilatory effects of bradykinin can be expected in the presence of ACE inhibition and may vary in different vessels. Additionally, some ACE inhibitors may also facilitate some non-kinin-mediated endothelium-dependent relaxations (25,26). Indeed, a difference in potentiation of endothelium-dependent relaxations to methacholine, after pretreatment with either spirapril or captopril, could be observed in isolated rings of human internal mammary arteries (27). The lack of inhibition of serum ACE activity in the captopril-treated patients may have been due to an artifact. During long-time storage of plasma, captopril dissociates from ACE, leading to underestimation of the degree of ACE inhibition (28). To minimize this effect of dissociation of the inhibitor-enzyme complex, all samples were immediately stored at - 8 0 ° C and were assessed within 48 hours. Furthermore, serum ACE activity, determined by the same technique as in our study, has been shown to be significantly reduced at the expected peak effect of captopril in a comparative study with captopril and ramipril (29). In addition, a possible storage artifact cannot explain the significant increase in serum ACE activity at 6 and 12 weeks. Blockade of angiotensin II production by ACE inhibition may induce ACE messenger RNA expression (30). As a consequence, discontinuation of ACE inhibition leads to increased ACE synthesis and an overshoot in serum ACE activity. As the time between the evening dose and morning sampling of captopril was relatively long, the increase in serum ACE activity may have been due to induction of ACE expression.
Conclusion Prolonged inhibition of serum ACE activity of spirapril did not favorably affect exercise capacity when compared with the short-acting ACE inhibitor captopril; however, the number of patients in our study was small and this may have caused a random error in the exercise data. Therefore, larger long-term studies comparing both exercise duration and neurohumoral changes are required to determine the differences between spirapril and other currently available ACE inhibitors.
References 1. Packer M: Treatment of chronic heart failure. Lancet 1992;340:92-5 2. Riegger GAJ: The effects of ACE inhibitors on exercise capacity in the treatment of congestive heart failure. J Cardiovasc Pharmacol 1990;15(suppl. II):41-6 3. CONSENSUS Trial Study Group: Effects of enalapril on mortality in severe congestive heart failure: results of the cooperative North Scandinavian Enalapril Survival Study. N Engl J Med 1987;316:1429-35 4. The SOLVD Investigators: Effects of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med 1991;325: 293-302 5. Levine BT, Olivari MT, Cohn JT: Angiotensin converting enzyme inhibitors in congestive heart failure: overview in comparison of captopril and enalapril. Am J Med 1986; 81(suppl. 4C):36-9 6. Giles TD, Katz R, Sullivan JM, Wolfson P, Haugland M, Kirlin R Powers E, Rich S, Hackshaw B, Chiaramida A, Rouleau JL, Fisher MB, Pigeon J, Rush JE: Short- and long-acting angiotensin-converting enzyme inhibitors: a randomized trial of lisinopril versus captopril in the treatment of congestive heart failure. J Am Coll Cardiol 1989; 13:1240-7 7. Colfer HT, Ribner HS, Gradman A, Hughes CV, Kappoor A, Lasdiaw JC, for the Benazepril Heart Failure Study Group: Effects of once daily benazepril therapy on exercise tolerance and manifestations of chronic congestive heart failure. Am J Cardiol 1992;70:354-8 8. Northridge DB, Rose E, Raftery ED, Lahiri A, Elder AT, Shaw TR, Henderson E, Dargir HJ: A multicentre, doubleblind, placebo-controlled trial of quinapril in mild, chronic heart failure. Eur Heart J 1993; 14:4093-9 9. Pitt B: Angiotensin-converting inhibitors in patients with congestive heart failure: a class effect? Am J Cardiol 1991; 68:106-8 10. Giles TD: Importance of long-acting angiotensin-converting enzyme inhibitors for congestive heart failure. Am J Cardiol 1992;70:98C-101C 11. Van den Broek SAJ, van Bruggen A, de Graeff PA, Hillege H, van Gilst WH, Wesseling H, Lie 1<21:The acute hemodynamic, hormonal, and pharmacokinetic properties of oral spirapril in patients with moderate to severe heart failure. J Cardiovasc Pharmacol 1991;18:614-21 12. Van den Broek SAJ, van Veldhuisen, de Graeff PA, Landsman MLJ, Hillege H, Lie KI: Comparison between New York Heart Association Classification and peak oxygen consumption in the assessment of functional status and prognosis in patients with mild to moderate chronic congestive heart failure secondary to either ischemia or idiopathic dilated cardiomyopathy. Am J Cardiol 1992;70: 359-63 13. Cohen EL, Grim CE, Corm JW, Blough WM, Guyer MB, Kern DC, Lucas CP: Accurate and rapid measurement of plasma renin activity by radioimmunoassay. J Lab Clin Med 1971;77:1025-38
Spirapril/Captopril Differences in CHF 14. Kwarts E, Beukenveld G, Gazendam J: Evaluation of a simple colorimetric assay for serum angiotensin-converting enzyme assay: comparison with a new ion-pair liquid chromatography-assisted assay. Ann Clin Biochem 1982; 19:227-32 15. Pratt JJ, Boonman R, Woldring MG, Donker AJM: Special problems in the radioimmunoassay of plasma aldosterone without prior extraction and purification. Clin Chim Acta 1978;84:329-37 16. Smedes F, Kraak JG, Poope H: Simple and fast solvent extraction system for selective and quantitive isolation of adrenaline, noradrenaline and dopamine from plasma and urine. J Chromatogr 1982;231:25-39 17. Rector TS, Kubo SH, Cohn JN: Patients' self-assessment of their congestive heart failure: Part 2, Content, reliability and validity of a new measure, the Minnesota Living With Heart Failure Questionnaire. Heart Failure 1987;3:198-9 18. Kubo HK, Gollub S, Bourge R, Rahko R Cobb F, Jessup M, Brozena S, Brodsky M, Kirlin R Shanes J, Konstam M, Gradman A, Morledge J, Cinquegrani M, Singh S, LeJemtel T, Nicklas J, Troha J, Cohn JN: Beneficial effects of pimobendan on exercise tolerance and quality of life in patients with heart failure: results of a multicenter trial. Circulation 1992;85:942-49 19. Narang R, Swedberg K, Cleland JGF: What is the ideal study design for evaluation of treatment for heart failure? Insights from trials assessing the effect of ACE inhibitors on exercise capacity. Eur Heart J 1996; 17:120-34 20. Shaw TRD, Duncan FM, Williams BC, Crichton E, Thomson SA, Davis JRE, Rademaker M, Edwards CRW: Plasma free captopril concentrations during short and long term treatment with oral captopril for heart failure. Br Heart J 1985;54:160-5 21. Packer M, Lee WH, Yushak M, Medina N: Comparison of captopril and enalapril in patients with severe chronic heart failure. N Engl J Med 1986;315:847-53
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22. Unger T, Gohlke P: Tissue renin-angiotensin systems in the heart and vasculature: possible involvement in the cardiovascular actions of converting enzyme inhibitors. Am J Cardiol 1990;65:31-10I 23. Hirsch AT, Talsness CE, Smith AD, Schunkert H, Ingelfinger JR, Dzau VJ: Differential effects of captopril and enalapril on tissue renin-angiotensin systems in experimental heart failure. Circulation 1992;86:1566-74 24. Dzau VJ, Re R: Tissue angiotensin systems in cardiovascular medicine: a paradigm shift? Circulation 1994;89:493-8 25. Kerth PA, Vanhoutte PM: Effects of perindoprilat and endothelium-dependent relaxations and contractions in isolated blood vessels. Am J Hypertens 1991;4: 226S-34S 26. Nakamura M, Funakoshi T, Yoshida H, Arakawa N, Suzuki T, Hiramori K: Endothelium-dependent vasodilation is augmented by angiotensin converting enzyme inhibitors in healthy volunteers. J Cardiovasc Pharmacol 1992;20: 949-54 27. Pinto YM, Buikema H, van Gilst WH: Hyperactive tissue renin-angiotensin systems in cardiovascular dysfunction: experimental and clinical hypotheses. Clin Exp Hypertens 1995; 17:441-68 28. Boomsma F, de Bruyn JHB, Derkx FHM, Schalekamp MADH: Opposite effects of captopril on angiotensin Iconverting enzyme 'activity' and 'concentration': relation between enzyme inhibition and long-term blood pressure response. Clin Sci 1981;60:491-8 29. De Graeff PA, Kingma JH, Dunselman PHJM, Wesseling H, Lie Kh Acute hemodynamic and hormonal effects of ramipril in chronic congestive heart failure and comparison with captopril. Am J Cardiol 1987;59:164D-70D 30. Schunkert H, Ingelfinger JR, Hirsch AT, Pinto Y, Remme WJ, Jacob H, Dzau VJ: Feedback regulation of angiotensin converting enzyme activity and mRNA levels by angiotensin. Circ Res 1993;72:312-8
Clinical Investigations Clinical and Neurohumoral Differences Between Spirapril and Captopril in Mild to Moderate Chronic Congestive Heart Failure STAN A. J. VAN DEN BROEK, MD,* PIETER A. DE GRAEFF, MD,t DIRK J. VAN VELDHUISEN, MD, FACC,* WIEK H. VAN GILST, PhD,t HANS HILLEGE, MD,* HARRY WESSELING, MD,t KONG I. LIE, MD* Groningen, The Netherlands
ABSTRACT Background: This study was done to determine whether the difference in duration of action of the long-acting angiotensin-converting enzyme (ACE) inhibitor spirapril compared with the short-acting ACE inhibitor captopril affects clinical efficacy in patients with congestive heart failure. Methods and Results: The effects on exercise capacity, neurohumoral status, and quality of life were studied in 20 patients with mild to moderate congestive heart failure in a doubleblind, randomized, comparative study in parallel groups with a duration of 12 weeks. All assessments during the study were performed in the morning, before intake of the study medication, to avoid the expected peak effect of the ACE inhibitors used. Mean peak oxygen consumption (peak Vo2) was 17.4 mL/min/kg (range, 14.2-19.9 mL/min/kg) and mean left ventricular ejection fraction was 28% (range, 13-40%). Exercise duration in tile captopril group showed a significant increase after 12 weeks (P < .05) of treatment compared with the spirapril group. Peak oxygen consumption tended only to increase in the captopril-treated patients compared with the spirapril-treated patients. Serum ACE activity was significantly different between the two treatment groups during treatment (P < .0001) and showed only a significant decrease in the spirapril group. There was no difference in improvement of quality of life between the two treatment groups. Conclusions: This study showed that the effects of the ACE inhibitors spirapril and captopril on exercise capacity are not related to the degree of inhibition of serum ACE activity. Key words: angiotensin-converting enzyme inhibitor, exercise capacity, serum angiotensinconverting enzyme activity.
Angiotensin-converting enzyme (ACE) inhibitors have become a cornerstone in the treatment of conges-
tive heart failure (CHF). They have been shown to improve not only haemodynamics, clinical status, and exercise performance (1,2), but survival as well (3,4). Although both long- and short-acting ACE inhibitors are effective in patients with C H F (5-8), the question remains whether all ACE inhibitors are equal or do differences in duration of fiction affect clinical efficacy (9). It has been suggested that prolonged ACE inhibition may be required if exercise improvement is expected throughout the day (10). Therefore, we compared spirapril, a rather new ACE inhibitor, with a prolonged dura-
From the *Department of Cardiology/Thoraxcenter and "?Department of Pharmacology~Clinical Pharmacology, University Hospital of Groningen, Groningen, The Netherlands.
Supported by a grant from Sandoz Pharma, Basel, Switzerland. Manuscript received August 30, 1996; revised manuscript received March 31, 1997; revised manuscript accepted May 21, 1997. Reprint requests: Dirk J. van Veldhuisen, MD, Thoraxcenter/Departmerit of Cardiology, University Hospital Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands. ©1997 Churchill Livingstone Inc.
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tion of action, with captopril, the only currently used ACE inhibitor with a short duration of action. Spirapril is a nonsulfydryl-containing ACE inhibitor that has demonstrated beneficial hemodynamic and neurohumoral effects in patients with moderate to severe CHF (11). The therapeutic efficacy of spirapril as compared with other ACE inhibitors in CHF has not been studied yet. Because of the different durations of action of the two ACE inhibitors, all clinical and neurohumoral examinations were performed in the morning before intake of the morning dose of the study drug. This design was deliberately chosen to avoid the possibility of bias from the "peak" drug effect and to determine whether the longer duration of inhibition of serum ACE activity of spirapril affects the clinical outcome.
Materials and Methods Patients Patients were eligible for the study if they met the following entry criteria: (1) chronic CHF class II-III according to the New York Heart Association classification, (2) left ventricular ejection fraction _<40%, and (3) peak oxygen consumption (peak Vo2) < 20 mL/min/kg. Patients with acute myocardial infarction or coronary bypass surgery less than 3 months prior to the study, patients with unstable angina pectoris, and those with a systolic blood pressure less than 100 mmHg and/or diastolic pressure less than 60 mmHg were excluded from the study. Patients in whom angina pectoris, chronic obstructive pulmonary disease, or claudication limited their exercise tolerance were also excluded.
Study Design This was a double-blind, randomized, comparative study in parallel groups with a duration of 12 weeks after a single blind placebo run-in period of 1 week. Patients were evaluated in the screening period, the placebo period, and at the end of weeks 1, 3, 6, and 12. The protocol was performed in accordance with the guidelines established in the Declaration of Helsinki and approved by the ethical committee of the University Hospital Groningen. Written informed consent was obtained from each patient prior to entry into the study.
chloride-restricted diet of 3-5 g sodium daily. At the end of the placebo period, patients received a first dose of either spirapril (3.0 rag) or captopril (6.25 mg). If the first dose was tolerated well, the patients continued with spirapril 6 mg once daily + 2 placebos or captopril 12.5 mg three times daily. At the end of 3 and 6 weeks, the dosage could be doubled if an insufficient clinical response and no adverse effects had occurred at the lower drug dose.
Cardiopulmonary Exercise Test Exercise testing on a treadmill with respiratory gas exchange measurements was conducted as previously described (12). It was performed during the screening period, during the placebo run-in period, and at the end of weeks 6 and 12. All tests were performed in the morning, before intake of the study medication. The first exercise test was used for screening as well as to familiarize the patient with the test. All patients terminated the test because of dyspnea or fatigue. In all patients the gas exchange anaerobic threshold was reached (the point at which carbon dioxide production increases disproportionately in relation to oxygen consumption). Peak Vo2 was defined as oxygen consumption (mL/min/kg) at peak exercise calculated as the mean of values during the last minute of exercise. Both peak Vo2 and exercise time were considered as endpoints for exercise capacity.
Neurohumoral Parameters Blood samples were drawn from an indwelling catheter in the brachial vein after 30 minutes of supine rest to analyze serum ACE activity, plasma renin activity, and plasma norepinephrine and aldosterone levels in the placebo run-in period and at the end of weeks 1, 6, and 12. Established techniques were used to determine serum ACE activity, plasma renin activity and plasma norepinephrine and aldosterone levels (13-16). Blood samples for routine blood chemistry were obtained at each visit. All blood samples were drawn in the morning, before intake of the study medication (thus, approximately 24 hours after the last dosage of spirapril and approximately 12 hours after the last dosage of captopril).
Quality of Life Medication Diuretics and/or digoxin were allowed as concomitant medication, but the dosage was kept constant during the study. Long-acting nitrates, calcium antagonists, or other vasodilators, as well as inotropic agents (except digitalis), if used, had to be discontinued, before entry in the placebo period. No patient had previously been treated with an ACE inhibitor. All patients were on a sodium
To assess the quality of life, the Minnesota Living With Heart Failure Questionnaire was used (17,18). This self-administered test of 21 questions specifically assesses the limitations commonly associated with CHE A low score indicates a better quality of life than a high score. The questionnaire was filled in by the patient at each visit, after a brief set of standardized instructions.
Spirapril/Captopril Differences in CHF
Radionuclide Ventriculography and Chest Radiography Left ventricular ejection fraction was determined by means of multiple-gated cardiac blood pool imaging with 350 M B q technetium-99m in the screening period, the placebo period, and at the end of week 12. A standard posteroanterior roentgenogram of the chest, in upright position at full inspiration, was obtained in the placebo period and at the end of week 12 to measure the cardiothoracic ratio.
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Table 1. Baseline Clinical Characteristics of the Patients in the Spirapril and Captopril Groups Who Completed the Study Spirapril (n = 9)
Captopril (n = 9)
Sex 7M, 2F Etiology 8 CAD, 1 IDC New York Heart Associationclass 7 II, 2 III Age 55 + 12 Cardiothoracicratio 0.51 +0.06 Left-ventricularejection fraction (%) 30 + 6 Mean arterial pressure (mm Hg) 96 + 11
5M, 4F 8 CAD, 1 IDC 7 lI, 2 III 62 + 7 0.51 +0.05 26 + 9 91 + 7
Exercise parameters
Exercise duration (s) Voz rest (mL/min) VO2 exercise (mL/min) Peak Vo2 (mL/min/kg)
Statistical A n a l y s i s
Qualitive differences between the two treatment groups were compared by the chi-square statistic. Quantitative differences were tested with analysis of variance and Student's t-test, paired for within-group differences, unpaired for between group differences. Multiple analysis of variance for repeated measurements was used to compare changes in time in response to drug treatment. Data are expressed as means + SD. Differences were considered statistically significant at the 5% level, two-sided.
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1117 + 185 331 _+66 1498 _+356 18.2 + 1.8
1008 + 103 290 + 64 1236 + 170 16.9 + 1.7
31 _+15
27 + 6
2.6 + 2.3 3.0 _+1.2 0.5 + 0.2
5.1 + 8.9 3.8 + 2.0 0.6 + 0.4
Neurohumoral parameters
Angiotensin-converting enzyme (U/L) Plasma renin activity(nmol/L/h) Norepinephrine(nmol/L) Aldosterone(nmol/L)
Values expressed as means + SD. There were no significant differences between the two groups. CAD, coronary artery disease; CTR, cardiothoracic ratio; IDC, idiopathic dilated cardiomyopathy; peak Vo2, peak oxygen consumption; Voa exercise, oxygen consumption at maximal exercise; Vo2 rest, oxygen consumption at rest.
Results Patients
A total of 20 patients entered the study. They were all in sinus rhythm and had a history of C H F of more than 3 months. There were 14 men and 6 women ranging in'age from 39 to 73 years. Congestive heart failure was cansed by coronary artery disease in 18 patients and by idiopathic dilated cardiomyopathy in 2. Mean peak Vo2 was 17.4 mL/min/kg (range, 14.2-19.9 mL/min/kg) and mean left ventricular ejection fraction was 28% (range, 13-40%). Patients were randomized to receive either spirapril (n = 9) or captopril (n = 11). Eighteen patients completed the study; 2 patients in the captopril group were withdrawn after 3 weeks of treatment because o f adverse events (1 patient complained of increasing dizziness, 1 patient had gastrointestinal complaints). The average daily doses at the end of the study were 9.3 mg (range, 6 - 1 2 rag) and 50 mg (range, 37.5-75 rag) for spirapril and captopril, respectively. At baseline, there were no statistically significant differences in clinical characteristics between the patients in both groups who completed the study (Table 1).
Exercise Data The effects on exercise capacity between the spirapril and captopril are shown in Figures 1 and 2. There was no significant change in peak Vo2 between the spirapril and captopril groups after 6 and 12 weeks of treatment, although peak Vo2 showed a tendency to increase in the
captopfil group. Within the captopril group the increase was significant at week 6, 18.8 _+2.4 mL/min/kg (P < .05), but not at week 12, 19.2 + 3.6 (P = .11), compared with baseline. Exercise duration was significantly increased after 12 weeks of treatment in the captopriI group compared with the spirapril group (P < .05).
Peak oxygen consumption Change in peak V02 (ml/min/kg) 8
NS r - - ]
NS I
E
6 4 2 0 -2
--2-
i
-4 I
I
Week 6
Week 12
[ ] zplmpdl [ ] oeptoprll Fig. 1. Change in peak VO2 (mL/min/kg) between the spirapril- and captopril-treated patients at weeks 6 and 12. Values are expressed as mean change + SD.
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Serum ACE activity
Exercise time ACE
Change In exercise time (see) NS
(u/i) s0
p < 0.05
I
F--I 40
300 30~ 200 20 100 10 0 0
-1 O0
Week 6
Week 12
[ ] splraprll [ ] captoprll
q
I
E
I
Baseline
Week 1
Week 6
Week 12
Fig. 3. Serum angiotensin-converting enzyme (ACE) activity during treatment with either spirapril or captopril. Values are expressed as means + SD. *P < .0001 between the groups.
Fig. 2. Change in exercise time (seconds) between the spirapril- and captopril-treated patients at weeks 6 and 12. Values are expressed as mean change + SD. show significant changes in serum creatinine, urea, potassium, and sodium levels during the study.
Neurohumoral Changes
Quality of Life
Serum ACE activity was significantly different between the two treatment groups at the end of weeks 1, 6, and 12 (P < .0001). In the spirapril group, serum ACE activity decreased significantly at the end of weeks 1, 6, and 12 compared with the end of the placebo period. In the captopril group, there was no significant change in serum ACE activity at the end of week 1 when compared with the end of the placebo period; however, there was a significant increase in serum ACE activity at the end of week 6 (P < .01) and week 12 (P < .01) (Fig. 3). There were no significant changes in plasma levels of aldosterone, renin activity, or norepinephrine between the spirapril and captopril groups (Table 2). In none of the two treatment groups did routine blood chemistry
The changes in quality of life as determined by the Minnesota Living With Heart Failure Questionnaire are summarized in Figure 4. There were no significant differences between the spirapril- and captopril-treated patients. New York Heart Association class improved in four patients receiving spirapril and in five patients receiving captopril. In none of the patients who completed the study did New York Heart Association class or quality of life deteriorate.
Noninvasive Hemodynamic Measurements During therapy, mean arterial pressure, measured before intake of the morning dose, decreased both in the
Table 2. Plasma Renin Activity and Plasma Norepinephrine and Aldosterone Levels at the End of Placebo, Week 1, Week 6, and Week 12 in the Patients Who Completed the Study Plasma Renin Activity (nmol/L/h)
Spirapril (n =
Placebo Week 1 Week 6 Week 12
Plasma Aldosterone (nmol/L)
9)
Placebo Week 1 Week 6 Week 12
Captopril (n =
Plasma Norepinephrine (nmol/L)
2.6 7.7 4.9 6.7
_+ 2.3 + 10.2 -+ 3.5 + 7.6
3.0 3.5 2.7 3.0
_+ 1.2 + 1.0 + 0.8 -+ 1.2
5.1 3.1 7.4 4.7
-+ 8.9 + 1.2 _+7.9 -+ 5.1
3.8 + 2.0 3.4_+ 1.6 2.9 + 1.5 3.1 _+ 1.5
0.46 0.36 0.38 0.37
_+0.15 _+0.25 _+0.15 -+ 0.14
9) 0.62 + 0.41 0.39+0.17 0.44 +- 0.22 0.54 _+ 0.46
Values are expressed as means _+ SD. There were no significant changes between or within the groups.
Spirapril/Captopril Differences in CHF Change In Minnesota CHF questionnaire 0 -5
.10 .15 .20 .25
[
1
I
NS
.30 Spirepril
Captopril
[ ] Week 1 [ ] Week 3 [ ] Week 6 [ ] Week 12
Fig. 4. Changes from baseline in quality of life as determined by the Minnesota Living With Heart Failure Questionnaire. Values are expressed as mean change + SD. No significant difference between the groups at weeks 1, 3, 6, and 12.
patients receiving spirapril and in the patients receiving captopril; however, this decrease was significant only in the spirapril group at week 6, 96 + 11 mmHg, versus 90 + 12 mmHg at baseline (P < .05). There were no significant differences between the two treatment groups with respect to mean arterial pressure, left ventricular ejection fraction, and cardiothoracic ratio. Adverse Events
In the spirapril group, one patient experienced temporary loss of appetite. In the captopril group, two patients were withdrawn at the end of week 3: one patient because of increasing complaints of dizziness, one patient because of abdominal pain. Furthermore, one patient in the captopril group developed a stomatitis, and one patient a psoriatiform skin lesion. Both patients completed the study, and the complaints disappeared after the study medication was stopped at 12 weeks. No serious adverse events occurred.
Discussion This study compared the new long-acting ACE inhibitor spirapril with captopril, the only short-acting ACE inhibitor currently in use for the treatment of CHF. The main finding of this study is that spirapril, in contrast to captopril, did not increase exercise capacity despite a significant decrease in serum ACE activity when compared with captopril. Both peak Vo2 and exercise duration were considered endpoints for exercise
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capacity, because from the trials with ACE inhibitors it has not been shown that determination of peak Vo2 is superior to exercise duration alone (19). Differences in structure and pharmacologic properties of ACE inhibitors may lead to differences in action. Captopril is an active drug in its ingested form, with a plasma peak concentration within 1 hour of drug intake in patients with CHF. Its peak effect on hemodynamic response occurs 1 to 2 hours after administration of the drug, and the hemodynamic effects return to resting levels within 8 hours (5,20). During long-term treatment it has been suggested that on a three-times-daily dosage regimen, maximal inhibition of the renin-angiotensin system was not maintained throughout the dosage interval (20). Unlike captopril, spirapril is administered as a prodrng that is rapidly metabolized to the diacid form spiraprilate. This pharmacologically active metabolite reaches its peak plasma level concentration 4 hours after drug intake in patients with CHE In a dose-ranging study we showed that maximal hemodynamic effects occur approximately 4 to 6 hours after drug administration, with inhibition of serum ACE activity even after 24 hours (11). It has been suggested that prolonged ACE inhibition may be required when exercise improvement is expected throughout the day (10). To avoid the expected "peak" effect, we performed measurements of exercise capacity and neurohumoral parameters in the morning, before intake of the study medication, that is, approximately 12 and 24 hours after the last dose intake of captopril and spirapril, respectively. Our results show that at this time point, inhibition of serum ACE activity was still present in the spirapril-treated patients but not in those in the captopril group; however, exercise capacity failed to increase in the spirapril group. In fact, only in the captopril group did exercise capacity increase significantly compared with the spirapril group. This suggests that constant suppression of serum ACE activity is not necessary for, and does not lead to enhancement of exercise capacity. This may be attributed to the fact that intermittent ACE inhibition with short-acting ACE inhibitors has less pronounced blood pressure-lowering effects compromising systemic perfusion and organ function than sustained ACE inhibition with long-acting ACE inhibitors (21). The inhibition of plasma ACE does not fully explain the effects of ACE inhibitors. Several studies have demonstrated a duration and magnitude of blood pressure reduction in response to ACE inhibitors that appeared to correlate better with the inhibition of vascular or tissue ACE than with the inhibition of serum ACE activity (22-24). As a consequence, ACE inhibitors may differ with respect to different degrees of penetration into tissues and different binding characteristics of ACE. Although at present data on clinical
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consequences of these differences are lacking and vascular or tissue ACE in our study was not measured, one can speculate that the effect of captopril on exercise capacity in our study, despite the absence of inhibition of serum ACE activity, may be related to interference with a vascular or tissue renin-angiotensin system. ACE, however, is not only a key enzyme in the renin-angiotensin system, but also acts on a variety of other peptides such as bradykinin. Augmentation of the dilatory effects of bradykinin can be expected in the presence of ACE inhibition and may vary in different vessels. Additionally, some ACE inhibitors may also facilitate some non-kinin-mediated endothelium-dependent relaxations (25,26). Indeed, a difference in potentiation of endothelium-dependent relaxations to methacholine, after pretreatment with either spirapril or captopril, could be observed in isolated rings of human internal mammary arteries (27). The lack of inhibition of serum ACE activity in the captopril-treated patients may have been due to an artifact. During long-time storage of plasma, captopril dissociates from ACE, leading to underestimation of the degree of ACE inhibition (28). To minimize this effect of dissociation of the inhibitor-enzyme complex, all samples were immediately stored at - 8 0 ° C and were assessed within 48 hours. Furthermore, serum ACE activity, determined by the same technique as in our study, has been shown to be significantly reduced at the expected peak effect of captopril in a comparative study with captopril and ramipril (29). In addition, a possible storage artifact cannot explain the significant increase in serum ACE activity at 6 and 12 weeks. Blockade of angiotensin II production by ACE inhibition may induce ACE messenger RNA expression (30). As a consequence, discontinuation of ACE inhibition leads to increased ACE synthesis and an overshoot in serum ACE activity. As the time between the evening dose and morning sampling of captopril was relatively long, the increase in serum ACE activity may have been due to induction of ACE expression.
Conclusion Prolonged inhibition of serum ACE activity of spirapril did not favorably affect exercise capacity when compared with the short-acting ACE inhibitor captopril; however, the number of patients in our study was small and this may have caused a random error in the exercise data. Therefore, larger long-term studies comparing both exercise duration and neurohumoral changes are required to determine the differences between spirapril and other currently available ACE inhibitors.
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