Comparison of the First Dose Response of Fosinopril and Captopril in Congestive Heart Failure

A Randomized, Double-Blind, Placebo Controlled Study

Beyhan ERYONUCU, MD, Lale KOLDAS, MD, Faruk AYAN, MD, Nurgul KESER, MD, and Necati SIRMACI, MD

SUMMARY The purpose of this study was to compare the safety and tolerability of recommended initial doses of fosinopril (FOS) with those of captopril (CAP), in diuretic-treated, salt depleted "high risk" patients with congestive heart failure. Thirty patients were randomized in a double blind fashion to receive a single dose of either FOS 10 mg, CAP 6.25 mg or placebo. CAP produced a significant early and brief fall in BP, while the first-dose hypotensive response with FOS did not differ significantly from placebo. Baseline plasma angiotensin converting enzyme (ACE) activity was similar in all groups. Only CAP showed an acute and significant fall in plasma ACE activity, whereas FOS and placebo did not change ACE activity. There was no correlation between mean arterial pressure or percentile change in mean arterial pressure and plasma ACE activity. Also no correlation was found between high or low ACE activity level and first dose hypotension. The prac- tical importance of the results are: For patients with congestive heart failure, FOS and CAP have different effects on BP after the first dose, and this effect may be dependent on the plasma ACE activity level. FOS produces ACE inhibition and BP changes similar to placebo so it is the safer choice for the treatment of congestive heart failure.(Jpn Heart J 2001; 42: 185-191)

Key words: Fosinopril, Captopril, First dose hypotension, Angiotensin converting enzyme

ANGIOTENSIN-CONVERTING enzyme (ACE) inhibitors relieve symptoms, improve exercise capacity and haemodynamic functions and quality of life, thus reducing hospitalization rates, mortality and morbidity in the treatment of heart failure.1-4) An excessive fall in blood pressure (BP) is a serious problem with these drugs. The main mechanism responsible for this effect is probably venodilation through a reduction in the angiotensin II level and / or reflex vagal-hypotension

From Department of Cardiology, Istanbul University Cerrahpasa¸ Medical Faculty, Istanbul, Turkey. Address for correspondence: Beyhan Eryonucu, MD, Yüzüncü Yil Üniversitesi Tip Fakültesi Kardiyoloji AD, 65200 Van, Istanbul, Turkey. Received for publication August 17, 2000. Revised and accepted October 23, 2000. 185 Jpn Heart J 186 ERYONUCU, ET AL March 2001 mediated via the Bezhold-Jarisch reflex and may be an expression of individual sensitivity or responsiveness to the drug and dose used.5,6) The risk of first dose- hypotension is greater for elderly, diuretic-treated, salt depleted, moderate-to- severe heart failure patients and may lead to renal, cardiac and cerebral complica- tions.7,8) Several studies have indicated that oral ACE inhibitors have different acute effects on BP and the decrease in BP is not always dose-related. As a result, it is recommended a low initial dose be used.9,10) The purpose of this study was to compare the first dose hypotensive effect, the safety and tolerability of recommended initial doses of a long-acting ACE inhibitor fosinopril (FOS) with those of a short-acting, prototype ACE inhibitor captopril (CAP) and placebo in "high risk" patients with congestive heart failure concomitantly receiving diuretics and digitalis.11,12)

MATERIALS AND METHODS After a 7 day stabilization period, 30 patients with symptomatic but stable heart failure (New York Heart Association (NYHA) grades II-III) confirmed by clinical history, examination and cardiologic investigations were randomized in a double blind fashion to receive a single dose of either CAP 6.25 mg (Group l), FOS 10 mg (Group II) or placebo (Group III). All patients were treated with digoxin and diuretics. None of the patients were receiving beta blockers or anti- arrhythmic agents. All patients gave informed consent for participation in the study, which had been approved by the hospital ethical committee. Drug doses were selected as the usually recommended initial doses for the treatment of heart failure. The 3 randomized groups had similar ages, severity and etiology of heart failure (Table I), initial BP and serum electrolyte state. Patients were maintained in the supine position for 1 hour before and during the 6 hours following treatment. Supine systolic blood pressure (SBP) and diastolic blood pressure (DBP) and heart rate were measured just before and 0.5, 1, 2, 3, 4, 6 and 24 hours after

Table I. Summary of Clinical Characteristics of Patients Studied

Captopril (n = 10) Fosinopril (n = 10) Placebo (n = 10)

Male/ female (n) 6 / 4 5 / 5 5 / 5 Age (mean ± SD) 57±12 56 ± 11 58 ± 9 NYHA Class II-III 4-6 5-5 7-3 Ischemic heart disease 3 4 3 Valvular heart disease 3 3 2 Hypertension 1 1 2 Dilated cardiomyopathy 1 1 0 Ischemic + Hypertension 2 1 3 Atrial fibrillation 2 2 1 Ejection fraction (%) 35 ± 5 37 ± 3 36 ± 3 Vo l 4 2 No 2 FIRST DOSE RESPONSE OF FOSINOPRIL AND CAPTOPRIL 187 drug administration using an aneroid sphygomanometer (Erka-239942, Erka, Germany). Blood pressures were determined by averaging 3 measurements obtained 2 minutes apart or 5 measurements if any of the first 3 SBP measurements varied by more than 10 mmHg. Mean arterial pressure (MAP = (SBP- DBP) / 3+DBP)) changes were calculated before and after therapy. For the eval- uation of serum ACE activity, blood samples were taken just before and 2, 4, 8 and 24 hours after drug administration. Quantitative determination of ACE activity was measured by a colorimetric method (Bühlmann Laboratories AG-ACE colorimetric) at a single laboratory. For statistical analysis of differences between groups, analysis of variance (ANOVA) and Scheffe’s test were used. Correlations between the change in mean arterial BP (∆% MAP) and ACE activity were obtained using the Pearson correlation coefficient test. Data are presented as mean ± standard deviation. Statistical significance was defined as a two-tailed p value < 0.05.

RESULTS CAP produced a significant early (maximal fall after 2 hours, from baseline 120.5 ± 14.3 to 107.5 ± 13.17; (p < 0.05), brief fall in SBP which was asymptomatic except for 1 patient. On the other hand, a statistically insignificant first-dose hypotensive response with FOS took place later (maximal fall after 4 hours from 123 ± 16.8 to 114 ± 15.9; NS) lasting longer and did not differ from placebo (maximal fall after 6 hours from 122.5 ± 14.1 to 115.8 ± 12.1). There were no significant differences between the baseline SBP and DBP measurements in any group. The changes in mean arterial pressure after oral administration of CAP,

Figure. Mean percentage change in mean arterial pressure (% MAP) from baseline after drug or placebo administration. * Statistically significant difference in Captopril induced blood pressure change compared to Fosinopril and Placebo, p < 0.05. Jpn Heart J 188 ERYONUCU, ET AL March 2001

FOS and placebo from baseline are shown in the Figure. The maximal decreases in BP after administration of CAP, FOS or placebo were 31, 22 and 20%, respectively. Captopril caused an early and short-lived (1-2 hours) decrease in mean arterial BP whereas FOS resulted in a slower onset of decline, which began after 2 hours, became maximal after 4 hours, persisted for several hours, and did not differ from placebo (Table II). After placebo, there was a variable, modest decrease in mean arterial BP over the next 6 hours, reflecting either a diurnal change or the response to continued bed rest. There were no significant differences in baseline plasma ACE activity among any groups. The changes in plasma ACE activity after administration of drugs from baseline and between group differences are shown in Table III. Plasma ACE activity was decreased 2 and 4 hours after CAP administration. After 8 and 24 hours, plasma ACE activity did not differ from the baseline value. In addition, FOS did not change ACE activity. There was no correlation between mean arterial BP or percentile change in mean arterial pressure (∆%MAP) and ACE activity. Also, no correlation was found between ACE activity level and first dose hypotension.

Table II. Changes in Mean Arterial Pressure after Oral Administration of Fosino- pril, Captopril and Placebo

Hours Fosinopril (n = 10) Captopril (n = 10) Placebo (n = 10)

Baseline 95 ± 10.2 90.3 ± 10.2 93.4 ± 8.6 0.5 92.9 ± 10.3 85.6 ± 11.7# 92.4 ± 8.3 1 91.7 ± 10.3 82.8 ± 11.6*# 89.3 ± 7.1* 2 90.3 ± 9.4* 88.1 ± 12.4* 89.5 ± 8.6 3 88.8 ± 11.1* 87.5 ± 11.9 88.5 ± 9 4 88.6 ± 11* 90.9 ± 7.3 88.6 ± v10.9 6 89.9 ± 12.6* 93.3 ± 7.9# 88.7 ± 11.6* 24 94.4 ± 6.7 91.8 ± 7.2 91.1 ± v5.8

* Statistically significant difference from baseline, p < 0.05. # Comparison of the first-dose hypotensive effect with placebo, p < 0.05.

Table III. Changes in Plasma ACE Activity after Oral Administration of Fosinopril, Captopril and Placebo

Hours Captopril (n = 10) Fosinopril (n = 10) Placebo (n = 10)

Baseline 54.3 ± 27.2 42.6 ± 21.2 45.2 ± 24.6 2 31.1 ± 20.4* 33.5 ± 18.8 51.4 ± 18.4 4 30.3 ± 23* 35.4 ± 22.4 48.3 ± 17.5 8 42.7 ± 22.1 40.1 ± 20 49.5 ± v18.6 24 51.4 ± 27.4 41.2 ± 23.4 48.5 ± 19.1

* Statistically significant difference from baseline, p < 0.05. Vo l 4 2 No 2 FIRST DOSE RESPONSE OF FOSINOPRIL AND CAPTOPRIL 189

DISCUSSION Hypotensive episodes associated with initiation of ACE inhibitor therapy for heart failure are generally asymptomatic and the therapy need not be discon- tinued, however, potentially serious consequences may occur. The origin of this response may be explained by the reflex activation of the circulating and tissue based renin angiotensin system either as a response to chronic heart failure, pre- ceding or concurrent diuretic treatment, and venodilation or vagally mediated reflex hypotension via the Bezold-Jarisch reflex.5,7,13,14) We preferred to choose patients at greater risk for developing first-dose hypotension; such as elderly, diuretic treated, moderate to severe heart failure patients. While the Captopril Multicenter Research Group obtained an incidence of 33.3% for symptomatic first dose hypotension in patients with chronic heart failure receiving 25 mg captopril, Cleland, et al. described an incidence of 11.5% using 5 or 10 mg enalapril and Di Carlo, et al. an incidence of 13.3% with 2.5 mg enalapril.1,7,15) ln another study performed by Hasford, et al. an incidence of 5.2% with 2.5 mg enalapril was reported.16) In our study, a symptomatic first dose hypotensive effect was only observed in 1 patient (10%) in the captopril group. Captopril caused an early and short-lived (1-2 hours) decrease in MAP (maximal 31%) whereas FOS resulted in a slower onset of decline which began after 2 hours, became maximal after 4 hours, persisted until 6 hours and did not differ from placebo (maximal 22% vs 20%, respectively). The hypotensive effect after placebo may be due to prolonged bed rest or diurnal changes. Our findings agree with those of MacFay- den, et al.9) who demonstrated a qualitative difference in the acute response to ACE inhibitor with similar structure and metabolism (enalapril and perindopril) and an early and brief fall in BP with captopril in a similar, placebo-controlled study. The hypotensive effect of enalapril and captopril and time course of action have been established in several studies.17,18) It has been shown that enalapril and lisinopril-like ACE inhibitors with long durations of action, have a higher incidence of serious adverse events than short-acting agents.19) While a pronounced fall in BP is not a marker of benefit, small BP decreases may be associated with benefit.20) Our study indicates that clinically significant differences in response to ACE inhibitor therapy can be observed also in patients with "high risk" congestive heart failure. We found similar baseline ACE activity but different BP and ACE inhibition responses. While CAP caused an early and acute fall in BP and ACE activity, FOS-induced hypotension was later, longer lasting, gradual and similar to those caused by placebo. Similarly, a statistically significant change in plasma ACE activity after FOS administration was not determined. The dosages used in this study were recommended initial doses for FOS and CAP. However, a statistically insignificant first-dose hypotensive response with FOS may be due Jpn Heart J 190 ERYONUCU, ET AL March 2001 to the difference in effective dosages of this drug because ACE inhibition of FOS is weak at this dose. We conclude that oral CAP and FOS have different effects on mean arterial BP after the first dose, and this effect may be dependent on the plasma ACE- activity level. FOS produced ACE-inhibition and first-dose BP changes similar to placebo, and FOS appears to be less likely to lead to early and / or prolonged BP decrease. Therefore, FOS can be used safely in initial doses even in salt-depleted, diuretic-treated "high risk" patients with congestive heart failure whose BP should be monitored until stabilization.

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