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J Am Coll Cardiol, 2000; 36:479-486 © 2000 by the American College of Cardiology Foundation |
a Department of Cardiology, Christchurch Hospital, Christchurch, New Zealand
Manuscript received July 21, 1999; revised manuscript received January 28, 2000, accepted March 30, 2000.
Reprint requests and correspondence: Prof. Hamid Ikram, Department of Cardiology, Christchurch Hospital, Private Bag 4710, Christchurch, New Zealand t.nz
HAMIDI{at}chhlth.gov
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Abstract |
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We sought to examine the effects of long-term vasopeptidase inhibition in patients with heart failure.
BACKGROUND
The long-term effects of omapatrilat, an agent that inhibits both neutral endopeptidase and angiotensin-converting enzyme, on clinical status, neurohormonal indexes and left ventricular function in patients with chronic heart failure (CHF) have not been previously documented.
METHODS
Forty-eight patients in New York Heart Association functional class II or III, with left ventricular ejection fraction (LVEF) 
40% and in sinus rhythm were randomized to a dose-ranging pilot study of omapatrilat for 12 weeks. Measurements were performed at baseline and 12 weeks.
RESULTS
There was an improvement in functional status, as reported by the patient (p < 0.001) and physician (p < 0.001) at 12 weeks. Dose-dependent improvements in LVEF (p < 0.001) and LV end-systolic wall stress (sigma) (p < 0.05) were seen, together with a reduction in systolic blood pressure (p < 0.05). There was evidence of a natriuretic effect (p < 0.001), and total blood volume decreased (p < 0.05). Omapatrilat induced an increase in postdose plasma atrial natriuretic peptide levels (p < 0.01) in the high dose groups, with a reduction in predose plasma brain natriuretic peptide (p < 0.001) and epinephrine (p < 0.01) levels after 12 weeks of therapy. Omapatrilat was well tolerated.
CONCLUSIONS
The sustained hemodynamic, neurohumoral and renal effects of omapatrilat, together with improved functional status, suggest that vasopeptidase inhibition has potential as a new therapeutic modality for the treatment of CHF.
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Omapatrilat, a vasopeptidase inhibitor, is a single molecule that simultaneously inhibits both NEP and ACE (10). In animal studies, vasopeptidase inhibitors have been shown to decrease LV end-diastolic pressure and peripheral vascular resistance, with an increase in cardiac output, compared with selective inhibitors of ACE and NEP alone (11). Omapatrilat improves LV remodeling and survival in cardiomyopathic hampsters, compared with equipotent doses of a selective ACE inhibitor (12). We investigated the long-term effects of this novel agent in a dose-ranging pilot study in patients with CHF.
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Methods |
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Study design.
Approval for this single center, noninvasive substudy was provided by the Canterbury Ethics Committee of the Health Funding Authority of New Zealand, and all patients gave written, informed consent. Patients recruited were concurrently enrolled in either 1) a 12-week multicenter, double-blind, randomized, invasive hemodynamic trial (n = 40); or 2) a 12-week multicenter, double-blind, randomized exercise trial (n = 8) (13). Both studies had a dose-ranging design with an active low dose (2.5 mg of omapatrilat) control group. The 2.5-mg dose was chosen as an active control therapy because in healthy male subjects it has been shown that 2.5 mg of omapatrilat caused significant ACE inhibition over 24 h, but, by contrast to higher doses of omapatrilat, no significant NEP inhibition, as measured by changes in urinary ANP and urinary second messenger, cyclic 3',5'-guanosine monophosphate (cGMP) (14). Forty-eight patients in New York Heart Association (NYHA) functional class II or III congestive heart failure, with a left ventricular ejection fraction (LVEF) 40% and in sinus rhythm, were enrolled. All ACE inhibitors and angiotensin II receptor antagonists were stopped at least four days before baseline measurements and for the entire study period of 12 weeks. All other cardiac medications were continued throughout the study. The protocol allowed for up to four supplemental doses of furosemide (over 24 h) for worsening heart failure during the 12 weeks of the trial. However, if an increase in the maintenance dose was necessary, patients were withdrawn from the study. After baseline measurements, the patients were randomized to one of five omapatrilat doses: 2.5, 5, 10, 20 or 40 mg/day for 12 weeks. Patients underwent an outpatient review at one, two, four, six and eight weeks. At 12 weeks, measurements were repeated on therapy four h after the final dose of omapatrilat.
Methodology. All measurements were performed in a quiet laboratory maintained at a constant temperature between 22°C and 25°C at midday. Patients abstained from food, caffeine-containing drinks and cigarettes; this fasting lasted for at least 4 h before measurement. M-mode and two-dimensional echocardiographic studies were performed in the left lateral recumbent position using a Hewlett-Packard 1500 Sonos with a 2.5 MHz transducer. Cardiac volumes were measured at end diastole (defined as the onset of the Q wave on the electrocardiogram) and end systole (defined as the first high frequency component of the aortic second heart sound as measured by phonocardiography) in three cardiac cycles, and the mean values were computed. The LVEF was measured from the apical four-chamber view by the single-plane ellipsoid method (15). Stroke volume was measured by the LV outflow method using pulsed wave Doppler echocardiography (average of five cardiac cycles) (16).
Digital applanation tonometry (Millar Instruments, Houston, Texas) of the left radial artery was performed for 8 s and calibrated to the brachial sphygmomanometric blood pressure obtained at the time of pulse recording. Using a generalized transfer function (PWV Medical, Sydney, Australia), the mean ascending aortic systolic pressure, mean diastolic pressure, end-systolic pressure and waveform were derived (17,18). We used simultaneous M-mode or pulsed wave Doppler echocardiography and digital applanation tonometry to derive LV meridional end-systolic wall stress (sigma) (19,20), rate-corrected velocity of circumferential fiber shortening (20), total peripheral resistance (21) and myocardial oxygen demand as measured by the rate–pressure product (22). All echocardiographic measurements were performed by a single operator who had no knowledge of the group allocation of the patients. The mean intrapatient variability (repeatability) for observations in three patients each repeated on three consecutive days showed a coefficient of variation of 4.2% for LV internal dimension at end systole, 9.8% for ejection fraction, 4.8% for end-systolic pressure and 7.1% for stroke volume. Functional class (NYHA) was assessed at baseline and 12 weeks. The clinician’s and subject’s assessment of the change in functional status at three months, compared with baseline, was determined by a global assessment scale: improved (greatly, moderately or slightly), unchanged or worsened.
Venous blood and blood volumes were measured from a subgroup, as part of the concomitant hemodynamic study during the hospital period, for right heart catheterization at baseline and 12 weeks. Venous blood was drawn with the patient lying quietly while semirecumbent at baseline before the first dose of omapatrilat and at 3 h, 12 h and 24 h after the first dose of the drug for measurements of plasma ANP and cGMP. These were repeated after the final dose of the drug at 12 weeks. Venous blood was also drawn at baseline (predose) and at 12 weeks for ANP, brain natriuretic peptide (BNP), endothelin, catecholamines and aldosterone. Samples were taken into chilled EDTA vacutainers, placed immediately on ice and centrifuged within 20 min at –4°C, and the plasma was stored at –80°C for assay (23–27). The endothelin extraction method was the same as for ANP (23). Endothelin-1 was assayed by adding 100 µl of plasma extract or standard to 100 µl of diluted endothelin-1 antiserum (Peninsula Laboratories, Belmont, California) with cross reactivities of 100% for endothelin-1, 17% for human big endothelin, 7% for endothelin-2, 7% for endothelin-3 and 0% for ANP. The assay was incubated for 3 h at room temperature, after which 100 µl of iodine-125–endothelin-1 (10,000 cpm) was added and incubated for 22 to 24 h at 4°C. Bound and free endothelin-1 was separated by a solid-phase second antibody method, and the precipitates were countered for radioactivity. The recovery rate of endothelin-1 from human plasma was 91% at 36 pmol/liter, and extracts of human plasma were diluted in parallel with the standard curve. The assay had a mean detection limit of 1.4 pmol/liter over 30 assays. The intra-assay coefficient of variation was 6.25%, and the interassay coefficient of variation was 16.4% at 2.5 pmol/liter.
Plasma volume was measured by the indocyanine green dilution technique, with indocyanine green (0.25 mg/kg) injected into the right heart catheter and venous blood withdrawn 3 to 12 min after the injection from the opposite arm (28).
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Measurements of renal function were performed in a subgroup of patients as part of the concomitant hemodynamic study at baseline and 12 weeks. Patients were placed on bed rest for 
12 h before the start of collection (which was begun immediately after administration of drug) and throughout the 24-h urine collection period at baseline and at 12 weeks. Urine volume and sodium and creatinine levels were measured. Medications other than the study drug were withheld over this period. Both oral fluids and solids were regulated over the period of collection.
Statistical analysis. Changes from baseline to three months for all subjects grouped together were assessed using the paired t test. The dose groups are as follows: 2.5 mg as the active control group, 5 to 10 mg as the low dose group and 20 to 40 mg as the high dose group. We used two-way analysis of variance with repeated measures to explore the relation between the variable and dose group, followed by Tukey’s test to explore pairwise differences when this showed significant effects (p < 0.05). Analysis of variance for hormonal and renal data was performed after logarithmic transformation, with mean absolute values given in the Results section. Clinician and subject assessment of the change in heart failure status at three months was analyzed by using the Mann-Whitney U test, and differences between the variable and dose group by using the Kruskal-Wallis test. Categoric variables were assessed by using the Fisher exact test. Group data are expressed as the mean value ± SEM.
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Results |
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There was an improvement in NYHA functional class at 12 weeks in the 20- to 40-mg group (39% improving by one functional class), compared with the 2.5-mg group (0%) (p < 0.05), but no difference between the 5- to 10-mg group (23%) and the 2.5-mg control group.
At 12 weeks, the patients’ score for functional status had improved (p < 0.001) (Table 2). There was significantly greater improvement with the 5- to 10-mg doses (p < 0.001) and 20- to 40-mg doses (p < 0.001), compared with the 2.5-mg dose. The clinician’s 12-week score for the patients’ heart failure status also indicated overall improvement (p < 0.001). Again, improvement was more pronounced in the higher dose groups compared with the 2.5-mg control group (p < 0.05).
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LV systolic function: change from baseline to 12 weeks for all 41 patients combined (Table 3). There was a small fall in heart rate (p < 0.05). The LVEF improved (p < 0.001), with no significant change in end-diastolic volume, but a reduction in end-systolic volume (p < 0.01). The stroke volume index increased slightly (p < 0.05), with no significant change in cardiac output or cardiac index. Myocardial oxygen demand, as measured by the rate–pressure product, fell (p < 0.0001). Both systolic (p < 0.0001) and diastolic (p < 0.05) brachial blood pressures fell, along with total peripheral resistance (p < 0.001).
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Total blood volume for all groups was lower at 12 weeks compared with baseline (p < 0.05), with a tendency for a greater fall in the 20- to 40-mg group compared with the 2.5-mg group (p = 0.09). Plasma hematocrit did not change.
Neurohormones. High dose omapatrilat caused a prompt and vigorous increase in plasma ANP after the first dose (p = 0.07 for group, p = 0.2 for time, p < 0.05 for interaction), with a significant increase in ANP at 3 h in the high dose group compared with both the 2.5-mg group (p < 0.01) and the 5- to 10-mg group (p < 0.05). Similar early dose-dependent increases were seen with plasma cGMP (p < 0.05 for group, p < 0.01 for time, p < 0.01 for interaction) (Fig. 1A). Subsequently, ANP and cGMP fell to near baseline levels.
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Neurohormones: change from baseline for all groups combined (n = 33) over 12 weeks (Table 5).
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Neurohormones: change between the groups over 12 weeks (Table 6). There was no difference between the groups in terms of change in plasma levels of ANP from predose day 1 to predose week 12. The BNP level fell in all groups over 12 weeks. Endothelin-1 was significantly lower in the 20- to 40-mg group compared with both the 5- to 10-mg group (p < 0.001) and the 2.5-mg group (p < 0.01) at baseline. Over 12 weeks, there was a significant fall in endothelin-1 in the 5- to 10-mg group compared with the 20- to 40-mg group (p < 0.01), with no difference between the 2.5-mg group and the 20- to 40-mg group. There were no differences between the groups in terms of epinephrine, norepinephrine and aldosterone levels over 12 weeks.
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Discussion |
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Because of the clearly established benefits of ACE inhibition in CHF, no placebo group was included on the basis of ethical grounds, and higher doses of vasopeptidase inhibition (NEP plus ACE inhibition) were compared with the 2.5-mg dose, which has been reported to inhibit ACE but not NEP (14).
Effects on clinical status and tolerability. Overall, omapatrilat had beneficial effects, as evidenced by improvement in clinical status over three months, with a dose-dependent reduction in episodes of acute heart failure. Omapatrilat was well tolerated, with transient symptomatic hypotension seen only at higher doses. This was readily managed by a diuretic reduction and did not require discontinuation of the drug. In this study, unlike in clinical practice, there was no stepwise increase in the dosage, and the results confirm that dose titration would be appropriate on commencing the drug. No episodes of angioedema were seen.
Effect on LV function. The improvement in ejection fraction was dose-dependent. Left ventricular systolic performance is predominantly dependent on preload, myocardial contractility and afterload. An inverse relation exists between the mean velocity of circumferential fiber shortening and LV end-systolic wall stress (20). This relation is sensitive to the altered contractile state, is independent of preload, incorporates both afterload and heart rate and can be accurately determined by noninvasive means without manipulation of loading conditions (20). We have shown both a fall in myocardial oxygen consumption, as shown by the rate–pressure product, and a dose-dependent reduction in afterload. Despite a significant improvement in LVEF, there was no increase in the contractile state, as measured by the rate-corrected velocity of circumferential fiber shortening, and no deleterious increase in estimated myocardial oxygen demand. Left ventricular performance, as measured by the relation between end-systolic wall stress (sigma) and rate-corrected velocity of circumferential fiber shortening, was enhanced in the higher dose groups, secondary to a reduction in afterload. In the absence of changes in LV preload (i.e., end-diastolic volume), we were unable to detect a protective effect against LV remodeling with 12 weeks of treatment.
In previous studies, pure NEP inhibition did not induce a sustained reduction in systolic blood pressure (8,31,32). However, omapatrilat induced a dose-dependent reduction in systolic and diastolic blood pressure, with a fall in total peripheral vascular resistance, suggesting an effect of combined inhibition of ACE and NEP not observed with the pure NEP inhibitors candoxatril or sinorphan (8,31,32).
Effects on renal function and blood volume. The baseline 24-h urine measurements were started with the administration of the first dose of omapatrilat, whereas concomitant medications, including diuretics, were withheld for 24 h. Normally, withdrawal of diuretics produces a powerful antidiuresis (33). Natriuretic peptides (3,4) and pure NEP inhibitors (31,34) induce natriuresis, and we found that there was greater sodium and volume excretion over 24 h at the 12-week study compared with baseline, both days on which diuretics were withheld. This change in urine indexes after 12 weeks of therapy with omapatrilat may reflect changes in intrarenal sodium-conserving mechanisms, due to enhanced local action of ANP, and reduced activity of sympathetic and renin-angiotensin-aldosterone systems, as reflected in reduced plasma epinephrine and aldosterone levels. In contrast, it is unlikely that a negative daily balance of water and sodium existed throughout the 12-week study without adverse consequences. Importantly, there was preservation of renal function with no deterioration in creatinine clearance over the three months, despite the sizeable decline in arterial pressure and blood volume.
Previous studies (35) have shown that other vasodilators modify regional blood flow, with a change in apparent plasma and blood volume. Pure NEP inhibitors have been suggested as alternatives to diuretics. To our knowledge, our data include the first measurements of blood volume after 12-week therapy for congestive heart failure. It is likely that the reduction in blood volume is partly due to an increase in urinary fluid and sodium loss. Atrial natriuretic peptide given in the short term causes contraction of blood volume by inducing a shift from vascular to extravascular space (36). However, we did not see a change in hematocrit over 12 weeks of combined ACE and NEP inhibition to support this. Further mechanistic studies of the fall in blood volume with vasopeptidase inhibition are required.
Effect on neurohormones. Ideally, therapeutic interventions in heart failure should produce favorable effects on both hemodynamic and neurohormonal systems. The beneficial hemodynamic changes seen in this study with omapatrilat were paralleled by improvement in the neurohormonal profile. Inhibition of NEP by omapatrilat in patients with heart failure was demonstrated by increased plasma ANP and cGMP after initial (higher) doses of omapatrilat. In contrast, early treatment with pure ACE inhibition has been shown to cause a fall in ANP (37,38). Subsequently, ANP levels fell to near baseline levels over the 24 h, consistent with reduced ANP secretion, presumably secondary to improved hemodynamic data. With long-term therapy, the fall in predose BNP at 12 weeks presumably reflects a reduction of LV wall stress and, consequently, a reduction in BNP secretion, which overcame any tendency for NEP inhibition to increase plasma BNP through reduced clearance. In contrast, predose ANP levels after long-term therapy are sustained. The likely mechanism underlying the different responses of plasma ANP and BNP resides in NEP’s greater affinity for ANP than BNP (39) (i.e., the effect of reduced ANP secretion is perfectly balanced by delayed clearance). Postdose increments in plasma ANP and cGMP with higher doses were similar at day 1 and after 12 weeks of long-term therapy at day 83, mitigating against tolerance of NEP’s inhibitory effect with long-term treatment.
There was no evidence for activation of the sympathetic nervous system over 12 weeks in response to the significant falls in blood pressure. Rather, a reduction in heart rate and plasma epinephrine suggests that sympathetic activity might have been attenuated. Unchanged plasma norepinephrine also mitigates against generalized activation of the sympathetic nervous system, possibly due to a sympathoinhibitory effect of ANP with higher omapatrilat doses (40,41). Reduced epinephrine over 12 weeks may reflect reduced adrenal sympathetic nervous system traffic in response to beneficial hemodynamic changes and perhaps a fall in angiotensin II levels.
Study limitations. This study lacks a true placebo limb. Full withdrawal of ACE inhibition is not appropriate. The use of an active control group may have resulted in underestimation of dose-related changes. The groups do allow comparison of low dose vasopeptidase inhibition (ACE inhibition only) with high dose effects (ACE and NEP inhibition). The hemodynamic improvements seen may be due to increasing ACE inhibition with higher doses. However, the rise in plasma ANP and cGMP with higher doses is consistent with NEP inhibition.
Conclusions. In this first report of long-term treatment with a vasopeptidase inhibitor in patients with symptomatic heart failure, omapatrilat induced a dose-dependent improvement in both functional and hemodynamic status. Plasma ANP is increased relative to BNP, which fell over the long term, presumably reflecting a reduction in LV wall stress, the primary secretory stimulus for this peptide. The improvements in functional status are paralleled by improvements in hemodynamic status, with reductions in afterload, arterial pressure and central blood volume. The data suggest enhanced excretion of sodium and water, with no deterioration of renal function. We conclude that higher doses of omapatrilat appear to have effects due to both ACE inhibition and ANP augmentation. On the basis of these results, this drug is suitable for larger comparative trials with morbidity and mortality end points. Omapatrilat may be a significant new therapy in the treatment of CHF.
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Footnotes |
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