- Email: [email protected]
Effects of omapatrilat on systemic arterial function in patients with chronic heart failure
Effects of Omapatrilat on Systemic Arterial Function in Patients With Chronic Heart Failure Dougal R. McClean,
MB, CHB,
Hamid Ikram, MD, PhD, Amanda H. Garlick, and Ian G. Crozier, MD
The mechanisms of action of omapatrilat, an agent that inhibits both neutral endopeptidase 24.11 and angiotensin-converting enzyme, on arterial function in patients with heart failure have not been previously reported. Forty-eight patients in New York Heart Association functional class II to III, left ventricular ejection fraction <40%, and in sinus rhythm were randomized to a dose-ranging (2.5, 5, 10, 20, or 40 mg) study of omapatrilat for 12 weeks. Measurements were obtained at baseline and 12 weeks. Decreases in systolic (25.0 ⴞ 4.5 vs 2.8 ⴞ 5.0 mm Hg, p <0.05) and mean arterial (13.9 ⴞ 3.0 vs 0.3 ⴞ 3.3 mm Hg, p <0.05) pressure were seen after 12 weeks of therapy with higher doses. Ventricular-arterial coupling was im-
proved with a dose-related decrease in augmentation index (ⴚ13.8 ⴞ 1.7% vs ⴙ6.1 ⴞ 2.1%, p <0.01). There was no change in resting forearm blood flow between groups; however, maximum forearm vasodilator response during reactive hyperemia increased in the highdose groups compared with the control group (ⴙ266 ⴞ 43% vs ⴚ14 ⴞ 92%, p <0.05). Omapatrilat induced an increase in postdose plasma atrial natriuretic peptide levels (30 ⴞ 11 vs ⴚ2 ⴞ 7 pmol/L, p <0.01) in highdose groups consistent with endopeptidase 24.11 inhibition. Omapatrilat shows beneficial changes in ventricular-vascular coupling and arterial function in heart failure. 䊚2001 by Excerpta Medica, Inc. (Am J Cardiol 2001;87:565–569)
mapatrilat is the first of a new class of drugs called vasopeptidase inhibitors that simultaO neously inhibit both neutral endopeptidase 24.11 and
evant to its effects in heart failure. This study describes the effects of 12 weeks of chronic omapatrilat therapy on arterial BP, ventricular-vascular coupling, and maximum forearm vasodilator response in patients with congestive heart failure.
angiotensin-converting enzyme (ACE) using a single molecule.1 In low renin, normal, and high renin animal models of hypertension, omapatrilat has been shown to lower blood pressure (BP) to a greater degree than selective inhibition of either enzyme alone.2 In normal volunteers, omapatrilat has previously been shown to cause significant ACE inhibition with doses of 2.5 to 75 mg, with the 10-mg dose having been shown to induce similar 24-hour in vivo ACE inhibition compared with 20 mg of fosinopril.3,4 The 2.5-mg dose was chosen as an active control in this study because it has been shown to cause significant ACE inhibition over 24 hours but, in contrast to higher doses of omapatrilat, no significant neutral endopeptidase 24.11 inhibition, as measured by changes in urinary atrial natriuretic peptide (ANP) and urinary second messenger cyclic guanosine monophosphate.3 Vasopeptidase inhibition may alter the balance toward vasodilatation by inhibiting angiotensin II, restoring the physiologic actions of ANP, and possibly having a synergistic effect on decreasing kinin degradation.5 Therefore, the mechanisms of action of this new agent on the arterial system, which should ideally produce a depressor response and vasodilation, is relFrom the Department of Cardiology, Christchurch Hospital, Christchurch, New Zealand. This work was supported by a project grant from Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey. Manuscript received June 27, 2000; revised manuscript received and accepted September 11, 2000. Address for reprints: Hamid Ikram, MD, PhD, Department of Cardiology, Christchurch Hospital, Private Bag 4710, Christchurch, New Zealand. E-mail: [email protected]. ©2001 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 87 March 1, 2001
METHODS The study was approved by the Canterbury Ethics Committee of the Health Funding Authority, and all patients gave written informed consent before the study. The study was a single-center, noninvasive pilot study. Patients enrolled were concurrently taking part in either: (1) a 12-week multicenter, double-blind, randomized, invasive hemodynamic trial (40 patients); or (2) a 12-week multicenter, double-blind, randomized exercise trial (8 patients).3 Patients with New York Heart Association II to III congestive heart failure, left ventricular ejection fraction ⱕ40%, and in sinus rhythm were enrolled. All ACE inhibitors and angiotensin II receptor antagonists were discontinued at least 4 days before baseline measurements, and for the entire 12 weeks. All other concomitant cardiac medications were continued throughout the study. Patients could receive up to 4 supplemental doses of furosemide (over 24 hours) for worsening heart failure; however, if an increase in maintenance dose was necessary, patients were then withdrawn from the study. After baseline measurements were obtained, patients were randomized to 1 of 5 omapatrilat doses: 2.5, 5, 10, 20, or 40 mg once daily for 12 weeks. At 12 weeks, measurements were repeated after the final dose of omapatrilat. All measurements were obtained in a quiet laboratory maintained at a constant temperature between 22°C and 25°C. Patients abstained from food, caf0002-9149/01/$–see front matter PII S0002-9149(00)01432-6
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BP was calculated (1/3 pulse pressure ⫹ diastolic BP). Digital applaOmapatrilat Dose nation tonometry (Millar Instruments, Houston, Texas) of the left Total 2.5 mg 5–10 mg 20–40 mg radial artery was performed for 8 Variable (n ⫽ 48) (n ⫽ 15) (n ⫽ 18) (n ⫽ 15) seconds. Each recording was ensemMean age (yrs) 67 ⫾ 1 67 ⫾ 2 70 ⫾ 3 66 ⫾ 2 ble averaged, giving an average Men 44 (92%) 14 (93%) 15 (83%) 15 (100%) waveform for each subject, and calCreatinine (mmol/L) 0.11 ⫾ 0.01 0.11 ⫾ 0.01 0.11 ⫾ 0.01 0.12 ⫾ 0.01 Presumed etiology of ibrated to the mean and diastolic braheart failure chial sphygmomanometric BP obIschemic 42 (88%) 14 (93%) 15 (83%) 13 (86%) tained at the time of pulse recording. Idiopathic cardiomyopathy 4 (8%) 1 (7%) 2 (11%) 1 (7%) With use of a generalized transfer Systemic hypertension 2 (4%) 0 1 (6%) 1 (7%) NHYA function (PWV Medical, Sydney, Class II 29 (58%) 8 (53%) 11 (61%) 9 (60%) Australia), ascending aortic end-sysClass III 20 (42%) 7 (47%) 7 (39%) 6 (40%) tolic pressure and waveform were Treatment derived.6,7 Wave reflection was meaACE inhibitors 40 (83%) 13 (86%) 15 (89%) 12 (80%) sured by the augmentation index, AII blockers 5 (10%) 2 (13%) 0 3 (20%) Diuretics 45 (94%) 14 (93%) 17 (94%) 14 (93%) which was calculated from the ratio Digoxin 14 (29%) 3 (20%) 6 (33%) 5 (33%) of the difference between the pres blockers 7 (15%) 2 (13%) 2 (11%) 3 (20%) sure at the respective peaks or inflecAspirin 33 (69%) 10 (67%) 12 (67%) 11 (73%) tions (P2 ⫺ P1) divided by the pulse AII ⫽ angiotensin II; NYHA ⫽ New York Heart Association. pressure (systolic BP ⫺ diastolic BP).8,9 Forearm blood flow was measured in the right forearm using venous occlusion plethysmography with mercury-in-Silastic strain gauges, a plethymographic balancing system and amplifier, and a rapid cuff inflator (DE Hokanson, Issaquah, Washington).10 The right arm was elevated and passively supported above the height of the right atrium to ensure adequate venous drainage between measurements. A mercury-in-Silastic strain gauge that had been electrically calibrated was placed around the right forearm at the region of greatest circumference. Before each forearm blood flow determination, a right upper arm cuff was set at 40 mm Hg, and circulation to the hand was stopped by inflating a right wrist cuff to 200 mm Hg. Forearm blood flow was derived from FIGURE 1. Change in augmentation index after 12 weeks of omapatrilat therapy. **p <0.01 versus 2.5-mg control group. the rate of initial increase in forearm circumference during venous occlusion and was expressed in ml/100 ml forearm tissue/min. Recordings were begun ⬎60 seconds after wrist cuff inflation to allow flow to stabilize. Resting forearm blood flow was taken as the average of at least 3 flow measurements made at 15-second intervals. Maximum forearm vasodilator response was calculated by measuring maximum forearm blood flow during reactive hyperemia, following the right upper arm cuff inflated to 200 mm Hg for 3 minutes. At 5-, 15-, and 30-second intervals after cuff deflation, maximum forearm blood flow (expressed as percent change in pretreatment values) was measured. Venous blood was obtained from a subgroup as part of the concomitant hemodynamic study during FIGURE 2. Change in maximum forearm vasodilator response hospitalization for right-sided cardiac catheterization during reactive hyperemia after 12 weeks of omapatrilat therat baseline and at 12 weeks. Venous blood was withapy. *p <0.05 versus 2.5-mg control group. drawn with the patient lying quietly while semirecumbent at baseline before dosing, and at 3, 12, and 24 feine-containing drinks, and cigarettes for ⬎4 hours hours after the first dose of the drug. These were before measurements, and rested for at least 30 min- repeated after the final dose of the drug at 12 weeks. utes before baseline measurements. BP was measured Samples were placed in chilled vacutainers, placed by a brachial sphygmomanometer and mean arterial immediately on ice, centrifuged within 20 minutes at TABLE 1 Bastline Characteristics
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with the 2.5-mg group (p ⬍0.05) with no difference compared with Omapatrilat Dose the 20- to 40-mg group. Maximum forearm vasodilator response during 2.5 mg 5–10 mg 20–40 mg reactive hyperemia increased over 12 Systolic BP baseline (mm Hg) 132 ⫾ 6 130 ⫾ 6 133 ⫾ 6 weeks in the 5- to 10-mg and 20- to Systolic BP 12 wks (mm Hg) 128 ⫾ 6 112 ⫾ 5 108 ⫾ 6* 40-mg groups compared with the Diastolic BP baseline (mm Hg) 73 ⫾ 3 72 ⫾ 4 75 ⫾ 3 2.5-mg group (p ⬍0.05). There was Diastolic BP 12 wks (mm Hg) 74 ⫾ 3 63 ⫾ 3 67 ⫾ 3 Mean BP baseline (mm Hg) 92 ⫾ 3 91 ⫾ 4 94 ⫾ 3 no difference between the 5- to 10Mean BP 12 wks (mm Hg) 92 ⫾ 3 79 ⫾ 3 80 ⫾ 4* and 20- to 40-mg groups after 12 AI baseline (%) 125 ⫾ 6 125 ⫾ 3 122 ⫾ 4 weeks of therapy (Figure 2). † AI 12 wks (%) 131 ⫾ 6 123 ⫾ 3 108 ⫾ 3 Neurohormones: High-dose omaResting FBF baseline (ml/min/100 ml) 2.0 ⫾ 0.2 2.5 ⫾ 0.2 3.0 ⫾ 0.3* Resting FBF 12 wks (ml/min/100 ml) 2.1 ⫾ 0.2 2.1 ⫾ 0.2 2.7 ⫾ 0.2 patrilat caused a prompt and vigorMaximum forearm vasodilator response ous increase in plasma ANP after the Baseline (%) 627 ⫾ 118 279 ⫾ 54* 508 ⫾ 61 first dose (30 ⫾ 11 vs ⫺2 ⫾ 7 12 wks (%) 612 ⫾ 117 566 ⫾ 62* 773 ⫾ 73* pmol/L, p ⬍0.01) compared with *p ⬍0.05 versus 2.5 mg; †p ⬍0.01 versus 2.5 mg. 2.5-mg dose. Subsequently, ANP deAI ⫽ augmentation index; FBF ⫽ forearm blood flow. creased to near baseline levels (Figure 3a). After 12 weeks, high-dose omapatrilat induced an increase in ⫺4°C, and plasma stored at ⫺80°C before assay for ANP compared with day 1 predose levels, with a significant increase in the 20- to 40-mg group at 3 plasma ANP.11 Statistical analysis: We combined some dose groups hours compared with 2.5-mg dose (35 ⫾ 14 vs ⫺15 ⫾ to give 2.5 mg as “active control,” 5 to 10 mg as the 9 pmol/L, p ⬍0.01) (Figure 3b). low-dose group, and 20 to 40 mg as the high-dose group. We used 2-way analysis of variance with re- DISCUSSION peated measures to explore the relation between variIn this 12-week pilot study with omapatrilat in able and dose group. Post hoc comparisons were per- patients with chronic heart failure, there was (1) a formed with Tukey’s honest significant difference test decrease in systolic and mean BP, (2) a dose-depenwhen this showed significant effects (p ⬍0.05). Group dent improvement in wave reflection as measured by data are expressed as mean value ⫾ SEM. augmentation index, (3) improvements in maximum forearm vasodilator response during reactive hyperemia in both the 5- to 10- and 20- to 40-mg groups, RESULTS Forty-eight patients were enrolled (Table 1) and 7 suggesting an improvement in endothelial dysfuncpatients did not return for the 12-week measurements. tion, and (4) evidence of increased plasma ANP with Three patients were withdrawn from the 12-week higher doses. In previous studies, pure endopeptidase study in the 2.5-mg group owing to worsening heart 24.11 inhibition has not induced a sustained reduction failure (20%) compared with 1 in the 5- to 10-mg in systolic BP. In contrast, in this 12-week pilot study, group (5%) and none in the 20- to 40-mg group. Two higher doses of omapatrilat induced reductions in syspatients (1 in the 20- to 40-mg group and 1 in the 5- tolic and mean BP, suggesting an effect of vasodilato 10-mg group) did not wish to return for the con- tation not observed with the endopeptidase 24.11 incomitant 12-week hemodynamic study, and 1 patient hibitors candoxatril or sinorphan in heart failure.12–14 in the 20- to 40-mg group developed septicemia after Arterial stiffening predisposes to systolic and diacatheterization and was withdrawn. Forty-one patients stolic dysfunction, and thus heart failure.15 Early recompleted the 12-week study and data are presented flected waves are associated with higher vascular imfor these patients. pedance, an index of left ventricular pulsatile load.8,9 Twelve-week therapy with omapatrilat caused a In congestive heart failure, the failing ventricle acts as dose-dependent decrease in arterial pressure. Systolic a pressure source, with increased wave reflection BP decreased significantly in the 20- to 40-mg group causing an increase in both left ventricular wall stress (p ⬍0.05) compared with the 2.5-mg group. There and myocardial oxygen consumption.8 Ideally, heart was a trend toward a decrease in diastolic BP (p ⫽ failure treatment should reduce or offset the effects of 0.06). Mean arterial BP decreased significantly in the early wave reflection on the heart. In this study, the 20- to 40-mg group (p ⬍0.05) compared with the improvement in BP is accompanied by a significant 2.5-mg group. Augmentation index fell significantly decrease in wave reflection with higher doses of omain the 20- to 40-mg group compared with the 2.5-mg patrilat, reflecting improved ventricular-vascular cougroup (p ⬍0.01) (Figure 1). There was no change in pling. body weight or hematocrit between groups over the 12 The mechanism of how omapatrilat improves enweeks.3 dothelial function is likely to be multifactorial. ACE There was no change in resting forearm blood flow inhibition inhibits the formation of the potent vasoover 12 weeks between groups. The baseline forearm constrictor angiotensin II.16 The beneficial effect of vasodilator response during reactive hyperemia was quinalaprilat in healthy volunteers is blocked by coinsignificantly less in the 5- to 10-mg group compared fusion of a bradykinin-receptor antagonist, which sugTABLE 2 Dose-Related Changes Over 12 Weeks
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doses of omapatrilat. In contrast, acute treatment with pure ACE inhibition has been shown to cause a decrease in ANP at 3 hours.20 Subsequently, ANP levels fell to near baseline by 24 hours, possibly due to reduced plasma ANP secretion presumably secondary to improved hemodynamics, or alternatively, decreased endopeptidase 24.11 inhibition at 24 hours. Postdose increments in plasma ANP with higher doses were similar at day 1 and after 12 weeks of chronic therapy at day 83, suggesting a lack of tolerance of endopeptidase 24.11 inhibitory effect with chronic treatment. Exogenous ANP infusions have shown modest decreases in peripheral vascular resistance in human heart failure,21 and the forearm vasodilator responses to intra-arterial infusions of ANP do not appear to be attenuated in heart failure.22 ANP given short-term induces a transcapillary fluid shift; however, there was no change in hematocrit to support this occurrence.23 The absence of a change in body weight may reflect that 94% of patients were also taking diuretics. From this study, it is unknown to what degree the improvements in systolic BP, wave reflection, and maximum forearm vasodilator response are due to the increase in ANP. Study limitations: This pilot study lacks a true placebo limb. The groups do allow comparison of low-dose 2.5 mg omapatriFIGURE 3. Change from baseline in plasma ANP after initial dose of omapatrilat (ACE inhibition only) with high-dose lat (a) and following final dose after 12 weeks of chronic omapatrilat therapy effects (endopeptidase 24.11 and ACE in(b). **p <0.01 versus 2.5-mg control group. hibition). The improvements in vascular function may be due to increasing ACE gests it also causes accumulation of bradykinin by inhibition with higher doses. However, the increase in inhibition of kininase II, resulting in release of nitric plasma ANP with higher doses suggests endopeptioxide and endothelium-derived releasing factor from dase 24.11 inhibition. Beta-blocker use was low in this endothelial cells.17 ACE inhibition also causes in- study group. It is unlikely that this would have signifcreased endothelial release of vasodilator prostaglan- icantly influenced the results, because  blockers such dins.18 In the postinfarcted rat heart, combined inhi- as atenolol have less beneficial effects on wave reflecbition of ACE and endopeptidase 24.11 with omapat- tion and endothelial dysfunction than ACE inhibitors rilat significantly increased the half-life time of or angiotensin I receptor antagonists.24,25 A crossover bradykinin compared with enalaprilat.19 Therefore, design may have been helpful to remove baseline omapatrilat may offer further benefits in increasing differences in resting variables. Nevertheless, in this heterogeneous heart failure group, significant imnitric oxide bioavailability. The improvement in endothelial dysfunction ap- provements were seen in a variety of measures of pears to plateau in the 5- to 10-mg group, with no vascular function. The study was only for 12 weeks’ further improvement with higher doses. We cannot duration, and it remains to be demonstrated whether discount that there may be tissue endopeptidase inhi- longer treatment with the vasopeptidase inhibitor bition occurring in the 5- to 10-mg group, possibly omapatrilat may produce further beneficial effects on enhancing increased nitric oxide bioavailability in ad- endothelial function and wave reflection. dition to ACE inhibition. The lower baseline vasodilator response in the 5- to 10-mg group, suggesting more severe endothelial dysfunction, may have accen- 1. Robl JA, Sun C-Q, Stevenson J, Ryono DE, Simpkins LM, Cimarusti MP, tuated the chronic effect in this group. Dejnekat T, Slusarchyk WA, Chao S, Stratton L, et al. Dual metalloprotease Plasma endopeptidase 24.11 inhibition by omapat- inhibitors: mercaptoacetyl-based fused heterocyclic dipeptide mimetics as inhibof angiotensin-converting enzyme and neutral endopeptidase. J Med Chem rilat in patients with heart failure was demonstrated by itors 1997;40:1570 –1577. increased plasma ANP at 3 hours after initial higher 2. Trippodo NE, Robl JA, Assad MM, Fox M, Panchal BC, Schaeffer TR. Effects 568 THE AMERICAN JOURNAL OF CARDIOLOGY姞
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of omapatrilat in low, normal, and high renin experimental hypertension. Am J Hypertens 1998;11:363–373. 3. McClean DR, Ikram H, Garlick AH, Richards AM, Nicholls MG, Crozier IG. The clinical, cardiac, renal, arterial and neurohormonal effects of omapatrilat, a vasopeptidase inhibitor, in patients with chronic heart failure. J Am Coll Cardiol 2000;36:479 – 486. 4. Massien C, Azizi M, Guyene TT, Vesterqvist O, Mangold B, Menard J. Pharmacodynamic effects of dual neutral endopeptidase-angiotensin-converting enzyme inhibition versus angiotensin-converting enzyme inhibition in humans. Clin Pharmacol Ther 1999;65:448 – 459. 5. Burnett JC Jr. Vasopeptidase inhibition. J Hypertens 1999;17(suppl 1):S37– S43. 6. Chen CH, Nevo E, Fetics B, Pak PH, Yin FC, Maughan WL, Kass DA. Estimation of central aortic pressure waveform by mathematical transformation of radial tonometry pressure. Circulation 1997;95:1827–1836. 7. Karamanoglu M, O’Rourke MF, Avolio AP, Kelly RP. An analysis of the relationship between central aortic and peripheral upper limb pressure waves in man. Eur Heart J 1993;14:160 –167. 8. Saba PS, Roman MJ, Pini R, Spitzer M, Ganau A, Devereux RB. Relation of arterial pressure waveform to left ventricular and carotid anatomy in normotensive subjects. J Am Coll Cardiol 1993;22:1873–1880. 9. Haywood CS, Kelly RP. Gender-related differences in the central arterial pressure waveform. J Am Coll Cardiol 1997;30:1863–1871. 10. Hokanson DE, Summer DS, Strandness DEJ. An electrically calibrated plethysmograph for direct measurement of limb blood flow. IEEE Trans Biomed Eng 1975;22:25–29. 11. Yandle T, Espiner E, Nicholls M, Duff H. Radioimmunoassay and characterisation of atrial natriuretic peptide in human plasma. J Clin Endocrinol Metab 1986;61:71–78. 12. Northridge DB, Alabaster CT, Connell JMC, Dilly SG, Lever AF, Jardine AG, Barclay PL, Dargie HJ, Findlay IN, Samuela GMR. Effects of UK 69 578: a novel atriopeptidase inhibitor. Lancet 1989;2:591–593. 13. Kahn JC, Patey M, Dubois-Rande JL, Merlet P, Castaigne A, Lim-Alexandre C, Lecomte JM, Duboc D, Gros C, Schwartz JC. Effect of sinorphan on plasma atrial natriuretic factor in congestive heart failure. Lancet 1990;335:118 –119. 14. Kentsch M, Otter W, Drummer C, Notges A, Gerzer R, Muller-Esch G. Neutral endopeptidase 24.11 inhibition may not exhibit beneficial hemodynamic
effects in patients with congestive heart failure. Eur J Clin Pharmacol 1996;51: 269 –272. 15. Westerhof N, O’Rourke MF. Hemodynamic basis for the development of left ventricular failure in systolic hypertension and for its logical therapy. J Hypertens 1995;13:943–952. 16. Biollaz J, Burnier M, Turini GA, Brunner DB, Porchet M, Gomez HJ, Jones KH, Ferber F, Abrams WB, Gavras H, Brunner HR. Three new long-acting converting enzyme inhibitors: relationship between plasma converting enzyme and response to angiotensin I. Clin Pharmacol Ther 1981;29:665– 670. 17. Hornig B, Kohler C, Drexler H. Role of bradykinin in mediating vascular effects of angtiotensin-converting enzyme inhibitors in humans. Circulation 1997;95:1115–1118. 18. Nakamura M, Funokoshi T, Arakawa N, Yoshida H, Makita S, Hiramori K. Effect of angiotensin converting enzyme inhibitors on endothelium-dependent peripheral vasodilatation in patients with chronic heart failure. J Am Coll Cardiol 1994;24:1321–1327. 19. Raut R, Rouleau JL, Blais C Jr, Gosselin H, Molinaro G, Sirois MG, Lepage Y, Crine P, Adam A. Bradykinin metabolism in the postinfarcted rat heart: role of ACE and neutral endopeptidase 24.11. Am J Physiol 1999;276:H1769 –H1779. 20. Crozier IG, Nicholls MG, Ikram H, Espiner E, Yandle TG. Atrial natriuretic peptide levels in congestive heart failure in man before and after converting enzyme inhibition. Clin Exp Pharmacol Physiol 1989;16:417– 424. 21. Molina CR, Fowler MB, McCrory S, Peterson C, Myers BD, Schroeder JS, Murad F. Hemodynamic, renal and endocrine effects of atrial natriuretic peptide infusion in severe heart failure. J Am Coll Cardiol 1988;12:175–186. 22. Kubo SH, Atlas SA, Laragh JH, Cody RJ. Maintenance of forearm vasodilator action of atrial natriuretic factor in congestive heart failure secondary to ischemic or idiopathic dilated cardiomyopathy. Am J Cardiol 1992;15:1306 – 1309. 23. Meyer DJ, Huxley VH. Capillary hydraulic conductivity is elevated by cGMP-dependent vasodilators. Circ Res 1992;70:382–91. 24. Ting C-T, Chen C-H, Chang M-S, Yin FCP. Short and long term effects of antihypertensive drugs on arterial reflections, compliance and impedance. Hypertension 1995;26:524 –530. 25. Schriffrin EL, Park JB, Intengan HD, Touyz RM. Correction of arterial structure and endothelial function in human essential hypertension by the angiotensin receptor antagonist losarten. Circulation 2000;101:1653–1659.
SYSTEMIC HYPERTENSION/EFFECTS OF OMAPATRILAT ON ARTERIAL FUNCTION
569
MB, CHB,
Hamid Ikram, MD, PhD, Amanda H. Garlick, and Ian G. Crozier, MD
The mechanisms of action of omapatrilat, an agent that inhibits both neutral endopeptidase 24.11 and angiotensin-converting enzyme, on arterial function in patients with heart failure have not been previously reported. Forty-eight patients in New York Heart Association functional class II to III, left ventricular ejection fraction <40%, and in sinus rhythm were randomized to a dose-ranging (2.5, 5, 10, 20, or 40 mg) study of omapatrilat for 12 weeks. Measurements were obtained at baseline and 12 weeks. Decreases in systolic (25.0 ⴞ 4.5 vs 2.8 ⴞ 5.0 mm Hg, p <0.05) and mean arterial (13.9 ⴞ 3.0 vs 0.3 ⴞ 3.3 mm Hg, p <0.05) pressure were seen after 12 weeks of therapy with higher doses. Ventricular-arterial coupling was im-
proved with a dose-related decrease in augmentation index (ⴚ13.8 ⴞ 1.7% vs ⴙ6.1 ⴞ 2.1%, p <0.01). There was no change in resting forearm blood flow between groups; however, maximum forearm vasodilator response during reactive hyperemia increased in the highdose groups compared with the control group (ⴙ266 ⴞ 43% vs ⴚ14 ⴞ 92%, p <0.05). Omapatrilat induced an increase in postdose plasma atrial natriuretic peptide levels (30 ⴞ 11 vs ⴚ2 ⴞ 7 pmol/L, p <0.01) in highdose groups consistent with endopeptidase 24.11 inhibition. Omapatrilat shows beneficial changes in ventricular-vascular coupling and arterial function in heart failure. 䊚2001 by Excerpta Medica, Inc. (Am J Cardiol 2001;87:565–569)
mapatrilat is the first of a new class of drugs called vasopeptidase inhibitors that simultaO neously inhibit both neutral endopeptidase 24.11 and
evant to its effects in heart failure. This study describes the effects of 12 weeks of chronic omapatrilat therapy on arterial BP, ventricular-vascular coupling, and maximum forearm vasodilator response in patients with congestive heart failure.
angiotensin-converting enzyme (ACE) using a single molecule.1 In low renin, normal, and high renin animal models of hypertension, omapatrilat has been shown to lower blood pressure (BP) to a greater degree than selective inhibition of either enzyme alone.2 In normal volunteers, omapatrilat has previously been shown to cause significant ACE inhibition with doses of 2.5 to 75 mg, with the 10-mg dose having been shown to induce similar 24-hour in vivo ACE inhibition compared with 20 mg of fosinopril.3,4 The 2.5-mg dose was chosen as an active control in this study because it has been shown to cause significant ACE inhibition over 24 hours but, in contrast to higher doses of omapatrilat, no significant neutral endopeptidase 24.11 inhibition, as measured by changes in urinary atrial natriuretic peptide (ANP) and urinary second messenger cyclic guanosine monophosphate.3 Vasopeptidase inhibition may alter the balance toward vasodilatation by inhibiting angiotensin II, restoring the physiologic actions of ANP, and possibly having a synergistic effect on decreasing kinin degradation.5 Therefore, the mechanisms of action of this new agent on the arterial system, which should ideally produce a depressor response and vasodilation, is relFrom the Department of Cardiology, Christchurch Hospital, Christchurch, New Zealand. This work was supported by a project grant from Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey. Manuscript received June 27, 2000; revised manuscript received and accepted September 11, 2000. Address for reprints: Hamid Ikram, MD, PhD, Department of Cardiology, Christchurch Hospital, Private Bag 4710, Christchurch, New Zealand. E-mail: [email protected]. ©2001 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 87 March 1, 2001
METHODS The study was approved by the Canterbury Ethics Committee of the Health Funding Authority, and all patients gave written informed consent before the study. The study was a single-center, noninvasive pilot study. Patients enrolled were concurrently taking part in either: (1) a 12-week multicenter, double-blind, randomized, invasive hemodynamic trial (40 patients); or (2) a 12-week multicenter, double-blind, randomized exercise trial (8 patients).3 Patients with New York Heart Association II to III congestive heart failure, left ventricular ejection fraction ⱕ40%, and in sinus rhythm were enrolled. All ACE inhibitors and angiotensin II receptor antagonists were discontinued at least 4 days before baseline measurements, and for the entire 12 weeks. All other concomitant cardiac medications were continued throughout the study. Patients could receive up to 4 supplemental doses of furosemide (over 24 hours) for worsening heart failure; however, if an increase in maintenance dose was necessary, patients were then withdrawn from the study. After baseline measurements were obtained, patients were randomized to 1 of 5 omapatrilat doses: 2.5, 5, 10, 20, or 40 mg once daily for 12 weeks. At 12 weeks, measurements were repeated after the final dose of omapatrilat. All measurements were obtained in a quiet laboratory maintained at a constant temperature between 22°C and 25°C. Patients abstained from food, caf0002-9149/01/$–see front matter PII S0002-9149(00)01432-6
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BP was calculated (1/3 pulse pressure ⫹ diastolic BP). Digital applaOmapatrilat Dose nation tonometry (Millar Instruments, Houston, Texas) of the left Total 2.5 mg 5–10 mg 20–40 mg radial artery was performed for 8 Variable (n ⫽ 48) (n ⫽ 15) (n ⫽ 18) (n ⫽ 15) seconds. Each recording was ensemMean age (yrs) 67 ⫾ 1 67 ⫾ 2 70 ⫾ 3 66 ⫾ 2 ble averaged, giving an average Men 44 (92%) 14 (93%) 15 (83%) 15 (100%) waveform for each subject, and calCreatinine (mmol/L) 0.11 ⫾ 0.01 0.11 ⫾ 0.01 0.11 ⫾ 0.01 0.12 ⫾ 0.01 Presumed etiology of ibrated to the mean and diastolic braheart failure chial sphygmomanometric BP obIschemic 42 (88%) 14 (93%) 15 (83%) 13 (86%) tained at the time of pulse recording. Idiopathic cardiomyopathy 4 (8%) 1 (7%) 2 (11%) 1 (7%) With use of a generalized transfer Systemic hypertension 2 (4%) 0 1 (6%) 1 (7%) NHYA function (PWV Medical, Sydney, Class II 29 (58%) 8 (53%) 11 (61%) 9 (60%) Australia), ascending aortic end-sysClass III 20 (42%) 7 (47%) 7 (39%) 6 (40%) tolic pressure and waveform were Treatment derived.6,7 Wave reflection was meaACE inhibitors 40 (83%) 13 (86%) 15 (89%) 12 (80%) sured by the augmentation index, AII blockers 5 (10%) 2 (13%) 0 3 (20%) Diuretics 45 (94%) 14 (93%) 17 (94%) 14 (93%) which was calculated from the ratio Digoxin 14 (29%) 3 (20%) 6 (33%) 5 (33%) of the difference between the pres blockers 7 (15%) 2 (13%) 2 (11%) 3 (20%) sure at the respective peaks or inflecAspirin 33 (69%) 10 (67%) 12 (67%) 11 (73%) tions (P2 ⫺ P1) divided by the pulse AII ⫽ angiotensin II; NYHA ⫽ New York Heart Association. pressure (systolic BP ⫺ diastolic BP).8,9 Forearm blood flow was measured in the right forearm using venous occlusion plethysmography with mercury-in-Silastic strain gauges, a plethymographic balancing system and amplifier, and a rapid cuff inflator (DE Hokanson, Issaquah, Washington).10 The right arm was elevated and passively supported above the height of the right atrium to ensure adequate venous drainage between measurements. A mercury-in-Silastic strain gauge that had been electrically calibrated was placed around the right forearm at the region of greatest circumference. Before each forearm blood flow determination, a right upper arm cuff was set at 40 mm Hg, and circulation to the hand was stopped by inflating a right wrist cuff to 200 mm Hg. Forearm blood flow was derived from FIGURE 1. Change in augmentation index after 12 weeks of omapatrilat therapy. **p <0.01 versus 2.5-mg control group. the rate of initial increase in forearm circumference during venous occlusion and was expressed in ml/100 ml forearm tissue/min. Recordings were begun ⬎60 seconds after wrist cuff inflation to allow flow to stabilize. Resting forearm blood flow was taken as the average of at least 3 flow measurements made at 15-second intervals. Maximum forearm vasodilator response was calculated by measuring maximum forearm blood flow during reactive hyperemia, following the right upper arm cuff inflated to 200 mm Hg for 3 minutes. At 5-, 15-, and 30-second intervals after cuff deflation, maximum forearm blood flow (expressed as percent change in pretreatment values) was measured. Venous blood was obtained from a subgroup as part of the concomitant hemodynamic study during FIGURE 2. Change in maximum forearm vasodilator response hospitalization for right-sided cardiac catheterization during reactive hyperemia after 12 weeks of omapatrilat therat baseline and at 12 weeks. Venous blood was withapy. *p <0.05 versus 2.5-mg control group. drawn with the patient lying quietly while semirecumbent at baseline before dosing, and at 3, 12, and 24 feine-containing drinks, and cigarettes for ⬎4 hours hours after the first dose of the drug. These were before measurements, and rested for at least 30 min- repeated after the final dose of the drug at 12 weeks. utes before baseline measurements. BP was measured Samples were placed in chilled vacutainers, placed by a brachial sphygmomanometer and mean arterial immediately on ice, centrifuged within 20 minutes at TABLE 1 Bastline Characteristics
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with the 2.5-mg group (p ⬍0.05) with no difference compared with Omapatrilat Dose the 20- to 40-mg group. Maximum forearm vasodilator response during 2.5 mg 5–10 mg 20–40 mg reactive hyperemia increased over 12 Systolic BP baseline (mm Hg) 132 ⫾ 6 130 ⫾ 6 133 ⫾ 6 weeks in the 5- to 10-mg and 20- to Systolic BP 12 wks (mm Hg) 128 ⫾ 6 112 ⫾ 5 108 ⫾ 6* 40-mg groups compared with the Diastolic BP baseline (mm Hg) 73 ⫾ 3 72 ⫾ 4 75 ⫾ 3 2.5-mg group (p ⬍0.05). There was Diastolic BP 12 wks (mm Hg) 74 ⫾ 3 63 ⫾ 3 67 ⫾ 3 Mean BP baseline (mm Hg) 92 ⫾ 3 91 ⫾ 4 94 ⫾ 3 no difference between the 5- to 10Mean BP 12 wks (mm Hg) 92 ⫾ 3 79 ⫾ 3 80 ⫾ 4* and 20- to 40-mg groups after 12 AI baseline (%) 125 ⫾ 6 125 ⫾ 3 122 ⫾ 4 weeks of therapy (Figure 2). † AI 12 wks (%) 131 ⫾ 6 123 ⫾ 3 108 ⫾ 3 Neurohormones: High-dose omaResting FBF baseline (ml/min/100 ml) 2.0 ⫾ 0.2 2.5 ⫾ 0.2 3.0 ⫾ 0.3* Resting FBF 12 wks (ml/min/100 ml) 2.1 ⫾ 0.2 2.1 ⫾ 0.2 2.7 ⫾ 0.2 patrilat caused a prompt and vigorMaximum forearm vasodilator response ous increase in plasma ANP after the Baseline (%) 627 ⫾ 118 279 ⫾ 54* 508 ⫾ 61 first dose (30 ⫾ 11 vs ⫺2 ⫾ 7 12 wks (%) 612 ⫾ 117 566 ⫾ 62* 773 ⫾ 73* pmol/L, p ⬍0.01) compared with *p ⬍0.05 versus 2.5 mg; †p ⬍0.01 versus 2.5 mg. 2.5-mg dose. Subsequently, ANP deAI ⫽ augmentation index; FBF ⫽ forearm blood flow. creased to near baseline levels (Figure 3a). After 12 weeks, high-dose omapatrilat induced an increase in ⫺4°C, and plasma stored at ⫺80°C before assay for ANP compared with day 1 predose levels, with a significant increase in the 20- to 40-mg group at 3 plasma ANP.11 Statistical analysis: We combined some dose groups hours compared with 2.5-mg dose (35 ⫾ 14 vs ⫺15 ⫾ to give 2.5 mg as “active control,” 5 to 10 mg as the 9 pmol/L, p ⬍0.01) (Figure 3b). low-dose group, and 20 to 40 mg as the high-dose group. We used 2-way analysis of variance with re- DISCUSSION peated measures to explore the relation between variIn this 12-week pilot study with omapatrilat in able and dose group. Post hoc comparisons were per- patients with chronic heart failure, there was (1) a formed with Tukey’s honest significant difference test decrease in systolic and mean BP, (2) a dose-depenwhen this showed significant effects (p ⬍0.05). Group dent improvement in wave reflection as measured by data are expressed as mean value ⫾ SEM. augmentation index, (3) improvements in maximum forearm vasodilator response during reactive hyperemia in both the 5- to 10- and 20- to 40-mg groups, RESULTS Forty-eight patients were enrolled (Table 1) and 7 suggesting an improvement in endothelial dysfuncpatients did not return for the 12-week measurements. tion, and (4) evidence of increased plasma ANP with Three patients were withdrawn from the 12-week higher doses. In previous studies, pure endopeptidase study in the 2.5-mg group owing to worsening heart 24.11 inhibition has not induced a sustained reduction failure (20%) compared with 1 in the 5- to 10-mg in systolic BP. In contrast, in this 12-week pilot study, group (5%) and none in the 20- to 40-mg group. Two higher doses of omapatrilat induced reductions in syspatients (1 in the 20- to 40-mg group and 1 in the 5- tolic and mean BP, suggesting an effect of vasodilato 10-mg group) did not wish to return for the con- tation not observed with the endopeptidase 24.11 incomitant 12-week hemodynamic study, and 1 patient hibitors candoxatril or sinorphan in heart failure.12–14 in the 20- to 40-mg group developed septicemia after Arterial stiffening predisposes to systolic and diacatheterization and was withdrawn. Forty-one patients stolic dysfunction, and thus heart failure.15 Early recompleted the 12-week study and data are presented flected waves are associated with higher vascular imfor these patients. pedance, an index of left ventricular pulsatile load.8,9 Twelve-week therapy with omapatrilat caused a In congestive heart failure, the failing ventricle acts as dose-dependent decrease in arterial pressure. Systolic a pressure source, with increased wave reflection BP decreased significantly in the 20- to 40-mg group causing an increase in both left ventricular wall stress (p ⬍0.05) compared with the 2.5-mg group. There and myocardial oxygen consumption.8 Ideally, heart was a trend toward a decrease in diastolic BP (p ⫽ failure treatment should reduce or offset the effects of 0.06). Mean arterial BP decreased significantly in the early wave reflection on the heart. In this study, the 20- to 40-mg group (p ⬍0.05) compared with the improvement in BP is accompanied by a significant 2.5-mg group. Augmentation index fell significantly decrease in wave reflection with higher doses of omain the 20- to 40-mg group compared with the 2.5-mg patrilat, reflecting improved ventricular-vascular cougroup (p ⬍0.01) (Figure 1). There was no change in pling. body weight or hematocrit between groups over the 12 The mechanism of how omapatrilat improves enweeks.3 dothelial function is likely to be multifactorial. ACE There was no change in resting forearm blood flow inhibition inhibits the formation of the potent vasoover 12 weeks between groups. The baseline forearm constrictor angiotensin II.16 The beneficial effect of vasodilator response during reactive hyperemia was quinalaprilat in healthy volunteers is blocked by coinsignificantly less in the 5- to 10-mg group compared fusion of a bradykinin-receptor antagonist, which sugTABLE 2 Dose-Related Changes Over 12 Weeks
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doses of omapatrilat. In contrast, acute treatment with pure ACE inhibition has been shown to cause a decrease in ANP at 3 hours.20 Subsequently, ANP levels fell to near baseline by 24 hours, possibly due to reduced plasma ANP secretion presumably secondary to improved hemodynamics, or alternatively, decreased endopeptidase 24.11 inhibition at 24 hours. Postdose increments in plasma ANP with higher doses were similar at day 1 and after 12 weeks of chronic therapy at day 83, suggesting a lack of tolerance of endopeptidase 24.11 inhibitory effect with chronic treatment. Exogenous ANP infusions have shown modest decreases in peripheral vascular resistance in human heart failure,21 and the forearm vasodilator responses to intra-arterial infusions of ANP do not appear to be attenuated in heart failure.22 ANP given short-term induces a transcapillary fluid shift; however, there was no change in hematocrit to support this occurrence.23 The absence of a change in body weight may reflect that 94% of patients were also taking diuretics. From this study, it is unknown to what degree the improvements in systolic BP, wave reflection, and maximum forearm vasodilator response are due to the increase in ANP. Study limitations: This pilot study lacks a true placebo limb. The groups do allow comparison of low-dose 2.5 mg omapatriFIGURE 3. Change from baseline in plasma ANP after initial dose of omapatrilat (ACE inhibition only) with high-dose lat (a) and following final dose after 12 weeks of chronic omapatrilat therapy effects (endopeptidase 24.11 and ACE in(b). **p <0.01 versus 2.5-mg control group. hibition). The improvements in vascular function may be due to increasing ACE gests it also causes accumulation of bradykinin by inhibition with higher doses. However, the increase in inhibition of kininase II, resulting in release of nitric plasma ANP with higher doses suggests endopeptioxide and endothelium-derived releasing factor from dase 24.11 inhibition. Beta-blocker use was low in this endothelial cells.17 ACE inhibition also causes in- study group. It is unlikely that this would have signifcreased endothelial release of vasodilator prostaglan- icantly influenced the results, because  blockers such dins.18 In the postinfarcted rat heart, combined inhi- as atenolol have less beneficial effects on wave reflecbition of ACE and endopeptidase 24.11 with omapat- tion and endothelial dysfunction than ACE inhibitors rilat significantly increased the half-life time of or angiotensin I receptor antagonists.24,25 A crossover bradykinin compared with enalaprilat.19 Therefore, design may have been helpful to remove baseline omapatrilat may offer further benefits in increasing differences in resting variables. Nevertheless, in this heterogeneous heart failure group, significant imnitric oxide bioavailability. The improvement in endothelial dysfunction ap- provements were seen in a variety of measures of pears to plateau in the 5- to 10-mg group, with no vascular function. The study was only for 12 weeks’ further improvement with higher doses. We cannot duration, and it remains to be demonstrated whether discount that there may be tissue endopeptidase inhi- longer treatment with the vasopeptidase inhibitor bition occurring in the 5- to 10-mg group, possibly omapatrilat may produce further beneficial effects on enhancing increased nitric oxide bioavailability in ad- endothelial function and wave reflection. dition to ACE inhibition. The lower baseline vasodilator response in the 5- to 10-mg group, suggesting more severe endothelial dysfunction, may have accen- 1. Robl JA, Sun C-Q, Stevenson J, Ryono DE, Simpkins LM, Cimarusti MP, tuated the chronic effect in this group. Dejnekat T, Slusarchyk WA, Chao S, Stratton L, et al. Dual metalloprotease Plasma endopeptidase 24.11 inhibition by omapat- inhibitors: mercaptoacetyl-based fused heterocyclic dipeptide mimetics as inhibof angiotensin-converting enzyme and neutral endopeptidase. J Med Chem rilat in patients with heart failure was demonstrated by itors 1997;40:1570 –1577. increased plasma ANP at 3 hours after initial higher 2. Trippodo NE, Robl JA, Assad MM, Fox M, Panchal BC, Schaeffer TR. Effects 568 THE AMERICAN JOURNAL OF CARDIOLOGY姞
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