Comparative analysis of the hemodynamic actions of captopril and sodium nitroprusside in severe chronic congestive heart failure

Comparative analysis of the hemodynamic actions of captopril and sodium nitroprusside severe chronic congestive heart failure

in

The hemodynamic actions of the systemic vasodilators parenteral sodium nitroprusside (NP) and oral captopril (CPT) were compared in 11 patients with severe chronic congestive heart failure (CHF). While the two agents produced similar reductions in mean blood pressure (NP, 90 to 70 mm Hg vs CPT, 88 to 74 mm Hg, p > 0.05) and left ventricular (LV) filling pressure (NP, 27 to 14 mm Hg vs CPT, 24 to 15 mm Hg, p > 0.05), they produced disparate effects on LV pump performance. NP raised cardiac index 35% (2.0 to 2.7 L/min/m*, p < O.OOS), whereas CPT increased this index 18% (1.9 to 2.2 L/minim*, p < 0.001). Concomitantly, the 31% elevation of stroke index produced by NP (26 to 34 ml/beat/m*, p < 0.001) was greater (p < 0.05) than the 15% rise produced by CPT (26 to 30 ml/beat/m*, p < 0.001). Simultaneously, stroke work index showed similarly greater augmentation, and total systemic vascular resistance declined more with NP. These findings suggest that oral CPT is a predominant ventricular preload-lowering agent primarily likely to improve dyspnea related to severe pulmonary congestion in patients with advanced chronic CHF. (AM HEART J 104:1211, 1982.)

John Hermanovich, M.D., Najam A. Awan, M.D., Henry Lui, M.D., and Dean T. Mason, M.D. Davis and Sacramento, Calif.

The inhibition of the angiotensin-converting enzyme (ACE) with oral captopril (CPT) has been demonstrated to produce marked improvement in depressed left ventricular (LV) function in patients with chronic congestive heart failure (CHF).lm7 These salutary effects of the drug on cardiac performance are primarily achieved by lowering of increased aortic outflow impedance and reduction of the accentuated venous tone characteristic of severe ventricular decompensation.3v6*7 It is important to note that since other efficacious systemic vaaodilator agents are presently available for extended therapy of severe CHF,8-‘o the precise characterization of the differential cardiocirculatory actions of diverse vasorelaxant agents is an imperative prerequisite for judicial selection of clinically appropriate ventricular unloading agents in individual patients with advanced myocardial dysfunction. In this regard, sodium nitroprusside (NP) is widely regarded as the From the Section of Cardiovascular Medicine, Departments and Physiology, University of California School of Medicine, mento Medical Center.

of Medicine and Sacra-

Supported in part by Program Project Grant HL 14780 from the National Heart, Lung and Blood Institutes, Bethesda, Md., and California Chapters of the American Heart Association, Dallas, Tex. Presented Association,

in part at the Annual Scientific Anaheim, Calif. 1979.

Reprint requests: cine, University

0002-8703/82/111211+

Sessions

Najam A. Awan, M.D., Section of California, School of Medicine,

04$00.40/O

0 1982

of the American

Heart

of Cardiovascular MediDavis, CA 95616.

The C. V. Mosby Co.

premier systemic vasodilator with salutary balanced arteriolar and venous vasorelaxing actions11*‘2 previously described to be predictive of the beneficial hemodynamic actions of several ventricular afterload reducing agents .13,l4 Accordingly, to properly characterize the relative effectiveness of CPT for achieving cardiac pump output enhancement and ventricular preload decline, we compared the hemodynamic actions of CPT to the vasoclilator responses obtained with NP. METHODS Patient population. The study population consisted of 11 patients (nine men and two women, mean age 62 years) with severe chronic CHF (mean ejection fraction 19%). All patients had stable (L 3 months) severe LV dysfunction despite therapy with digoxin and diuretics. None of the patients had valvular heart disease. The etiology of chronic CHF was ischemic cardiomyopathy due to coronary disease, with documented myocardial infarction confirmed by previous left-heart catheterization and angiography in eight patients and by characteristic ECG and nuclear scintigraphic criteria in the remaining three patients. To maintain a stable hemodynamic state during evaluation, the usual morning dose of diuretics was administered on the evening before study, and the usual daily dose of digoxin was ingested on the morning of the study. Cardiac catheterization. Systemic arterial preesure was measured directly through an intra-arterial Teflon cathe1211

November,

Hermanovich et al.

1212

60 0

C

American

** nl NP I

C I

CPT I n=ll

*+

26

1

i

NP

C

CPT

NP C **= p< 001

CPT

L &I CL+ 2.6 -\ 0 .E QE E = a 0

2.0 0

C +=p<.o1

1. Comparative effects of sodium NP and 100 mg CPT on mean blood pressure(A), LV filling pressure(B), and CI in 11 CHF patients. C = control. Fig.

ter placed in a brachial artery. Right atrial, pulmonary artery, and pulmonary artery wedge pressures were recorded with the Swan-Ganz catheter. Determinations of cardiac output (CO) by thermodilution were performed in triplicate (< 10% variation) usingiced salinesolution, and computations were done using a bedsidecomputer (Santa Barbara Technology, Inc., Santa Barbara, Calif.). Derived hemodynamic variables were calculated as follows: stroke work index (SWI) (gm . m/m”) = SI x (AP - LVFP) x 0.0136, where SI = stroke index, AP = mean systemic arterial pressure,and LVFP = left ventricular filling pressure (either mean pulmonary artery wedge or pulmonary artery diastolic pressure,with the particular method used for this variable remaining constant throughout the study for each patient); total systemic vascular resistance (TSVR) = 80 (AP - RAKO), where 80 is a conversion factor (mm Hg to dynes e set . cm+) and RA = mean right atria1 pressure.

lieart

1982 Journal

Drug administration. CPT and NP were administered in sequential randomized order to eachof the 11 patients. When NP wasadministered first (five patients), CPT was ingested 2 hours following termination of NP infusion. If CPT wasadministered first (six patients), NP wasinfused 16 to 24 hours subsequently (average 18.6 hours). While a predetermined 100 mg doseof oral CPT wasused in this study, NP wascarefully incrementally titrated to optimal cardiac effects (2 205%increasein CO and L 20% decline in LVFP). Hemodynamic measurementswere made prior to each drug administered, 1 hour after CPT, and 10 minutes after stable infusion of the optimal NP dose (average 33 crglmin). Statistical analysis. The data were analyzed using the paired t test and analysis of variance. RESULTS Cardiac function. Infusion of NP at a constant rate for 10 minutes reduced systolic and mean AP in all patients (Fig. 1, A). NP lowered mean AP from

90 rf: 12 to 71 f 8 mm Hg (21%) p < O.OOl), whereas CPT reduced mean AP from 88 +- 11 to 74 f 7 mm Hg (16%) p < 0.01). There were no statistically significant differences between NP and CPT in the declines of either systolic or mean blood pressures. The mean heart rate was not changed by NP or CPT. LVFP declined in each patient after administration of NP or CPT (Fig. 1, B). The mean control LVFP fell from 27 + 2 to 14 + 3 mm Hg (47%) p < 0.001) during NP infusion and from 24 t 4 to 15 -t 4 mm Hg after oral CPT (39%, p < 0.001). There was no significant difference in the fall of LVFP induced by NP compared to CPT. Cardiac index (CI) rose during NP infusion from 2.0 f 0.2 to 2.7 + 0.2 L/min/m” (35%, p < 0.005)

(Fig. 1, C). Similarly,

the CI was elevated

by oral

CPT from 1.9 rt 0.2 to 2.2 -e 0.2 L/min/m2 (16%, p < 0.001) (Fig. 1, C). However, the magnitude of CO increase caused by NP was significantly greater (p < 0.05) than that produced by CPT. Similarly, SI rose during NP infusion from 26 + 1.4 to 34 + 1.0 ml/beat/m* (31%, p < 0.01) and increased from 26 + 1.2 to 30 + 22 ml/m2 (15%) p < 0.001) with CPT (Fig. 2, A). The degree of elevations of SI achieved by NP exceeded CPT (p < 0.05). Mean control SW1 of 23 + 1.3 rose to 28 ? 1.6 ml/m2 (22%, p < 0.01) with NP; however, CPT resulted in an insignificant rise of SW1 from 23 -+ 1.7 to 24 + 2.0 gm + m/m2 (4%, p < 0.001) (Fig. 2, B). Thus, there was a substantially greater increase (p < 0.01) of SW1 caused by NP compared to CPT. Concomitantly, calculated TSAR declined 38 % with NP (1776 f 245 to 109 +_217 dynes I set . cmm5, p < 0.01) and 26% with CPT (1802 + 234 vs 1302 +

Volume Number

104 5, Part 2

I

334 dynes . set . cm+, p < 0.01). Thus, the decline in TSVR with NP was more (p < 0.05) than the fall in this variable obtained with CPT.

A

32 DISCUSSION

This investigation demonstrates that the salutary effects of CPT in substantially lowering elevated LV preload (Fig. 1, B) are similar to the markedly beneficial effects of NP. Both these drugs produced considerable decline in the abnormally increased LVFP in our patients. However, whereas NP produced a characteristic marked enhancement of cardiac pump output, the magnitude of this useful hemodynamic action was less with the oral ACE inhibitor (Fig. 1, C). Regardless, it should be emphasized that the greater than 15% augmentation of CI achieved by CPT is substantially helpful in heart failure management. Further, in a manner similar to the improvements in CI, SI was enhanced by CPT; however, the magnitude of augmentation of the SI was also less in degree than that provided by NP. Concomitantly, TSVR was diminished with both CPT and NP, but this derived index was likewise reduced to a greater extent by NP (Fig. 2, C). Mechanism of disparate hemodynamic effects. It is likely that the differential hemodynamic responses to the oral ACE inhibitor and NP observed in our patients are fundamentally determined by the relative magnitude of cardiocirculatory effects of these pharmacologic agents on the systemic capacitance and resistance circulations. Previous studies have indicated that NP is a balanced peripheral vasodilator providing equal declines in arteriolar resistance and venous tone. l2 In contrast, initial experience in our laboratories indicates that oral CPT provides predominant venodilation.6s7 In fact, the ratio of the degree of simultaneous arteriolar dilation and venous relaxation, which approached 0.61 f 11,6 clearly suggested that a greater extent of venous tone decline than aortic outflow impedance reduction should be anticipated with the use of this ACE inhibitor. Interestingly, this spectrum of hemodynamic arteriolovenous responses may indicate that the pharmacologic efficacy of CPT may be determined by mechanisms complementary to the retardation of angiotensin II generation, since the known contribution of the latter peptide to maintenance of venous tone is recognized to be minimal.15-l7 In this regard, the consideration of an elevated bradykinin concomitant with reduced angiotensin II in response to ACE inhibition by CPT is especially attractive in view of the awareness that inhibition of the converting enzyme decreases deactivation of the former amine.18v1g Thus, the resulting gradual rise of brady-

*

Captopril us nitroprusside in CHF

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I

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2. Actions of NP and CPT on SI (A), SW1 (B), and TSVR (C) in 11 CHF patients. C = Control.

Fig.

kininlg may explain the preponderant venodilator actions of CPT, particularly in light of the known scanty sympathetic innervation of the venous reservoir.20s21 Clinical implications. This spectrum of dominant venous dilator actions of CPT suggests that this agent may be especially beneficial in the management of patients with advanced CHF mainly characterized by abnormally elevated LVFP and marked dyspnea. In this setting, the substantial lowering of increased ventricular preload combined with modest CO augmentation may provide immensely successful relief of disabling symptomatology related to extensive pulmonary congestion. Indeed, in patients with high LVFP, oral CPT may be preferable to the long-acting nitrates, since the simultaneous lowering of aldosterone provided by this ACE inhibitor23 ~3,22 may obviate the occurrence of venodilator tolerance

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otherwise noted to occur in some heart patients on extended nitrate therapy.23

failure

Limitations of comparative hemodynamic evaluations. It must be realized that acute comparative

hemodynamic investigations provide only shortterm comparative data. This is especially pertinent in the case of a drug such as CPT that causes several complex interrelated pharmacologic effects.15* 22 Thus, it remains possible that during prolonged drug administration the acute spectrum of hemodynamic effects delineated herein may be considerably modulated. Certainly, the beneficial effects of diminished aldosterone production are not immediately discernible and probably contribute considerable additional benefit during chronic ambulatory therapy. We gratefully Drahun.

acknowledge

the

technical

assistance

of Raya

REFERENCES

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19so.

4. Dzau VJ, Colucci WS, Williams GH, Curfman G, Meggs L, Hollenbera NK: Sustained effectiveness of convertinaenzyme inhibition in patients with congestive heart failure. N Engl J Med 302:1373, 1980. 5. Levin TB, Franciosa JA, Cohn JN: Acute and long-term response to an oral converting-enzyme inhibitor, captopril, in congestive heart failure. Circulation 62:35, 1980. 6. Awan NA, Evenson MK, Needham KE, Win A, Mason DT: Efficacy of oral angiotensin-converting enzyme inhibition with captopril therapy in severe chronic normotensive congestive heart failure. AM HEART J 102:22, 1981. EA, Hermanovich J, Bommer WJ, 7. Awan NA, Amsterdam Needham KE. Mason DT: Lone-term hemodvnamic and clinical efficacy of captopril therapy in ambulatory management of severe chronic congestive heart failure. AM HEART J 103~474, 1982.

November, 1992 Heart Journal

8. Awan NA, Miller RR, DeMaria AN, Maxwell KS, Neumann AN, Mason DT: Efficacy of ambulatory systemic vasodilator therapy with oral prazosin in chronic congestive heart failure. Circulation 56:346, 1977. K, Werner J, Greenberg B, Hart R, 9. Massie B, Chatterjee Pamley WW: Hemodynamic advantage of combined administration of hydralazine orally and nitrates nonparenterally in the vasodilator therapy of chronic heart failure. Am J Cardiol 40:794, 1977. 10. Awan NA, Evenson MK, Needham KE, Mason DT: Management of refractory congestive heart failure with prazosin. AM HEART J 102:626, 1981. 11. Franciosa JA, Guiha NH, Limas CJ, Rodriguera E, Cohn JN: Improved ventricular function during nitroprusside infusion in acute myocardial infarction, Lancet 1:650, 1972. 12. Miller RR, Vismara LA, Williams DO, Amsterdam EA, Mason DT: Pharmacoloeical mechanisms for left ventricular unloading in clinical &ngestive heart failure: Differential effects of nitroprusside, phentolamine and nitroglycerin on cardiac function and peripheral circulation. Circ Res 39:127, 1976. RR, Mason DT: Comparison of effects of 13. Awan NA, Miller nitroprusside and prazosin on left ventricular function and peripheral circulation in chronic heart failure. Circulation 57:152, 1978. 14. Awan NA, Hermanovich J, Vera Z, Amsterdam EA, Mason DT: Cardiocirculatory actions of trimazosin and sodium nitronrusside in ischemic heart disease Clin Pharm Ther 31:290, 1982. 15. Ferguson RK, Brunner HR, Turine GA, Gavras H: A specific orally active inhibitor of angiotensin converting enzyme in man. Lancet 1~775, 1977. H, Faxon DP, Berkoben J, Brunner HR, Ryan TR: 16. Gavras Angiotensin converting enzyme inhibition in patients with congestive heart failure. Circulation 58:770, 1978. H, Brunner HR, Turine GA, Kershaw GR, Tift CP, 17. Gavras Cuttelod S, Gavras I, Vukovich RA, McKinstry DM: Antihypertensive effect of the oral angiotensin converting enzyme inhibition SQ 14225 in man. N Engl J Med 298:991, 1978. 18. Oparil S, Haber E: The renin-angiotensin system. N Engl J Med 291:389, 1974. 19. Williams GH, Hollenberg NK: Accentuated vascular and endocrine response to SQ20881 in hypertension. N Engl J Med 297:184, 1977. 20. Epstein SE, Bieser GD, Stampfer M, Braunwald E: Role of the venous system in baroreceptor mediated reflexes in man. J Clin Invest 47:139, 1968. 21. Fuxe K, Sedvall G: The distribution of adrenergic nerve fibers to blood vessels and skeletal muscle. Acta Physiol Stand 45~7.5, 1965. 22. Ferguson RK, Vlasses PH: Clinical pharmacology and therapeutic applications of the new oral angiotensin converting enzyme inhibitor, captopril. AM HEART J 101:650, 1981. 23. Mantle JA, Russel RO, Rogers WJ, Dustan HP, Rackley CE: Renal response to vasodilator therapy in heart failure. Clin Res 26:75OA, 1978.