AJH 1997;10:236S 241S Treatment of Heart Failure With Fosinopril An Angiotensin Converting Enzyme Inhibitor With a Dual and Compensatory Route of Excretion Giuseppe Mancia, Cristina Giannattasio, and Guido Grassi Congestive heart failure (CHF) is one of the most common and clinically important cardiovascular diseases. This pathologic state is characterized not only by well-defined hemodynamic alterations, but also by complex abnormalities involving the sympathetic nervous system, the renin-angiotensin system, and other hormones involved in cardiovascular homeostasis. In addition, there is an abnormality in the homeostatic cardiovascular control exerted by arterial baroreceptors and the viscoelastic properties of medium-size arteries are altered, causing a reduction in arterial compliance. All of these abnormalities can be favorably affected by angiotensin converting enzyme (ACE) The main factors that make congestive heart failure (CHF) of great clinical importance will be reviewed here. The importance of angiotensin converting enzyme (ACE) inhibitors in the treatment of this condition, and the potential advantages that fosinopril offers, will also be outlined. Although relatively infrequent in young subjects, heart failure becomes progressively more prevalent with age and is one of the most common diseases found in clinical practice in patients 65 years of age. 1 Given the increasing growth of the elderly population, physicians can expect an even greater prevalence of From the Cattedra di Medicina Interna, Ospedale S. Gerardo, Monza, Università di Milano and Centro Fisiologia Clinica e Ipertensione, Ospedale Maggiore IRCCS, Milano, Italy. Address correspondence and reprint requests to Professor Giuseppe Mancia, Cattedra Di Medicina Interna, Ospedale S Gerardo Via Donizett 103, Milano, Italy. inhibitors, which have been shown to improve not only the hemodynamic and neurohumoral profiles of CHF, but also patient survival. CHF is accompanied with a decline or some sort of effect on renal function. An ACE inhibitor with a dual route of excretion, such as fosinopril, may be especially useful in treating patients with CHF. Am J Hypertens 1997;10:236S 241S 1997 American Journal of Hypertension, Ltd. KEY WORDS: Congestive heart failure, sympathetic activity, reflex control of circulation, arterial compliance, angiotensin converting enzyme inhibitors, fosinopril. CHF in the future. In addition, CHF is a very severe disease, with a mortality of approximately 50% at 5 years after diagnosis. 2 The mortality rate depends on the severity of CHF, and in patients with severe CHF (New York Heart Association [NYHA] functional class IV) the mortality rate is as high as 50% 1 year after diagnosis. 3 Finally, CHF has enormous socioeconomic impact because of its high rate of hospitalization. A significant proportion of patients in NYHA class IV will be admitted to the hospital in any year, but hospitalization is also common in less severe cases. Data from the Studies Of Left Ventricular Dysfunction (SOLVD) 4 showed that the yearly hospitalization rate was 61% for patients with NYHA class III CHF and 26% for patients with NYHA class I CHF, ie, the mildest stage. TREATMENT WITH ACE INHIBITORS In recent years, the treatment of CHF has greatly improved. The most important advance has unques- 1997 by the American Journal of Hypertension, Ltd. 0895-7061/97/$17.00 Published by Elsevier Science, Inc. PII S0895-7061(97)00329-4
AJH OCTOBER 1997 VOL. 10, NO. 10, PART 2 FOSINOPRIL IN CONGESTIVE HEART FAILURE 237S FIGURE 1. Sensitivity of the baroreceptor heart rate (HR) and muscle sympathetic nerve activity (MSNA) reflex in the three groups of subjects (Control subjects n 17, open histogram; mild CHF n 17, dashed histogram; severe CHF n 19, dark histogram). Baroreflex sensitivity was separately calculated for baroreceptor stimulation (phenylephrine infusion, top) and deactivation (nitroprusside infusion, bottom). MAP, mean arterial pressure. Values are shown as means SEM. (Reproduced from Grassi et al, 9 with permission.) tionably been the introduction of ACE inhibitors. These drugs have allowed many treatment goals to be achieved, for example, reduction in symptoms, increase in exercise tolerance, and improvement in hemodynamic dysfunction. Moreover, ACE inhibitors have increased survival in patients with both severe and mild forms of the disease. 3 5 More recently, the Survival And Ventricular Enlargement (SAVE) and the SOLVD trials have demonstrated the ability of ACE inhibitors to delay the progression of CHF and to reduce overall hospitalization rates. 6,7 A typical feature of more severe CHF is neurohumoral activation of catecholamines, which has been shown to be related to survival. 8 In a study involving three groups of age-matched subjects 9 a control group of healthy subjects, a group with severe CHF, and a group with mild CHF (defined as NYHA class II with a left ventricular ejection fraction of 40%) plasma concentrations of vasopressin, atrial natriuretic peptide, norepinephrine, and renin were all increased in the severe CHF group. Some increases, however, were also seen in the mild CHF group. In particular, sympathetic activity, measured by the microneurographic technique, 10 showed a 40% and 80% increase in mild and severe CHF, respectively, clearly indicating that the increase in plasma norepinephrine was not attributable to a reduction in the clearance rate of the neurotransmitter, 11 but to an increased central sympathetic outflow. The process by which ACE inhibition affects this activation has been addressed in a study in which benazepril was administered for 8 weeks to subjects with mild CHF. In all subjects, sympathetic nerve activity, as measured by microneurography, was reduced by the ACE inhibitor, with an average reduction of approximately 30%. 12,13 The sympathetic nerve traffic reduction was accompanied by the increased ability of arterial baroreceptor stimulation, induced by phenylephrine infusion, to inhibit adrenergic drive. These findings may be important in understanding the pathophysiology of the increase in sympathetic activation characterizing heart failure. One hypothesis is that the sympathetic activation in CHF is attributable to an impairment of the tonic restraint of sympathetic activity by the baroreflex. 14 16 Indeed, compared with control subjects, in patients with severe CHF the ability of baroreceptor stimulation or deactivation to induce reflex bradycardia (sympathetic inhibition) or tachycardia (sympathetic excitation) reflexively is strikingly depressed. A less striking but still clearcut depression, is also apparent in patients with mild CHF (Figure 1). 9 We believe that we have identified at least one mechanism responsible for the baroreflex impairment found in CHF, explaining its reversal by ACE inhibition. Baroreceptors are stretch receptors, responsive to changes in arterial volume and therefore, dependent on arterial distensibility. 14 When arterial distensibility is measured in a radial artery by a technique that allows it to be assessed dynamically, CHF patients show stiffer arteries than control subjects. 17 There is also a clearly inverse relationship between arterial compliance and the baroreflex ability to modulate sympathetic nerve traffic, ie, the lower the compliance, the greater the sympathetic activity (Figure 2). 18 In studies comparing pretreatment responses to isometric stress with fosinopril and isradipine, fosinopril has been shown to preserve the physiologic increase in blood pressure, whereas isradipine failed to do so. With isradipine, blood pressure reached pretreatment stress levels. This augmented pressure increase was associated with an exaggerated stimulation of the sympathetic nervous system during isometric stress that resulted in a marked increase in cardiac output and total peripheral resistance but not heart rate. 19 When an ACE inhibitor is administered to heart
238S MANCIA ET AL AJH OCTOBER 1997 VOL. 10, NO. 10, PART 2 failure patients for 8 weeks, arterial compliance markedly increases (Figure 3); this does not occur in normotensive and hypertensive subjects followed over a similar time period. 20 Therefore, it appears that arterial stiffening is, at least in part, responsible for the FIGURE 2. Negative relationship between radial artery compliance, sympathetic nerve traffic (MSNA), bursts per minute [left top] and bursts per 100 heart beats [right top]) and baroreflex sensitivity (bottom) in patients with CHF. Baroreflex sensitivity was measured by averaging the slope of the relationship between 1) the reduction in sympathetic nerve traffic induced by increasing mean arterial pressure through stepwise infusions of phenylephrine (PHE, left bottom) and 2) the increase in sympathetic nerve traffic induced by reducing mean arterial pressure through stepwise infusions of nitroprusside (NTP, right bottom). (Modified from Grassi et al. 18 ) baroreflex failure to modulate adrenergic tone, thus favoring the occurrence of the sympathetic activation characterizing CHF. Reversing this stiffness is one of the mechanisms by which ACE inhibitors exert their beneficial effect. FIGURE 3. Increase in radial arterial compliance after 4 and 8 weeks of daily administration of 10 mg of benazepril in a group of CHF patients (CHF, bottom). Over the same time interval compliance showed no change in a control group of normotensive subjects (C, left top) and a control group of essential hypertensive subjects (H, right top). Data are shown as compliance pressure curves. Results are expressed as means SEM. The increase in the compliance index observed in CHF patients after ACE inhibitor treatment was statistically significant. (Reproduced from Giannattasio et al 20 with permission.)
AJH OCTOBER 1997 VOL. 10, NO. 10, PART 2 FOSINOPRIL IN CONGESTIVE HEART FAILURE 239S FIGURE 4. Changes in pulmonary capillary wedge pressure (PCWP), cardiac index (CI), stroke volume index (SVI), mean arterial blood pressure (MABP), heart rate (HR), and mean right atrial pressure (MRAP) after 10 weeks of fosinopril treatment, by daily dosage. (Reproduced from Deedwania, 21 with permission.) FOSINOPRIL AND CHF The ACE inhibitor fosinopril appears particularly promising for the treatment of CHF. Administration of fosinopril, in doses of 1, 20, or 40 mg/day, to subjects with CHF (NYHA 21 class I to class III) was associated with beneficial hemodynamic changes (Figure 4). Fosinopril administration produced a reduction in pulmonary capillary wedge pressure and right atrial pressure, an increase in stroke volume index, and a reduction in heart rate. It is clear from placebo-controlled, randomized, double-blind studies that the clinical manifestations of CHF are also favorably affected by fosinopril. In one study, for example, administration of fosinopril for 6 months caused an increase in exercise duration and a reduction of symptoms significantly greater than that seen in the placebo group. 22 In another study, exercise duration was increased and symptoms reduced when fosinopril was administered for 3 months (Figure 5). 23 Pooling data from the available studies to obtain a larger total number of subjects showed that, in the fosinopril-treated group, the number of cardiovascular events, worsening of CHF and the hospitalization rate were less than that observed in the placebo group. 21 These data suggest that fosinopril produces benefits similar to those previously observed with other ACE inhibitors. Side effects, such as hypotension, acute deterioration in renal function, cough, and angioneurotic edema, have been reported when ACE inhibitors are given to patients with CHF. Although some side effects are not clearly dose related (for example, cough), the dose relationship of side effects such as hypotension and acute deterioration in renal function makes FIGURE 5. Effects of 3 months of fosinopril treatment on clinical symptoms (left) and exercise duration (right) in 308 patients with CHF. Asterisks refer to the level of statistical significance (fosinopril v placebo). (Modified from Erhardt et al. 23 )
240S MANCIA ET AL AJH OCTOBER 1997 VOL. 10, NO. 10, PART 2 FIGURE 6. Plot of plasma endothelin (ET) concentrations in two groups of patients before and after 12 weeks of treatment with fosinopril (squares) and placebo (triangles). The 18 patients randomized to fosinopril treatment and the 16 patients randomized to placebo who finished this study have similar baseline plasma ET (3.6 1.2 and 3.5 1.3 pg/ml, respectively). Treatment with fosinopril reduced plasma ET to 2.5 0.7 pg/ml (P.005) in contrast to the nonsignificant increase in the group treated with placebo (4.3 2.5 pg/ml P NS) (Reproduced from Galatius- Jensen et al 28 with permission.) them progressively more frequent and severe as the plasma concentration of the ACE inhibitor increases. This can create a vicious circle, as renal function in subjects with CHF may already be impaired either because of reduced blood flow or renal disease, thus facilitating accumulation of the ACE inhibitor. In turn, renal function may be further impaired. In this respect, the dual and compensatory route of elimination of fosinopril, excreted through the kidney and through hepatic metabolism, 24,25 may represent an advantage for this ACE inhibitor. Data obtained from a study in which the accumulation of fosinopril was compared to that of enalapril and lisinopril in patients with CHF support this view (Data on file, Bristol Myers-Squibb). The drug accumulation was significantly less for fosinopril than for either enalapril or lisinopril, presumably because the dual and compensatory routes of elimination of fosinopril increase its clearance from the body when renal elimination was impaired. Hypertensive patients with previous ACE inhibitorassociated cough have experienced less frequent cough with fosinopril compared with other ACE inhibitor therapies. 26,27 These studies suggest that the production of coughing may vary among the different ACE inhibitors. Interestingly, recent data have indicated that endothelin may play a role in the progression of CHF, as a significant correlation between plasma endothelin and exercise test duration and composite heart failure score was demonstrated (P.001). 28 Patients with moderately severe CHF (n 34) had significantly (P.0001) elevated endothelin levels compared with a group of controls (n 21); mean levels were 3.5 pg/ml compared with 2.0 pg/ml, respectively. After treatment with fosinopril for 12 weeks, endothelin levels decreased significantly (P.005) to 2.5 pg/ml, compared with a slight increase in the placebo-treated group (Figure 6). This data indicated another possible mechanism for the benefit of ACE inhibitors. Furthermore, available data from placebo-controlled trials in more than 500 patients with CHF, treated for an average of 93 days, not only suggest that worsening of heart failure was much less with fosinopril than with placebo, but also that the two groups had similar rates of side effects. In particular, hypotension, which is a marker of the pharmacologic action of the drug rather than an adverse effect, as well as a marker of the dependence of blood and glomerular filtration pressure on angiotensin II in CHF patients, was relatively infrequent with fosinopril, suggesting good tolerability. 22,23 REFERENCES 1. Ho KKL, Pinsky JL, Kannel WB, et al: The epidemiology of heart failure: the Framingham study. J Am Coll Cardiol 1993;22(suppl A):6A 13A. 2. McKee PA, Castelli WP, McNamara PM, et al: The natural history of congestive heart failure: the Framingham study. N Engl J Med 1971;285:1441 1442. 3. Consensus Trial Study Group: Effects of enalapril in severe congestive heart failure: results of the Cooperative North Scandinavian Enalapril Survival Study. N Engl J Med 1987;316:1429 1435. 4. The SOLVD Investigators: Effect of enalapril on survival in patients with reduced left ventricular ejection fraction and congestive heart failure. N Engl J Med 1991;325:293 302. 5. The SOLVD Investigators: Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. N Engl J Med 1992;327:685 691. 6. Konstam MA, Kronenberg MW, Rousseau MF, et al, for the SOLVD Investigators: effects of the angiotensinconverting enzyme inhibitor enalapril on the long-term progression of left ventricular dilatation in patients with asymptomatic systolic dysfunction. Circulation 1993;88:2277 2283. 7. Pfeffer MA, Braunwald E, Moyé LA, et al, for the SAVE Investigators: Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction: results of the Survival And Ven-
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