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Congestive heart failure in elderly patients: Controlled study of delapril versus captopril
Congestive Heart Failure in Elderly Patientsz Controlled Study of Delapril Versus Captopril Domenico Acanfora, MD, Tonino Lanzillo, MD, Antimo Pa a, MD, Giancarlo Longobardi, MD, Giuseppe Furgi, MD, Carlo Rengo, MD, Enrico Meli Plo, MD, and Franc0 Rengo, MD In this controlled trial, 30 elderly patients with congest’ve heart failure, New York Heart Association (NYHA) classes II and Ill, were randomly assigned to treatment with captopril25 mg three times daily or delapril 15 mg twice daily. At the end of an 8-week treatment period, clinical symptoms of heart failure were significantly relieved by both drugs, with a consistent and statistically significant improvement in patients’ quality of life evaluated using a symptoms/activity scale (p
There was a relevant, but not statistically significant, increase in exercise duration in both treatment groups (10% captopril group, 14% delapril group), but the number of patients discontinuing the exercise test for dyspnea was 50% less in the delapril group. Neither drug had evident effects on echocardiographic left ventricular parameters. Two patients treated with captopril and 3 with delapril complained of mild-to-moderate adverse reactions. The safety of both drugs was confirmed by labomtory tests. (Am J Cardioll995;75:37F-43F)
C
ventricular function, signs and symptoms failure, quality of life, and safety.
ongestive heart failure (CHF) is particularly frequent in the elderly and is associated with a high mortality.1-3 Digitalis and diuretics are effective in relieving symptomsM and, in the last 10 years, it has been shown that vasodilators prolong survival and improve the clinical picture.7-9 The efficacy of these drugs appears to be dose- and age-related.‘O Studies in large populations of patients with heart failure suggest that angiotensin-converting enzyme (ACE) inhibitors are first-choice therapy for symptom relief and improving the quality of life and survival.11 Delapril, a recently developed nonsulfhydryl carboxylic ACE inhibitor, exhibits vasodilating activity with a low incidence of adverse reactions.12-l5 This therapeutic agent has been widely used in the treatment of hypertension,14J5 and its effects in patients with heart failure are under investigation. The aim of this study was to assess the effects of delapril 30 mg/day (15 mg twice daily) compared with captopril75 mg/day (25 mg three times daily) in elderly patients with New York Heart Association (NYHA) functional classes II and III heart failure. Evaluation parameters comprised changes in NYHA functional class, exercise tolerance, left
From the Clinica del Lavoro Foundation, Institute of Care and Scientific Research Medical Center of Campoli del Monte Taburno (D.A., T.L., A.P., G.L., G.F., E.M., F.R.) and Institute of Internal Medicine, Cardiology and Cardiovascular Surgery, Chair of Geriatrics, Federico II University School of Medicine, Naples, Italy (C.R., F.R.). Address for reprints: Domenico Acanfora, MD, Fondazione Clinica del Lavoro, Divisione di Cardiologia, Via Nino Bixio 10, 82030 Campoli del Monte Taburno, Benevento, Italy.
of heart
PATIENTS AND METHODS Thirty patients >65 years of age with CHF (NYHA functional classes II and III) were enrolled in the study. The protocol was approved by the hospital’s Ethics Committee and informed consent was obtained from all the patients. The study was conducted according to the Declaration of Helsinki (1964) and subsequent amendments. Patients were kept under close medical supervision during the entire study. Patients were excluded for the following reasons: myocardial infarction or myocardial revascularization surgery in the previous 3 months, worklimiting angina or intermittent claudication, cerebrovascular events in the previous 6 months, chronic bronchopulmonary diseases, atria1 fibrillation or severe arrhythmias, use of fixed heart rate pacemakers, hemodynamically significant aortic or mitral stenosis, severe renal (serum creatinine level > 2 mg/dL) or hepatic insufficiency, hematopoietic or endocrine diseases, systolic blood pressure in the standing position 2 190 mm Hg, known hypersensitivity or other contraindications for ACE inhibitors, serum potassium value <3 or > 5.5 mEq/liter, treatment with potassium-sparing diuretics, and chest-high acoustic impedance responsible for poor echocardiographic recordings. Before enrollment, patients underwent a complete clinical examination, electrocardiogram, and routine laboratory screening. During a washout A SYMPOSIUM:
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period of 2 weeks, administration of all vasodilating drugs and digitalis was stopped, diuretic therapy was optimized, and a placebo was introduced. All patients with sinus rhythm and at least 2 signs and symptoms of CHF, NYHA functional class II or III, left ventricular ejection fraction (2-dimensional echocardiography) I 45%, and a bicycle ergometer exercise duration of 3-12 minutes were randomly assigned to treatment with either delapril, 15 mg twice daily, or captopril, 25 mg three times daily, for an 8-week period. Before and after the run-in period, and every 2 weeks during treatment, patients underwent a general clinical examination. Blood pressure was measured using a mercury sphygmomanometer, on the same arm, after 5 minutes in the sitting position, and heart rate was recorded. At the same visits blood samples were taken for the measurement of blood urea nitrogen or serum sodium, potassium, and creatinine. Clinical signs and symptoms (nocturnal dyspnea, neck jugular distention, orthopnea, pulmonary rales, ankle edema, and clear 3rd heart sounds) were noted at the end of the run-in period and after 6 and 8 weeks of treatment. Patients underwent a bicycle ergometer exercise test at the same intervals. NYHA functional classification, echocardiogram, and chest radiograph were performed, and the quality of life was assessed using the symptoms/ activity scale, previously proposed by VigholtSorensen et all6 at the end of the run-in period and after 8 weeks of treatment. Patients performed the exercise test in the morning, in an air-conditioned room (24” C), sitting on an Ergo-Fit 700 bicycle ergometer, with an initial load of 20 W, increasing by 20 W every 3 minutes. At peak effort, patients were asked to continue the test for 15-20 seconds and blood pressure, heart rate, and electrocardiogram were recorded. The exercise test was discontinued if there was any sign of angina, dyspnea, muscle fatigue or exhaustion, lack of rise or progressive diminution in blood pressure, blood pressure > 250/ 120 mm Hg, poor increase in heart rate, threatening arrhythmias, or ST depression 22 mm at 80 msec from the J point. Three electrocardiographic leads (CM4, CM5, CM6) were continuously monitored during the test, whereas electrocardiogram and blood pressure were recorded at baseline, and at l-minute intervals during the exercise period until interruption, and every minute up to 5 minutes during the recovery phase. 38F
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The medical supervisor of the exercise test was not aware of the nature of the randomized therapy. Heart rate, systolic blood pressure at rest and at peak effort, the duration of exercise, and reasons for interruption were all considered for the statistical analysis. M-mode echocardiography was performed under 2-dimensional control with the patient in the 30” or 60” left lateral decubitus position using a phased-array echo Doppler system (HewlettPackard Sonos 1000) equipped with a 2.5 MHz transducer. All echocardiograms were examined by 2 expert echocardiographers. The M-mode echocardiogram carried out under B-mode control was used to obtain the left ventricular end-diastolic dimension (LVEDD) and left ventricular end-systole dimension (LVESD), as suggested by the American Association of Echocardiography, and the left ventricular shortening fraction was calculated as follows17: (LVEDD
- LVESD)/LVEDD
x 100
Left ventricular end-diastole volume (LVEDV) and left ventricular end-systole volume (LVESV) were then calculated with a planimeter from the 2-dimensional echocardiogram, using the apical projection that showed the mitralic distance best, under the control of the Doppler signal. Left ventricular ejection fraction was calculated as follows’? (LVEDD
- LVESV)/LVEDV
x 100
Statistical analysis: Continuous variables (echocardiographic parameters, duration of ergometric tests, systolic blood pressure, heart rate, and laboratory tests) were expressed as means + SD and were compared using Student’s t test for paired and unpaired samples. Paired variables (NYHA classification, clinical signs and symptoms, and the reason for interruption of the exercise test) were compared using the chi-square test (2 test for the difference between proportions of 2 unpaired samples) and the sign test. Statistical significance was set at p < 0.05.
RESULTS Table I shows the general characteristics of the 30 patients enrolled. Fifteen men (aged 70 2 3 years) were randomized to receive captopril and 14 men and 1 woman (ages 71 2 3 years) to receive delapril. Fourteen patients in the captopril group and 12 in the delapril group had heart failure secondary to ischemic heart disease; in 1 patient in each group it was secondary to hypertensive cardio75
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myopathy, and in 1 patient in the delapril group the etiology of congestive heart failure was primary cardiomyopathy. Thirteen of the patients taking captopril and 11 taking delapril were classified as NYHA functional class II, and the corresponding number in class III was 2 and 4. The left ventricular ejection fraction before treatment was 31 ? 9% for the captopril group and 29 ? 9% for the delapril patients. There were no significant differences between the groups for ergometric performances. Clinical signs and symptoms of heart failure were significantly relieved during active treatment (Table II). The clinical improvement corresponded to a better quality of life, objectively confirmed as a reduction in the symptoms/activity scale scores: for the captopril group the scores fell from 26 ? 4 to 19 ? 4 (p
TABLE Study
I Clinical
Characteristics
Population Clinical
at the
Beginning
and
Ergometric
of the
Run-in
Characteristics
Variables
of the
Period
Captopril
NO. Men/women Age (yr, meon f SD) lschemic heart disease Hypertensive heart disease Primary cardiomyopathy NYHAfunctionol class II NYHAfunctional class III Left ventricular ejection fraction (%) Ergometric variables Resting HR (beats/min; meon f SD) Resting SBP (mm Hg; meon 2 SD) Peak HR (beats/min; meon 2 SD) Peak SBP (mm Hg; meon ? SD) Duration of exercise (set; mean ? SD)
Delapril
15 15/o 70 f 3 14 1 0 13 2 31 29 75* 129 2 117220 166 * 469 +
HR = heart rate; NYHA = New York Heart Association;
15 14/l 71 a3 12 1 2 11 4 29 k 9
12 13 18 187
74 + 129 + 112226 156 + 442 +
13 17 20 129
SBP = systoltc blood pressure.
reported in the delapril group: 1 case of mild headache, 1 patient with mild dizziness, and 1 with hot facial flushes, during the early period of administration. At the end of the treatment period, no significant differences in weight, heart rate, and systolic blood pressure for patients treated with either drug were observed (Table V). The safety of the drugs was confirmed by laboratory tests, which showed no changes in blood urea nitrogen or serum sodium, potassium, and creatinine.
DISCUSSION We compared the effects of delapril, 15 mg twice daily, and captopril, 25 mg three times daily, in elderly patients with mild-to-moderate chronic CHF (NYHA functional classes II and III). The 2 drugs had comparable effects: both resulted in a significant reduction in the signs and symptoms of heart failure and improvement in NYHA functional class and quality of life. In elderly patients, CHF is often associated with a slight increase in systolic blood pressure without a corresponding increase in DBP.‘O The agerelated changes suggest a reduction in arterial compliance, consistent with an increase in vasal impedance and reduction in left ventricular ejection.18J9 No change was observed in the left ventricular ejection fraction of patients in either treatment group. In the absence of digitalis, the improvement in the clinical picture seems to be due to relief of left ventricular diastolic dysfunction so frequently seen with aging.2@-24Giles et a125observed an increase in left ventricular ejection fraction after treatment with lisinopril, a nonsulfhydryl ACE inhibitor, in A SYMPOSIUM:
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TABLE II Number Failure
and the Run-in
After
Percentage Period and
Signs and Symptoms Captopril or Delapril
of Patients with Clinical During Treatment with Captopril
End of Run-in Period Paroxysmal nocturnal dyspneo Jugularvein distension Orthopneo Pulmonary basilar roles Ankle edema Third heart sounds *p
tp
TABLE
Ill Heart
Run-in
Period
05,
and
and
3 7 3 11 4 5
$p
(20%) (47%) (20%) (73%) (27%) (33%)
YS end
Rate, Systolic Blood During Treatment
Delapril
6 Weeks
8 Weeks
0 3 0 2 1 1
0 3 (20%) 0 1 (7%)* 0 0
of run-in
(20%) (13%)* (7%) (7%)
End of Run-in Period 4 7 2 13 3 7
(27%) (47%) (13%) (87%) (20%) (46%)
Values
ore
mea”
2 SD.
HR
Pressure at Peak Effort and with Captopril or Delapril
6 Weeks
1182 17 168 2 16 496 + 158
128? 20 170? 26 538 t 180
rate;
TABLE IV Echocardiographic of Treatment
SBP
= systolic
Parameters
with Captopril
8 Weeks
0 4 (27%) 0 4 (27%)* 2(13%) 1 (7%)t
1 (7%) 2 (13%) 0 2 (13%)’ 0 ot
Duration
of Exercise
After
blood
8 Weeks
End of Run-in Period
6 Weeks
8 Weeks
126 2 20 166?18 545 f 178
111 223 153+20 480 + 139
117?23 162221 495 + 193
115-t 18 154 * 17 548 ? 180
pressure
After
the Run-in
Period
and
at the End of 8 Weeks
or Delapril Captopril (n = 15)
Delapril (n = 15)
After Run-in Period LVEDD (mm) LVESD (mm) SF (%) LVEF (56)
65 52 21 31
Values are me(ln T SD. = left ventricular
LVEDD end-syrtollc
end-dlastok SF = shortening
dimension;
TABLE V Body Treatment
Weight, Captopril
with
Values
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-c SD.
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DEP.
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End of Treatment
+ 6.5 2 7 -t9 2-9 dimewon; froctfon.
Heart Rate, or Delapril
66 52 22 32
f f + +
=
left
LVEF
and
Blood
End of Run-in Period Captopril (n = 15) Body weight (kg) HR (beats/min) SBP (mm Hg) DBP (mm Hg) Delapril (n = 15) Body weight (kg) HR (beats/min) SBP (mm Hg) DBP (mm Hg)
the
Delapril
End of Run-in Period
= heott
6 Weeks
period.
Captopril
Peak effort HR (mm Hg) Peak effort SBP (mm Hg) Duration of exercise (SK)
of Heart
7 8 7 9
67 + 8 55 + 9 19-t7 29 + 9 ventricular
Pressure
ejection
After
2 Weeks
4 Weeks
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HR
During
+ 11 + 11 + 16 *6
2 9 +8 + 14 + 6
75 2 9 76 2 9 124? 10 81 25
74 76 123 78
2 2 + +
= heart
16,
ventricular
75 78 127 81
75 71 126 82
pressure,
and
left
76* 12 76 + 8 123 + 15 79 2 4
75 76 121 79 blood
Period
=
8 7 5 8
12 9 18 9
75 2 9 74 2 11 119r 13 782 16 = d,astol,c/systol,c
LVESD
+ + + t
8 Weeks
76+ 79 + 130? 80 +
SBP
67 54 20 29
6 Weeks
762 13 75 + 7 128 + 16 80 + 8 9 8 12 4
fraction;
the Run-in
762 12 782 10 127 + 21 79 * 9
t 2 -t *
End of Treatment
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9 7 14 5
middle-aged patients with moderate-to-severe systolic dysfunction (left ventricular ejection fraction 2 35%) receiving digitalis. The lack of significant changes in left ventricular ejection fraction in the patients we studied may be explained by the low values at baseline ( <35% in 67% of the captopril group and 73% of the delapril group), by the fact that they were not receiving digitalis, and because age is an important factor in determining the response to many drugs. Several studies in middle-aged patients with CHF have shown a significant increase in exercise tolerance during treatment with ACE inhibitors.s29 The same good results, manifested as a progressive increase in exercise duration (10% in the captopril group, 14% in the delapril group) were noted in the present study, but without reaching statistical significance, probably due to the high variability and limited sample size. Age, cardiovascular diseases, and inactivity appear to be the main reasons for reduced working
FIGURE 1. Patient individual symptoms/activity scale scores at the end of the run-in period (baseline) and after 8 weeks of treatment (final) with captopril or delapril.
Captopril
40
I
capacity in the elderly. 30$31In patients with heart failure, many factors are responsible for reduced muscle performance. Massie et aP* believe that metabolic alterations secondary to hormonal changes, rather than a reduction in blood flow in the skeletal muscles, plays a fundamental role. This agrees with the report of Levine and Levine33 that in heart failure the percentage of cardiac output to skeletal muscles increases at the expense of the kidneys and skin. Chronic heart failure, however, is associated with structural alterations in skeletal muscle, which can limit its working capacity.34 The improvement of physical performance in treated patients with CHF is attributed mostly to a redistribution of blood flow rather than to an increase.35 In elderly patients, structural and functional changes, even in the absence of cardiovascular, respiratory, or musculoskeletal diseases, can often be due to prolonged inactivity.31 Ades et aP6 showed that continued physical activity is sufficient
40
1 J
: 0
Delapril
1 -I
30 -
30 -
20-
20 -
10 -
10 P-c 0.001
0
I
I Baseline
P< 0.001
I
0
I
I Final
I
Captopril Basal
FIGURE 2. New York Heart Association (NYHA) classification at the end of the run-in period (baseline) and after 8 weeks of treatment (final) with captopril or delapril. 2 = chi square.
I
I
I
Final
Baseline
Delapril Final
Basal
Final
Class NYHA I
Class NYHA II
Class NYHA III X*=11.8;P<0.005
x2 = 12.9; P< 0.005
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to increase working capacity in patients with coronary disease. In the present study the variable introduced was treatment with captopril or delapril, without appreciable improvement in working capacity. This is probably because these agents act only on some of the factors involved. The tendency to increase the working capacity was not accompanied by any significant change in heart rate or blood pressure during effort, but there was a significant reduction in the number of patients who discontinued the exercise test because of dyspnea. Together with the reductions in heart failure signs and symptoms and exercise dyspnea, most patients exhibited an objective improvement in their quality of life, as indicated by changes in the symptoms/activity scale scores. Recently, quality of life has started to be assessed in controlled clinical studies with ACE inhibitors in CHF, although the results to date are not uniform.37 It has been reported that captopril has a favorable impact on the quality of life compared with other vasodilators.38 Previous trials in patients with subclinical renal failure26>39 have demonstrated that ACE inhibitors may cause changes in renal function: an increase in blood urea nitrogen and serum creatinine, returning to normal values on reducing diuretic therapy. The patients in the present study showed no significant changes in their biochemical parameters, although they received constant diuretic therapy. The absence of such changes and the limited number of adverse reactions indicate that medium or long-term treatment with delapril should be safe in elderly patients with CHF. In conclusion, delapril, at a daily dosage of 30 mg (15 mg twice daily), is as effective as captopril, at a daily dosage of 75 mg (25 mg three times daily), in terms of relief of the signs and symptoms of CHF, quality of life improvement, and positive effects on exercise tolerance, and there are few adverse reactions. Long-term studies with larger numbers of patients should confirm the efficacy and safety profile of delapril in elderly patients with CHF. Acknowledgment: This study was partially supported by a grant from the Italian Ministry for University and Scientific Research and Technology (MURST) 1992. 1. Rengo F and CHF Italian scompenso cardiacs nell’anziano nari. G Gervn1ol1995 42188
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2. Shocken DD, Anieta Ml, Leaverton PE, Ross Ek Prevalence and mortality rate of congestive heart failure in the United States. J Am Cdl C&i01 19%?;24I301-306. 3. Parsley WW. Pathophysiology and current therapy of congestive heart failure. JAm Coil Car&o1 1989;13:771-778. 4. Griffiths BE, Penny WI, Lewis Ml, Henderson AH. Maintenance of the inotropic effect of digoxin on long-term treatment. Br Med J 1982;284:181% 1822. 5. Lee DC, Johnson RA, Bingham JB. Heart failure in out-patients: a randomized study of digoxin vs placebo. N En& .I Med 1982;306:699. 6. Dobbs SM, Kenyon wl Dobbs R.J. Maintenance digoxin after an episode of heart failure: place~mntrolled study in outpatients. Br Med J 1977,1:74% 752. 7. Cohn JN, Archibald DG, Ziesche S, Franc&a JA, Harston WE, Tristani FE, Dunkman B, Jacobs W, Francis GS, Flohr KH, Goldman S, Cobb FR, Shah PM, Saunders R, Fletcher RD, Lomb HS, Hughes VC, Baker B. Effect of vasodilator therapy on mortality in chronic congestive heart failure: results of a Veterans Administration Cooperative Study. N Engf J Med 1986;34:1547-1552. 8. Cohn JN, Johnson G, Ziesche S, Cobb F, Francis G, Tristani F, Smith R, Dunkman WB, Loeb H, Wang M, Bhat G, Goldman S, Fletcher RD, Doherty J, Hughes CV, Carson P, Citron G, Shabetai R, Haakenson C. A compalison of enalapril with hydralazine-iwsorbide dinitrate in the treatment of chronic congestive heart failure. N Engi J Med 1991;325:30>310. 9. Packer M, Lee WH, Yushak M, Medina N. Comparison of captopril and enalapril in patients with severe chronic heart failure. N En@ J Med 1986;315: 847-853. 10. Hughes CV, Wang M, Johnson G, Cohn JN. Influence of age on mechanisms and prognosis of heart failure. Circubion 1993;87(suppl Vl):Vl-lll-VI117. 11. Furberg CD, Yusuf S. Effects of vasodilators on survival in chronic congestive heart failure./lm J Canlio 1985;55:111&1113. 12. Oka Y, Nishikawa K, Kito G. Delapril. Cardiovac Drug Rev 1988;6:192205. 13. Saruta T, Nishikawa K. Characteristics of a new angiotensin converting enzyme inhibitor: delapril. Am J H~rtem l991;4:23.%28S. 14. Rahn KH. Comparison of the antihypertensive effects of delapril and enalapril. Am J Hpa?xm 1991;4:38S418. 15. Acanfora D, Papa A, Nicolino A. Effetti de1 delapril in aswciazione con indapamide in pazienti anziani ipertesi. G Ital Cur&l 1993;23(suppl 1):315. 16. Vigholt-Sorensen E, Faergeman 0, Snow HM. Effects of xamoterol, a beta-adrenoceptor partial agonist, in patients with ischemic dysfunction of the left ventricle. Br Heart J 1989;62:335-341. 17. Sabn DJ, De Maria A, Kiss10 J, Weynan A. The committee on M-mode standardization of the American Society of Echocardiography. Recommendations regarding quantification in M-mode echocardiography. Results of a survey of echocardiographic measurements. Cinxlafion 1978;38:1072-1081. 18. Aronow WS, Ahn C, Kronzon I. Prognosis of congestive heart failure in elderly patients with normal versus abnormal left ventricular systolic function associated with coronary artery disease. Am J Cardi 1990,65:1257-12.59. 19. Cohn JN. Vasodilator therapy for heart failure: the influence of impedance on left ventricular performance. Circulation 1973;4-8%3. 20. Lakatta EG. Changes in cardiovascular function with aping. Eur Heart J 1990;11(suppl C):22-29. 21. Grossman W. Diastolic dysfunction and congestive heart failure. C&U/Qtin 1990,81(suppl Ill):l-7. 22. Kessler KK. Heart failure with nomnl systolic function. Arch Intern Med 1988;148:2109-2111. 23. Dougherty AM, Naccarelli GC, Gray EL, Hi& CH, Goldstein RA Congestive heart failure with normal systolic function. Am J Cardiol 1984,54:7X+ 782. 24. Harizi RC, Bianm JA, Alpert JS. Diastolic dysfunction and congestive heart failure in clinical cardiology. Arch Intern Med 1988;14899-109. 25. Giles TD, Katz R, Sullivan JM, Wolfson P, Haugland M, Kirlii P, Powers E, Rich S, Hackshaw B, Chiaramida A, Rouldeau JL, Fisher MB, Pigeon J, Rush JE. Short- and long-acting angiotensin-converting enzyme inhibitors: a randomized study of lisinopril versus captopril in the treatment of congestive heart failure. JAm CON Car&l 1989;13:124&1247. 26. Chattejee K, Parsley WW, Cohn JN, Levine TB, Awan NA, Mason DT, Faxon DP, Creager M, Gawas HP, Fouad FM, Tarti RC, Hollenberg NK, Dzau V, LeJemtel TH, Sonnenblick EH, Turini GA, Bnmner HR. A cooperative multicenter study of captopril in congestive heart failure: hemodynamic effects and long-term response. Am Heati J 1985;l 10(supp12):439-447. 27. Ader R, Chattejee K, Ports T, Ports T, Bnmdage B, Hiramatsu B, Parm!ey W. Immediate and sustained hemodynamic and clinical improvement
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in chronic heart failure by an oral angiotensin-converting enzyme inhibitor. Cixula~ 1980,61:931-937. 28. Levine TB, Franc&a JA, Cohn JN. Acute and long-term response to an oral converting-enzyme inhibitor, captopril, in congestive heart failure. &U&Idon 1980;62:35-41. 29. Captopril Multicenter Research Group. A placebo-controlled study of captopril in refractory chronic heart failure. JAm Coil Cardiol1983;2:755-763. 30. Raven PB, Mitchell J. The effect of aging on the cardiovascular response to dynamic and static exercise. In: Weisfeldt ML, ed. The Aging Heart, Its Function and Response to Stress. New York: Raven Press, 1980269. 31. Posner JD, Gomxm KM, Howard BS, Klein HS, Woldow A. Exercise capacity in the elderly. Am J Car&l 1986;57:52. 32. Ma&e B, Conway M, Yonge R, Frostick S, Lediigham H, Sleight P, Radda G, Rajagopalan B. Skeletal muscle metabolism in patients with conges tive heart failure: relation to clinical severity and blood flow. Circulation 1987;76: 1009-1019. 33. Levine TB, Levine AB. Regional blood flow supply and demand in heart failure. Am Heati J 1990,120:1547-1551. 34. Lipkin DP, Jones DA, Round JM, Poole-Wilson PA. Abnormalities of
skeletal muscle in patients with chronic heart failure. Inf J Cat&l 1988;18:187195. 35. Drexler H, Faude F, Hoing S, Just H. Blood flow distribution withii skeletal muscle during exercise in the presence of chronic heart failure: effect of mihinone. Circ&ion 1987;76:1344-1352. 36. Ades PA, Hanson JS, Gunther PGS, Tonino RP. Exercise conditioning in the elderly coronary patient. JAm Geriatr Sot 1987;35:121-128. 37. Hill JF, Bulpitt CJ, Fletcher AE. Angiotensin converting enzyme inhibitors and quality of life: the European trial. Jf&mtens 1985$S91-S94. 38. Gorkin L, NorveIl NK, Rosen RC, Charles E, Shumaker Sk McIntyre KM, Capone RJ, Kostis J, Niaura R, Woods P, Hoskiig J, Garces C, Handberg E, Ahem DK, Follick MJ for the SOLVD Investigators. Assessment of quality of life as observed from the baseline data of the Studies of Left Ventricular Dysfunction (SOLD) study quality-life substudy. Am J Cardiol 1993;71:1069-1073. 39. Packer M, Lee WH, Medina N, Yushak M, Kessler PD. Functional renal insufficiency during long-term therapy with captopril and enalapril in severe chronic heart failure. Am In&m Med 1987;106346-354.
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There was a relevant, but not statistically significant, increase in exercise duration in both treatment groups (10% captopril group, 14% delapril group), but the number of patients discontinuing the exercise test for dyspnea was 50% less in the delapril group. Neither drug had evident effects on echocardiographic left ventricular parameters. Two patients treated with captopril and 3 with delapril complained of mild-to-moderate adverse reactions. The safety of both drugs was confirmed by labomtory tests. (Am J Cardioll995;75:37F-43F)
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ventricular function, signs and symptoms failure, quality of life, and safety.
ongestive heart failure (CHF) is particularly frequent in the elderly and is associated with a high mortality.1-3 Digitalis and diuretics are effective in relieving symptomsM and, in the last 10 years, it has been shown that vasodilators prolong survival and improve the clinical picture.7-9 The efficacy of these drugs appears to be dose- and age-related.‘O Studies in large populations of patients with heart failure suggest that angiotensin-converting enzyme (ACE) inhibitors are first-choice therapy for symptom relief and improving the quality of life and survival.11 Delapril, a recently developed nonsulfhydryl carboxylic ACE inhibitor, exhibits vasodilating activity with a low incidence of adverse reactions.12-l5 This therapeutic agent has been widely used in the treatment of hypertension,14J5 and its effects in patients with heart failure are under investigation. The aim of this study was to assess the effects of delapril 30 mg/day (15 mg twice daily) compared with captopril75 mg/day (25 mg three times daily) in elderly patients with New York Heart Association (NYHA) functional classes II and III heart failure. Evaluation parameters comprised changes in NYHA functional class, exercise tolerance, left
From the Clinica del Lavoro Foundation, Institute of Care and Scientific Research Medical Center of Campoli del Monte Taburno (D.A., T.L., A.P., G.L., G.F., E.M., F.R.) and Institute of Internal Medicine, Cardiology and Cardiovascular Surgery, Chair of Geriatrics, Federico II University School of Medicine, Naples, Italy (C.R., F.R.). Address for reprints: Domenico Acanfora, MD, Fondazione Clinica del Lavoro, Divisione di Cardiologia, Via Nino Bixio 10, 82030 Campoli del Monte Taburno, Benevento, Italy.
of heart
PATIENTS AND METHODS Thirty patients >65 years of age with CHF (NYHA functional classes II and III) were enrolled in the study. The protocol was approved by the hospital’s Ethics Committee and informed consent was obtained from all the patients. The study was conducted according to the Declaration of Helsinki (1964) and subsequent amendments. Patients were kept under close medical supervision during the entire study. Patients were excluded for the following reasons: myocardial infarction or myocardial revascularization surgery in the previous 3 months, worklimiting angina or intermittent claudication, cerebrovascular events in the previous 6 months, chronic bronchopulmonary diseases, atria1 fibrillation or severe arrhythmias, use of fixed heart rate pacemakers, hemodynamically significant aortic or mitral stenosis, severe renal (serum creatinine level > 2 mg/dL) or hepatic insufficiency, hematopoietic or endocrine diseases, systolic blood pressure in the standing position 2 190 mm Hg, known hypersensitivity or other contraindications for ACE inhibitors, serum potassium value <3 or > 5.5 mEq/liter, treatment with potassium-sparing diuretics, and chest-high acoustic impedance responsible for poor echocardiographic recordings. Before enrollment, patients underwent a complete clinical examination, electrocardiogram, and routine laboratory screening. During a washout A SYMPOSIUM:
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period of 2 weeks, administration of all vasodilating drugs and digitalis was stopped, diuretic therapy was optimized, and a placebo was introduced. All patients with sinus rhythm and at least 2 signs and symptoms of CHF, NYHA functional class II or III, left ventricular ejection fraction (2-dimensional echocardiography) I 45%, and a bicycle ergometer exercise duration of 3-12 minutes were randomly assigned to treatment with either delapril, 15 mg twice daily, or captopril, 25 mg three times daily, for an 8-week period. Before and after the run-in period, and every 2 weeks during treatment, patients underwent a general clinical examination. Blood pressure was measured using a mercury sphygmomanometer, on the same arm, after 5 minutes in the sitting position, and heart rate was recorded. At the same visits blood samples were taken for the measurement of blood urea nitrogen or serum sodium, potassium, and creatinine. Clinical signs and symptoms (nocturnal dyspnea, neck jugular distention, orthopnea, pulmonary rales, ankle edema, and clear 3rd heart sounds) were noted at the end of the run-in period and after 6 and 8 weeks of treatment. Patients underwent a bicycle ergometer exercise test at the same intervals. NYHA functional classification, echocardiogram, and chest radiograph were performed, and the quality of life was assessed using the symptoms/ activity scale, previously proposed by VigholtSorensen et all6 at the end of the run-in period and after 8 weeks of treatment. Patients performed the exercise test in the morning, in an air-conditioned room (24” C), sitting on an Ergo-Fit 700 bicycle ergometer, with an initial load of 20 W, increasing by 20 W every 3 minutes. At peak effort, patients were asked to continue the test for 15-20 seconds and blood pressure, heart rate, and electrocardiogram were recorded. The exercise test was discontinued if there was any sign of angina, dyspnea, muscle fatigue or exhaustion, lack of rise or progressive diminution in blood pressure, blood pressure > 250/ 120 mm Hg, poor increase in heart rate, threatening arrhythmias, or ST depression 22 mm at 80 msec from the J point. Three electrocardiographic leads (CM4, CM5, CM6) were continuously monitored during the test, whereas electrocardiogram and blood pressure were recorded at baseline, and at l-minute intervals during the exercise period until interruption, and every minute up to 5 minutes during the recovery phase. 38F
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The medical supervisor of the exercise test was not aware of the nature of the randomized therapy. Heart rate, systolic blood pressure at rest and at peak effort, the duration of exercise, and reasons for interruption were all considered for the statistical analysis. M-mode echocardiography was performed under 2-dimensional control with the patient in the 30” or 60” left lateral decubitus position using a phased-array echo Doppler system (HewlettPackard Sonos 1000) equipped with a 2.5 MHz transducer. All echocardiograms were examined by 2 expert echocardiographers. The M-mode echocardiogram carried out under B-mode control was used to obtain the left ventricular end-diastolic dimension (LVEDD) and left ventricular end-systole dimension (LVESD), as suggested by the American Association of Echocardiography, and the left ventricular shortening fraction was calculated as follows17: (LVEDD
- LVESD)/LVEDD
x 100
Left ventricular end-diastole volume (LVEDV) and left ventricular end-systole volume (LVESV) were then calculated with a planimeter from the 2-dimensional echocardiogram, using the apical projection that showed the mitralic distance best, under the control of the Doppler signal. Left ventricular ejection fraction was calculated as follows’? (LVEDD
- LVESV)/LVEDV
x 100
Statistical analysis: Continuous variables (echocardiographic parameters, duration of ergometric tests, systolic blood pressure, heart rate, and laboratory tests) were expressed as means + SD and were compared using Student’s t test for paired and unpaired samples. Paired variables (NYHA classification, clinical signs and symptoms, and the reason for interruption of the exercise test) were compared using the chi-square test (2 test for the difference between proportions of 2 unpaired samples) and the sign test. Statistical significance was set at p < 0.05.
RESULTS Table I shows the general characteristics of the 30 patients enrolled. Fifteen men (aged 70 2 3 years) were randomized to receive captopril and 14 men and 1 woman (ages 71 2 3 years) to receive delapril. Fourteen patients in the captopril group and 12 in the delapril group had heart failure secondary to ischemic heart disease; in 1 patient in each group it was secondary to hypertensive cardio75
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myopathy, and in 1 patient in the delapril group the etiology of congestive heart failure was primary cardiomyopathy. Thirteen of the patients taking captopril and 11 taking delapril were classified as NYHA functional class II, and the corresponding number in class III was 2 and 4. The left ventricular ejection fraction before treatment was 31 ? 9% for the captopril group and 29 ? 9% for the delapril patients. There were no significant differences between the groups for ergometric performances. Clinical signs and symptoms of heart failure were significantly relieved during active treatment (Table II). The clinical improvement corresponded to a better quality of life, objectively confirmed as a reduction in the symptoms/activity scale scores: for the captopril group the scores fell from 26 ? 4 to 19 ? 4 (p
TABLE Study
I Clinical
Characteristics
Population Clinical
at the
Beginning
and
Ergometric
of the
Run-in
Characteristics
Variables
of the
Period
Captopril
NO. Men/women Age (yr, meon f SD) lschemic heart disease Hypertensive heart disease Primary cardiomyopathy NYHAfunctionol class II NYHAfunctional class III Left ventricular ejection fraction (%) Ergometric variables Resting HR (beats/min; meon f SD) Resting SBP (mm Hg; meon 2 SD) Peak HR (beats/min; meon 2 SD) Peak SBP (mm Hg; meon ? SD) Duration of exercise (set; mean ? SD)
Delapril
15 15/o 70 f 3 14 1 0 13 2 31 29 75* 129 2 117220 166 * 469 +
HR = heart rate; NYHA = New York Heart Association;
15 14/l 71 a3 12 1 2 11 4 29 k 9
12 13 18 187
74 + 129 + 112226 156 + 442 +
13 17 20 129
SBP = systoltc blood pressure.
reported in the delapril group: 1 case of mild headache, 1 patient with mild dizziness, and 1 with hot facial flushes, during the early period of administration. At the end of the treatment period, no significant differences in weight, heart rate, and systolic blood pressure for patients treated with either drug were observed (Table V). The safety of the drugs was confirmed by laboratory tests, which showed no changes in blood urea nitrogen or serum sodium, potassium, and creatinine.
DISCUSSION We compared the effects of delapril, 15 mg twice daily, and captopril, 25 mg three times daily, in elderly patients with mild-to-moderate chronic CHF (NYHA functional classes II and III). The 2 drugs had comparable effects: both resulted in a significant reduction in the signs and symptoms of heart failure and improvement in NYHA functional class and quality of life. In elderly patients, CHF is often associated with a slight increase in systolic blood pressure without a corresponding increase in DBP.‘O The agerelated changes suggest a reduction in arterial compliance, consistent with an increase in vasal impedance and reduction in left ventricular ejection.18J9 No change was observed in the left ventricular ejection fraction of patients in either treatment group. In the absence of digitalis, the improvement in the clinical picture seems to be due to relief of left ventricular diastolic dysfunction so frequently seen with aging.2@-24Giles et a125observed an increase in left ventricular ejection fraction after treatment with lisinopril, a nonsulfhydryl ACE inhibitor, in A SYMPOSIUM:
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TABLE II Number Failure
and the Run-in
After
Percentage Period and
Signs and Symptoms Captopril or Delapril
of Patients with Clinical During Treatment with Captopril
End of Run-in Period Paroxysmal nocturnal dyspneo Jugularvein distension Orthopneo Pulmonary basilar roles Ankle edema Third heart sounds *p
tp
TABLE
Ill Heart
Run-in
Period
05,
and
and
3 7 3 11 4 5
$p
(20%) (47%) (20%) (73%) (27%) (33%)
YS end
Rate, Systolic Blood During Treatment
Delapril
6 Weeks
8 Weeks
0 3 0 2 1 1
0 3 (20%) 0 1 (7%)* 0 0
of run-in
(20%) (13%)* (7%) (7%)
End of Run-in Period 4 7 2 13 3 7
(27%) (47%) (13%) (87%) (20%) (46%)
Values
ore
mea”
2 SD.
HR
Pressure at Peak Effort and with Captopril or Delapril
6 Weeks
1182 17 168 2 16 496 + 158
128? 20 170? 26 538 t 180
rate;
TABLE IV Echocardiographic of Treatment
SBP
= systolic
Parameters
with Captopril
8 Weeks
0 4 (27%) 0 4 (27%)* 2(13%) 1 (7%)t
1 (7%) 2 (13%) 0 2 (13%)’ 0 ot
Duration
of Exercise
After
blood
8 Weeks
End of Run-in Period
6 Weeks
8 Weeks
126 2 20 166?18 545 f 178
111 223 153+20 480 + 139
117?23 162221 495 + 193
115-t 18 154 * 17 548 ? 180
pressure
After
the Run-in
Period
and
at the End of 8 Weeks
or Delapril Captopril (n = 15)
Delapril (n = 15)
After Run-in Period LVEDD (mm) LVESD (mm) SF (%) LVEF (56)
65 52 21 31
Values are me(ln T SD. = left ventricular
LVEDD end-syrtollc
end-dlastok SF = shortening
dimension;
TABLE V Body Treatment
Weight, Captopril
with
Values
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+ 6.5 2 7 -t9 2-9 dimewon; froctfon.
Heart Rate, or Delapril
66 52 22 32
f f + +
=
left
LVEF
and
Blood
End of Run-in Period Captopril (n = 15) Body weight (kg) HR (beats/min) SBP (mm Hg) DBP (mm Hg) Delapril (n = 15) Body weight (kg) HR (beats/min) SBP (mm Hg) DBP (mm Hg)
the
Delapril
End of Run-in Period
= heott
6 Weeks
period.
Captopril
Peak effort HR (mm Hg) Peak effort SBP (mm Hg) Duration of exercise (SK)
of Heart
7 8 7 9
67 + 8 55 + 9 19-t7 29 + 9 ventricular
Pressure
ejection
After
2 Weeks
4 Weeks
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HR
During
+ 11 + 11 + 16 *6
2 9 +8 + 14 + 6
75 2 9 76 2 9 124? 10 81 25
74 76 123 78
2 2 + +
= heart
16,
ventricular
75 78 127 81
75 71 126 82
pressure,
and
left
76* 12 76 + 8 123 + 15 79 2 4
75 76 121 79 blood
Period
=
8 7 5 8
12 9 18 9
75 2 9 74 2 11 119r 13 782 16 = d,astol,c/systol,c
LVESD
+ + + t
8 Weeks
76+ 79 + 130? 80 +
SBP
67 54 20 29
6 Weeks
762 13 75 + 7 128 + 16 80 + 8 9 8 12 4
fraction;
the Run-in
762 12 782 10 127 + 21 79 * 9
t 2 -t *
End of Treatment
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1995
9 7 14 5
middle-aged patients with moderate-to-severe systolic dysfunction (left ventricular ejection fraction 2 35%) receiving digitalis. The lack of significant changes in left ventricular ejection fraction in the patients we studied may be explained by the low values at baseline ( <35% in 67% of the captopril group and 73% of the delapril group), by the fact that they were not receiving digitalis, and because age is an important factor in determining the response to many drugs. Several studies in middle-aged patients with CHF have shown a significant increase in exercise tolerance during treatment with ACE inhibitors.s29 The same good results, manifested as a progressive increase in exercise duration (10% in the captopril group, 14% in the delapril group) were noted in the present study, but without reaching statistical significance, probably due to the high variability and limited sample size. Age, cardiovascular diseases, and inactivity appear to be the main reasons for reduced working
FIGURE 1. Patient individual symptoms/activity scale scores at the end of the run-in period (baseline) and after 8 weeks of treatment (final) with captopril or delapril.
Captopril
40
I
capacity in the elderly. 30$31In patients with heart failure, many factors are responsible for reduced muscle performance. Massie et aP* believe that metabolic alterations secondary to hormonal changes, rather than a reduction in blood flow in the skeletal muscles, plays a fundamental role. This agrees with the report of Levine and Levine33 that in heart failure the percentage of cardiac output to skeletal muscles increases at the expense of the kidneys and skin. Chronic heart failure, however, is associated with structural alterations in skeletal muscle, which can limit its working capacity.34 The improvement of physical performance in treated patients with CHF is attributed mostly to a redistribution of blood flow rather than to an increase.35 In elderly patients, structural and functional changes, even in the absence of cardiovascular, respiratory, or musculoskeletal diseases, can often be due to prolonged inactivity.31 Ades et aP6 showed that continued physical activity is sufficient
40
1 J
: 0
Delapril
1 -I
30 -
30 -
20-
20 -
10 -
10 P-c 0.001
0
I
I Baseline
P< 0.001
I
0
I
I Final
I
Captopril Basal
FIGURE 2. New York Heart Association (NYHA) classification at the end of the run-in period (baseline) and after 8 weeks of treatment (final) with captopril or delapril. 2 = chi square.
I
I
I
Final
Baseline
Delapril Final
Basal
Final
Class NYHA I
Class NYHA II
Class NYHA III X*=11.8;P<0.005
x2 = 12.9; P< 0.005
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to increase working capacity in patients with coronary disease. In the present study the variable introduced was treatment with captopril or delapril, without appreciable improvement in working capacity. This is probably because these agents act only on some of the factors involved. The tendency to increase the working capacity was not accompanied by any significant change in heart rate or blood pressure during effort, but there was a significant reduction in the number of patients who discontinued the exercise test because of dyspnea. Together with the reductions in heart failure signs and symptoms and exercise dyspnea, most patients exhibited an objective improvement in their quality of life, as indicated by changes in the symptoms/activity scale scores. Recently, quality of life has started to be assessed in controlled clinical studies with ACE inhibitors in CHF, although the results to date are not uniform.37 It has been reported that captopril has a favorable impact on the quality of life compared with other vasodilators.38 Previous trials in patients with subclinical renal failure26>39 have demonstrated that ACE inhibitors may cause changes in renal function: an increase in blood urea nitrogen and serum creatinine, returning to normal values on reducing diuretic therapy. The patients in the present study showed no significant changes in their biochemical parameters, although they received constant diuretic therapy. The absence of such changes and the limited number of adverse reactions indicate that medium or long-term treatment with delapril should be safe in elderly patients with CHF. In conclusion, delapril, at a daily dosage of 30 mg (15 mg twice daily), is as effective as captopril, at a daily dosage of 75 mg (25 mg three times daily), in terms of relief of the signs and symptoms of CHF, quality of life improvement, and positive effects on exercise tolerance, and there are few adverse reactions. Long-term studies with larger numbers of patients should confirm the efficacy and safety profile of delapril in elderly patients with CHF. Acknowledgment: This study was partially supported by a grant from the Italian Ministry for University and Scientific Research and Technology (MURST) 1992. 1. Rengo F and CHF Italian scompenso cardiacs nell’anziano nari. G Gervn1ol1995 42188
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2. Shocken DD, Anieta Ml, Leaverton PE, Ross Ek Prevalence and mortality rate of congestive heart failure in the United States. J Am Cdl C&i01 19%?;24I301-306. 3. Parsley WW. Pathophysiology and current therapy of congestive heart failure. JAm Coil Car&o1 1989;13:771-778. 4. Griffiths BE, Penny WI, Lewis Ml, Henderson AH. Maintenance of the inotropic effect of digoxin on long-term treatment. Br Med J 1982;284:181% 1822. 5. Lee DC, Johnson RA, Bingham JB. Heart failure in out-patients: a randomized study of digoxin vs placebo. N En& .I Med 1982;306:699. 6. Dobbs SM, Kenyon wl Dobbs R.J. Maintenance digoxin after an episode of heart failure: place~mntrolled study in outpatients. Br Med J 1977,1:74% 752. 7. Cohn JN, Archibald DG, Ziesche S, Franc&a JA, Harston WE, Tristani FE, Dunkman B, Jacobs W, Francis GS, Flohr KH, Goldman S, Cobb FR, Shah PM, Saunders R, Fletcher RD, Lomb HS, Hughes VC, Baker B. Effect of vasodilator therapy on mortality in chronic congestive heart failure: results of a Veterans Administration Cooperative Study. N Engf J Med 1986;34:1547-1552. 8. Cohn JN, Johnson G, Ziesche S, Cobb F, Francis G, Tristani F, Smith R, Dunkman WB, Loeb H, Wang M, Bhat G, Goldman S, Fletcher RD, Doherty J, Hughes CV, Carson P, Citron G, Shabetai R, Haakenson C. A compalison of enalapril with hydralazine-iwsorbide dinitrate in the treatment of chronic congestive heart failure. N Engi J Med 1991;325:30>310. 9. Packer M, Lee WH, Yushak M, Medina N. Comparison of captopril and enalapril in patients with severe chronic heart failure. N En@ J Med 1986;315: 847-853. 10. Hughes CV, Wang M, Johnson G, Cohn JN. Influence of age on mechanisms and prognosis of heart failure. Circubion 1993;87(suppl Vl):Vl-lll-VI117. 11. Furberg CD, Yusuf S. Effects of vasodilators on survival in chronic congestive heart failure./lm J Canlio 1985;55:111&1113. 12. Oka Y, Nishikawa K, Kito G. Delapril. Cardiovac Drug Rev 1988;6:192205. 13. Saruta T, Nishikawa K. Characteristics of a new angiotensin converting enzyme inhibitor: delapril. Am J H~rtem l991;4:23.%28S. 14. Rahn KH. Comparison of the antihypertensive effects of delapril and enalapril. Am J Hpa?xm 1991;4:38S418. 15. Acanfora D, Papa A, Nicolino A. Effetti de1 delapril in aswciazione con indapamide in pazienti anziani ipertesi. G Ital Cur&l 1993;23(suppl 1):315. 16. Vigholt-Sorensen E, Faergeman 0, Snow HM. Effects of xamoterol, a beta-adrenoceptor partial agonist, in patients with ischemic dysfunction of the left ventricle. Br Heart J 1989;62:335-341. 17. Sabn DJ, De Maria A, Kiss10 J, Weynan A. The committee on M-mode standardization of the American Society of Echocardiography. Recommendations regarding quantification in M-mode echocardiography. Results of a survey of echocardiographic measurements. Cinxlafion 1978;38:1072-1081. 18. Aronow WS, Ahn C, Kronzon I. Prognosis of congestive heart failure in elderly patients with normal versus abnormal left ventricular systolic function associated with coronary artery disease. Am J Cardi 1990,65:1257-12.59. 19. Cohn JN. Vasodilator therapy for heart failure: the influence of impedance on left ventricular performance. Circulation 1973;4-8%3. 20. Lakatta EG. Changes in cardiovascular function with aping. Eur Heart J 1990;11(suppl C):22-29. 21. Grossman W. Diastolic dysfunction and congestive heart failure. C&U/Qtin 1990,81(suppl Ill):l-7. 22. Kessler KK. Heart failure with nomnl systolic function. Arch Intern Med 1988;148:2109-2111. 23. Dougherty AM, Naccarelli GC, Gray EL, Hi& CH, Goldstein RA Congestive heart failure with normal systolic function. Am J Cardiol 1984,54:7X+ 782. 24. Harizi RC, Bianm JA, Alpert JS. Diastolic dysfunction and congestive heart failure in clinical cardiology. Arch Intern Med 1988;14899-109. 25. Giles TD, Katz R, Sullivan JM, Wolfson P, Haugland M, Kirlii P, Powers E, Rich S, Hackshaw B, Chiaramida A, Rouldeau JL, Fisher MB, Pigeon J, Rush JE. Short- and long-acting angiotensin-converting enzyme inhibitors: a randomized study of lisinopril versus captopril in the treatment of congestive heart failure. JAm CON Car&l 1989;13:124&1247. 26. Chattejee K, Parsley WW, Cohn JN, Levine TB, Awan NA, Mason DT, Faxon DP, Creager M, Gawas HP, Fouad FM, Tarti RC, Hollenberg NK, Dzau V, LeJemtel TH, Sonnenblick EH, Turini GA, Bnmner HR. A cooperative multicenter study of captopril in congestive heart failure: hemodynamic effects and long-term response. Am Heati J 1985;l 10(supp12):439-447. 27. Ader R, Chattejee K, Ports T, Ports T, Bnmdage B, Hiramatsu B, Parm!ey W. Immediate and sustained hemodynamic and clinical improvement
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skeletal muscle in patients with chronic heart failure. Inf J Cat&l 1988;18:187195. 35. Drexler H, Faude F, Hoing S, Just H. Blood flow distribution withii skeletal muscle during exercise in the presence of chronic heart failure: effect of mihinone. Circ&ion 1987;76:1344-1352. 36. Ades PA, Hanson JS, Gunther PGS, Tonino RP. Exercise conditioning in the elderly coronary patient. JAm Geriatr Sot 1987;35:121-128. 37. Hill JF, Bulpitt CJ, Fletcher AE. Angiotensin converting enzyme inhibitors and quality of life: the European trial. Jf&mtens 1985$S91-S94. 38. Gorkin L, NorveIl NK, Rosen RC, Charles E, Shumaker Sk McIntyre KM, Capone RJ, Kostis J, Niaura R, Woods P, Hoskiig J, Garces C, Handberg E, Ahem DK, Follick MJ for the SOLVD Investigators. Assessment of quality of life as observed from the baseline data of the Studies of Left Ventricular Dysfunction (SOLD) study quality-life substudy. Am J Cardiol 1993;71:1069-1073. 39. Packer M, Lee WH, Medina N, Yushak M, Kessler PD. Functional renal insufficiency during long-term therapy with captopril and enalapril in severe chronic heart failure. Am In&m Med 1987;106346-354.
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