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Enalapril as initial and sole treatment in severe chronic heart failure with sodium retention
International Elsevier
CARD10
341
Journal of Cardiology, 28 (1990) 341-346
01106
Enalapril as initial and sole treatment in severe chronic heart failure with sodium retention Inder S. Anand
‘, Gurcharan S. Kalra ‘, Roberto Ferrari *, Purshotam Peter C. Harris 3 and Philip A. Poole-Wilson 3
L. Wahi ‘,
’ Postgraduate Institute of Medical Education and Research, Chandigarh, India; ’ Chair of Cardiologv, Brescla, Ita!v; ’ National Heart and Lung Institute, (Received
24 November
1989; accepted
London, UK 21 March
1990)
Anand IS, Kalra GS, Ferrari R, Wahi PL, Harris PC, Poole-Wilson PA. Enalapril as initial and sole treatment in severe chronic heart failure with sodium retention. Int J Cardiol *1990:28:341-346. Five patients, who had never received any drug treatment hut who had severe chronic congestive heart failure with salt and water retention, were studied before and after a single dose of enalapril (10 mg orally). Three patients continued on enalapril as monotherapy (10 mg h.d. orally) for one month. Central haemodynamics, body fluid volumes, renal function and plasma hormones were measured at rest. The initial mean right atrial pressure was 13 f 4 mm Hg, pulmonary wedge pressure 29 f 4 mm Hg and cardiac index 1.8 f 0.2 I/min/m*. Enalapril, given acutely, caused only small changes. Two patients were withdrawn after the single dose of enalapril and treated with diuretics for clinical reasons. The remaining three patients each lost more than 4 kg in weight after one month of treatment with enalapril alone. Total body exchangeable sodium and total body water were reduced but central haemodynamics were unchanged. Although enalapril was of some benefit when given alone to patients with severe congestive heart failure, all five patients were finally treated with diuretics for clinical reasons. Enalapril is not recommended as the initial and only therapy for patients with severe congestive heart failure. Key words: Drug treatment;
Heart failure; Angiotensin-converting
Introduction Angiotensin-converting enzyme (ACE) inhibitors have been shown to improve the quality of life, increase exercise capacity [l] and reduce mortality [2] in patients with severe chronic heart
Correspondence to: Prof. Philip A. Poole-Wilson, Dept. of Cardiac Medicine, National Heart and Lung Institute, Dovehouse Street, London SW3 6LY, U.K. Supported by a grant from the British Heart Foundation.
0167-5273/90/$03.50
0 1990 Elsevier Science Publishers
enzyme (ACE) inhibitors
failure already treated with diuretics. ACE inhibitors are also widely prescribed for the treatment of hypertension. Their use in acute myocardial infarction, cardiogenic shock [3], post-myocardial infarction [4,5], in mild congestive heart failure [6] and to prevent the progression of left ventricular dysfunction without overt heart failure is more controversial and is being investigated. Some of the known effects of the inhibitors, particularly vasodilatation and inhibition of the renin angiotensin system, might be expected to be of benefit in patients with severe chronic heart
B.V. (Biomedical
Division)
342
failure and fluid overload. Other actions [6], such as effects on the kinin system, prostaglandin metabolism, the control of the cell growth, remodelling of the myocardium and actions on a tissue renin-angiotensin system, may also be important. Inhibition of angiotensin-converting enzyme is effective in the treatment of hypertension regardless of whether patients have an elevated blood renin activity. Likewise, in heart failure, the benefit of inhibition is not limited to those patients with a low resting plasma renin concentration [7,8]. In patients with moderate heart failure and limited fluid retention, plasma renin and aldosterone are not raised until patients are treated with diuretics [9,10], and ACE inhibitors alone are not sufficient therapy [ll]. In untreated patients with severe chronic heart failure elevation of plasma renin activity is variable, being considerably increased in some patients [12]. There are many reasons, therefore, why ACE inhibitors might be expected to be effective treatment in severe heart failure. This study was undertaken to determine whether an ACE inhibitor could be used with advantage as sole initial treatment in patients with severe chronic heart failure and fluid retention.
Methods Approval for the study was obtained hospital Ethical Committee. Written consent was obtained from all patients.
from the informed
Patients Five patients were admitted to the study. All were male, aged between 30 and 68 years. Heart failure had been present for between 6 and 12 months. The cause of heart failure assessed from the history, electrocardiogram and echocardiography was coronary artery disease in 1 and dilated cardiomyopathy in 4. The functional capacity of patients using the New York Heart Association classification was grade 4 in 4 patients and 2B in 1 patient. The venous pressure was raised by an average of 13 cm above the sternal angle. Three patients had ascites and peripheral oedema. All patients had an enlarged liver and crepitations were present in the lungs. The mean cardiothoracic
ratio was 0.68. No patient had cardiovascular drugs or diuretics.
received
any
Acute study Patients were admitted directly to the ward from the out-patient clinic. A Swan-Ganz catheter was inserted. Pressures were measured and related to the sternal angle. Cardiac output was measured by thermodilution, the value being the mean of three measurements. Systemic and pulmonary vascular resistance were calculated using standard formulae. Following 1 hour of rest, baseline measurements were made and the patients swallowed a tablet of enalapril (10 mg). Measurements were repeated at 4 and 6 hours. A light meal was allowed after the measurements at 4 hours. Body fluid volumes and renal function were measured using standard isotope dilution techniques [13]. All radioactive substances were obtained from Amersham International. The total dose of radiation for each subject was 2.6 mSv. Samples of blood were obtained for hormones after the patient had been resting in bed quietly for 30 minutes [14]. Plasma catecholamines were measured by high pressure liquid chromatography and all other hormones by radioimmunoassay. Chronic study Three patients were treated with enalapril 10 mg b.d. for a period of 1 month. After a week in hospital they were considered sufficiently well to return home and were studied again after 1 month. Statistics Results are expressed as mean + 1 SD. Where only 2 values were available only the mean has been given. Formal statistical analysis with a Student’s t-test was only performed where data were available on all 5 patients.
Results The baseline characteristics of the patients are shown in Table 1. Mean pulmonary wedge pressure was 29 + 4 mm Hg and cardiac index 1.8 k 0.2
343
l/min/m2. Plasma adrenaline was not raised. Plasma noradrenaline and atria1 natriuretic peptide were elevated in all patients. Renin activity and plasma aldosterone were raised in 1. Cortisol and growth hormone were raised in all and vasopressin in only 1. Plasma volume and extracellular volume were increased in all patients. Glomerular filtration rate and effective renal plasma flow were reduced. The total body exchangeable sodium and total body water were increased. These findings were compatible with the diagnosis of severe congestive heart failure and fluid overload [12].
TABLE
The acute effects of enalapril are shown in Table 1. Small falls were observed in pulmonary wedge pressure and mean aortic pressure at 4 hours. Cardiac index and stroke volume index rose. Two patients, treated acutely with enalapril, were judged to have responded insufficiently well to continue treatment with enalapril alone. They were withdrawn from the study and treated conventionally with diuretics (frusemide 40 mg b.d.). In these two patients weight fell by 7 and 6 kg over two months. Peripheral oedema, ascites and
1
Acute effects of enalaptil
(10 mg orally)
alone in patients
with severe chronic n
Initial
Heart rate (beats/mm) Right atria1 pressure (mm Hg) Mean pulmonary artery pressure (mm Hg) Mean pulmonary wedge pressure (mm Hg) Mean arterial pressure (mm Hg) Cardiac index (I/mm/m’) Stroke volume index (ml/m2) Pulmonary resistance index (dynes/s/cm-‘/m2) Systemic resistance index (dynes/s/cm-‘/m’)
5 5 5 5 5 5 5 5 5
104 13 43 29 99 1.8 18 709 3835
Adrenaline (pg/mf) Noradrenaline (pg/ml) Renin (ng/ml/h) Atria1 natriuretic peptide (pg/rnl) Cortisol (ng/ml) Growth hormone (ng/ml) Aldosterone (pg/ml) Vasopressin (pg/ml)
3 3 4 4 4 4 4 4
Extracellular volume (ml/kg) Plasma volume (ml/kg) Packed cell volume (%) Blood volume (ml/kg) Glomerular filtration rate (ml/min/1.73 m2) Effective renal plasma flow (ml/mm/l.73 m’) Total body exchangeable sodium (mmol/kg) Total body water (ml/kg) Body weight (kg) Sodium (mmol/l) Potassium (mmol/l) Urea (mg’dl) Creatinine (mg/dl) Haemoglobin (g/d])
4 4 4 2 4 4 4 4 5 5 5 5 5 5
heart
failure.
Mean f 1 SD. * P < 0.05.
4h
6h
f 18 f 4 f 7 + 4 f 13 i 0.2 + 4 *121 +400
101 12 41 26 94 2.2 24 553 3030
97 841 2.9 265 170 8+ 192 24
f 94 f381 + 6 i120 *loo 8 +340 + 20
110 + 45 1092 +603 4.5* 8 284 5166 170 * 40 10 + 2 153 +25 2 18 _+ 24
287 55 39 80 65 151 57 597 55 134 4.1 48 1.6 11.9
f f *
70 4.8 4
k i * + f * f f + +
26 60 12 60 8 4 0.6 14 0.4 1.6
* 13 + 4 & 9 + 7 + 20 * 0.2 * + 7* * 92 k288 *
104 k 16 13 + 4 39 * 11 26 F 7 99 * 18 1.9 f 0.2 19 f 2 568 & 94 3596 1208 Normal range 20 -130 160 -370 0.21.6 9 - 70 30 -130 0.21.0 25 -120 2 - 11 Normal values (mean f 1 SD) 227 513 43 + 3 46 + 1 62 + 7 99 f 3 479 119 45 i 2 536 +20 133 -145 3.55.0 15 -39 0.61.4 13 - 17
344
pulmonary oedema resolved. The other 3 patients were treated with enalapril(10 mg b.d. orally) and after 1 week were discharged from the hospital. They were readmitted after 1 month for reassessment. The findings in these patients are shown in Table 2. NYHA functional classification was judged to have improved by 1 class in each patient. All patients initially had pedal oedema which resolved in 1. Two patients had ascites and in 1 patient this resolved. Basal creps cleared in 1
TABLE Effects
patient. All patients lost more than 4 kg in weight. The mean pulmonary wedge pressure, right atria1 pressure and cardiac index did not change. The blood pressure was marginally reduced. There was a reduction in the pulmonary resistance index. Plasma hormones were unchanged apart from a small increase in plasma renin and a fall in plasma aldosterone. The patients showed a reduction in the extracellular volume, total body exchangeable sodium, total body water, and body weight. Effective renal plasma flow was unchanged and glomer-
2 of enalapril(10
mg b.d.) alone for 1 month
in patients
with severe chronic
heart
failure.
1 Month
Initial Heart rate (beats/mm) Right atrial pressure (mm Hg) Mean pulmonary artery pressure (mm Hg) Mean pulmonary wedge pressure (mm Hg) Mean arterial pressure (mm Hg) Cardiac index (l/min/m2) Stroke volume index (ml/m2) Pulmonary resistance index (dynes/s/cm-‘/m*) Systemic resistance index (dynes/s/cm-‘/m2) 3 3 3 3 3 3 3 2
Adrenaline (pg/ml) Noradrenaline (pg/ml) Renin (mg/ml/h) Atria1 natriuretic peptide (pg/ml) Cortisol (ng/ml) Growth hormone (ng/ml) Aldosterone (pg/ml) Vasopressin (pg/ml) Extracellular volume (ml/kg) Plasma volume (ml/kg) Packer cell volume (%) Blood volume (ml/kg) Glomerular filtration rate (ml/min/1.73 Effective renal plasma flow (ml/mm/l.73 Total body sodium (mmol/kg) Total body water (ml/kg) Weight (kg) Sodium (mmol/l) Potassium (mmol/l) Urea (mg/dl) Creatinine (mg/dl) Haemoglobin (g/dl)
m’) m2)
3 3 3 3 3
Mean + 1 SD.
99 14 47 31 107 1.9 20 640 3984
-, 21 + 2.8 + 7 f 2 + 10 f 0.2 + 5 +102 +112
93 14 39 30 106 1.9 21 396 3742
* 12 f 2 + 2 f 2.6 f 10 + 0.2 * 5 f185 +729
77 794 0.5 222 120 4.6 112 2.4
+ 42 +461 * 0.2 + 99 + 52 + 2 +147
63 515 0.8 94 120 10 43 2.2
* 16 k152 + 0.3 f 59 + 17 * 2 + 45
330 53 39 80
274 52 _ _
72 195 62 591 56
+ + +
61 204 53 529 51
137 4.4 36 1.6 11.1
* 7 + 0.3 f 17 + 0.3 + 1.2
16 52 10
* f f
136 + 4.3 + 42 + 1.3 + 11.2*
9 43 10 7 0.3 9 0.3 0.9
345
ular filtration rate had fallen. In view of the limited response to enalapril all patients were ultimately treated with diuretics. Discussion This paper does not report a controlled clinical trial with patients randomised to active treatment or placebo. Rather we describe our experience with enalapril, an angiotensin converting enzyme inhibitor, given as the initial and sole treatment to patients with severe chronic heart failure and fluid retention. A controlled and randomised trial was not considered appropriate in these ill patients until more information on the effects of enalapril was available. Having obtained that information it is our judgement that the results are not sufficiently encouraging to justify a formal trial. ACE inhibitors are widely used for the control of hypertension and the treatment of chronic congestive heart failure. The use of these agents in many other cardiovascular disorders [3-51 is currently under investigation. Severe chronic heart failure with sodium retention is currently treated with diuretics and in selected patients with digoxin. Nitrates and ACE inhibitors are often prescribed in addition. ACE inhibitors might be expected to be of value in chronic heart failure because of haemodynamic effects, renal actions, suppression of hormonal activation, and other effects on the kinin system, the prostaglandins, remodelling and the tissue renin-angiotensin system. The benefit of ACE inhibition is not well related to the initial plasma renin concentration [7,8]. The 5 patients investigated had severe chronic heart failure with the expected [12] haemodynamic changes, sodium and water retention, reduced renal blood flow and glomerular filtration rate. The initial dose of enalapril (10 mg) was high compared to the initial dose in recent large trials. Three patients were continued on treatment with enalapril (10 mg b.d. orally) alone for a period of 1 month. This is the dose currently recommended by the drug manufacturers. However after the initial treatment two patients we:: withdrawn from the study and at the end of one month the three remaining patients still had evidence ?f sodium and water retention and were begun on diuretics.
Thus, treatment with enalapril alone in these 5 patients was not sufficient to control sodium and water retention. The study was terminated because the investigators could not justify continuing with treatment which was less effective than conventional treatment and would not be shown to be advantageous unless very different results were found in all further patients. The angiotensin enzyme inhibitors bring about vasodilatation [15-171, sodium loss from the kidney provided blood pressure does not fall [15,16], and inhibit the formation of angiotensin II. In chronic heart failure treated with diuretics plasma renin activity, angiotensin II and aldosterone are often elevated. ACE inhibitors may act partly by counteracting the effects of these hormones. The elevation of plasma hormones is not due solely to heart failure but also to the treatment of heart failure with diuretics. In untreated mild heart failure plasma renin activity and aldosterone are not elevated [9,10] but increase when patients are treated with diuretics. In more severe heart failure the resting values of renin and angiotensin II are variable [12,18], plasma renin activity being increased in only 3 out of 8 patients [12]. In the present study plasma renin activity was increased in only one patient. The haemodynamic response and change in fluid compartments was not different in the single patient with a raised plasma renin activity from that in the other 4 patients. This suggests that the effects of ACE inhibition are not due solely to a reduction of plasma renin activity, a finding suggested by earlier reports [7,8]. Nevertheless it remains a possibility that part of the reason for a lack of response to enalapril was the low resting plasma renin activity. Many questions which arise from the findings in this study remain unresolved. Symptomatic improvement and weight loss was not accompanied by haemodynamic changes, indicating that symptoms are not directly related to resting haemodynamic measurements [19]. Weight loss was associated with a decrease of the extracellular volume but no change of haemodynamics and unimpressive changes in the plasma renin activity and aldosterone. The reasons for these observations are not clear but may relate to effects of ACE inhibitors other than an effect on the plasma
346
renin-angiotensin system. Another finding was a grossly elevated plasma growth hormone concentration approaching that found in acromegaly. This finding has been reported previously [12]. Some of the features of heart disease in acromegaly are similar to those found in chronic congestive heart failure [20]. An earlier study in mild heart failure has shown that in patients with a previous history of sodium and water retention captopril alone is not sufficient to prevent the recurrence of pulmonary oedema [ll]. The present findings show that enalapril given alone in patients with severe chronic heart failure has some effects which might be considered advantageous to patients. But the benefit is small and less than the response to diuretics. The use of ACE inhibitors alone as initial therapy in severe chronic heart failure is not recommended. References 1 The Captopril Multicentre Research Group. A placebo controlled trial of captopril in refractory chronic heart failure. J Am Co11 Cardiol 1983;2:755-763. 2 The CONSENSUS trial study group. Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N Engl J Med 1987;316:1429-1435. 3 Lipkin DP, Frenneaux M, Maseri A. Beneficial effect of captopril in cardiogenic shock. Lancet 1987;2:327. 4 Sharpe N, Murphy J, Smith H, Hannan S. Treatment of patients with symptomless left ventricular dysfunction after myocardial infarction. Lancet 1988;1:255-259. 5 Pfeffer MA, Lamas GA, Vaughan DE, Parisi AF, Braunwald E. Effect of captopril on progressive ventricular dilatation after anterior myocardial infarction. N Engl J Med 1988;319:80-86. 6 Williams GH. Converting enzyme inhibitors in the treatment of hypertension. N Engl J Med 1988;319:1517-1525. 7 Packer M, Medina N, Yushak M, Lee WH. Usefulness of plasma renin activity in predicting haemodynamic and clinical responses and survival during long term converting enzyme inhibition in severe chronic heart failure. Experi-
ence in 100 consecutive patients. Br Heart J 1985;54:298304. 8 Mettauer B, Rouleau J-L, Bichet D, et al. Differential long-term intrarenal and neurohumoral effects of captopril and prazosin in patients with congestive heart failure: importance of initial plasma renin activity. Circulation 1986;73:492-502. 9 Bayliss J, Norell M, Canepa-Anson R, Sutton G, PooleWilson P. Untreated heart failure: clinical and neuroendomine effects of introducing diuretics. Br Heart J 1987; 57~17-22. 10 Fyhrquist F, Tikkanen I. Atria1 natriuretic peptide in congestive heart failure. Am J Cardiol 1988;62:20A_24A. 11 Richardson A, Bayliss J, Striven AJ, Parameshwar J, Poole-Wilson PA, Sutton G. Double-blind comparison of captopril alone against frusemide plus amiloride in mild heart failure. Lancet 1987;2:709-711. 12 Anand IS, Ferrari R, Kalra GS, Wahi PL, Poole-Wilson PA, Harris PC. Edema of cardiac origin: studies of body water and sodium, renal function, hemodynamics and plasma hormones in untreated congestive heart failure. Circulation 1989;80:299-305. 13 Anand IS, Veal1 N, Kalra GS, et al. Treatment of heart failure with diuretics: body compartments, renal function and plasma hormones. Eur Heart J 1989;10:445-450. 14 Ferrari R, Ceconi C, Signorini C, Anand I, Harris P, Albertini A. Sample treatment for long-distance transport of plasma for hormone assay. Clin Chem 1989;35:331-332. 15 Dzau VJ, Colucci WS, Williams GH, Curfman G, Meggs L, Hollenberg NK. Sustained effectiveness of converting enzyme inhibition in patients with severe congestive heart failure. N Engl J Med 1980;302:1373-1379. 16 Creager MA, Halperin JL, Bernard DB, et al. Acute regional circulatory and renal hemodynamic effects of converting enzyme inhibition in patients with congestive heart failure. Circulation 1981;64:483-489. 17 Sharpe DN, Coxon RJ, Douglas JE, Long B. Low-dose captopril in chronic heart failure: acute haemodynamic effects and long-term treatment. Lancet 1980;2:1154-1157. 18 Brown JJ, Davies DL, Johnson VW, Lever AF, Robertson JIS. Renin relationships in congestive cardiac failure, treated and untreated. Am Heart J 1970;80:329-342. 19 Lipkin DP, Poole-Wilson PA. Symptoms limiting exercise in chronic heart failure. Br Med J 1986;292:1030-1031. 20 Rodrigues EA, Caruana MP. Lahiri A, Nabarro JDN, Jacobs HS, Raftery EB. Subclinical cardiac dysfunction in acromegaly: evidence for a specific disease of heart muscle. Br Heart J 1989;62:185-194.
CARD10
341
Journal of Cardiology, 28 (1990) 341-346
01106
Enalapril as initial and sole treatment in severe chronic heart failure with sodium retention Inder S. Anand
‘, Gurcharan S. Kalra ‘, Roberto Ferrari *, Purshotam Peter C. Harris 3 and Philip A. Poole-Wilson 3
L. Wahi ‘,
’ Postgraduate Institute of Medical Education and Research, Chandigarh, India; ’ Chair of Cardiologv, Brescla, Ita!v; ’ National Heart and Lung Institute, (Received
24 November
1989; accepted
London, UK 21 March
1990)
Anand IS, Kalra GS, Ferrari R, Wahi PL, Harris PC, Poole-Wilson PA. Enalapril as initial and sole treatment in severe chronic heart failure with sodium retention. Int J Cardiol *1990:28:341-346. Five patients, who had never received any drug treatment hut who had severe chronic congestive heart failure with salt and water retention, were studied before and after a single dose of enalapril (10 mg orally). Three patients continued on enalapril as monotherapy (10 mg h.d. orally) for one month. Central haemodynamics, body fluid volumes, renal function and plasma hormones were measured at rest. The initial mean right atrial pressure was 13 f 4 mm Hg, pulmonary wedge pressure 29 f 4 mm Hg and cardiac index 1.8 f 0.2 I/min/m*. Enalapril, given acutely, caused only small changes. Two patients were withdrawn after the single dose of enalapril and treated with diuretics for clinical reasons. The remaining three patients each lost more than 4 kg in weight after one month of treatment with enalapril alone. Total body exchangeable sodium and total body water were reduced but central haemodynamics were unchanged. Although enalapril was of some benefit when given alone to patients with severe congestive heart failure, all five patients were finally treated with diuretics for clinical reasons. Enalapril is not recommended as the initial and only therapy for patients with severe congestive heart failure. Key words: Drug treatment;
Heart failure; Angiotensin-converting
Introduction Angiotensin-converting enzyme (ACE) inhibitors have been shown to improve the quality of life, increase exercise capacity [l] and reduce mortality [2] in patients with severe chronic heart
Correspondence to: Prof. Philip A. Poole-Wilson, Dept. of Cardiac Medicine, National Heart and Lung Institute, Dovehouse Street, London SW3 6LY, U.K. Supported by a grant from the British Heart Foundation.
0167-5273/90/$03.50
0 1990 Elsevier Science Publishers
enzyme (ACE) inhibitors
failure already treated with diuretics. ACE inhibitors are also widely prescribed for the treatment of hypertension. Their use in acute myocardial infarction, cardiogenic shock [3], post-myocardial infarction [4,5], in mild congestive heart failure [6] and to prevent the progression of left ventricular dysfunction without overt heart failure is more controversial and is being investigated. Some of the known effects of the inhibitors, particularly vasodilatation and inhibition of the renin angiotensin system, might be expected to be of benefit in patients with severe chronic heart
B.V. (Biomedical
Division)
342
failure and fluid overload. Other actions [6], such as effects on the kinin system, prostaglandin metabolism, the control of the cell growth, remodelling of the myocardium and actions on a tissue renin-angiotensin system, may also be important. Inhibition of angiotensin-converting enzyme is effective in the treatment of hypertension regardless of whether patients have an elevated blood renin activity. Likewise, in heart failure, the benefit of inhibition is not limited to those patients with a low resting plasma renin concentration [7,8]. In patients with moderate heart failure and limited fluid retention, plasma renin and aldosterone are not raised until patients are treated with diuretics [9,10], and ACE inhibitors alone are not sufficient therapy [ll]. In untreated patients with severe chronic heart failure elevation of plasma renin activity is variable, being considerably increased in some patients [12]. There are many reasons, therefore, why ACE inhibitors might be expected to be effective treatment in severe heart failure. This study was undertaken to determine whether an ACE inhibitor could be used with advantage as sole initial treatment in patients with severe chronic heart failure and fluid retention.
Methods Approval for the study was obtained hospital Ethical Committee. Written consent was obtained from all patients.
from the informed
Patients Five patients were admitted to the study. All were male, aged between 30 and 68 years. Heart failure had been present for between 6 and 12 months. The cause of heart failure assessed from the history, electrocardiogram and echocardiography was coronary artery disease in 1 and dilated cardiomyopathy in 4. The functional capacity of patients using the New York Heart Association classification was grade 4 in 4 patients and 2B in 1 patient. The venous pressure was raised by an average of 13 cm above the sternal angle. Three patients had ascites and peripheral oedema. All patients had an enlarged liver and crepitations were present in the lungs. The mean cardiothoracic
ratio was 0.68. No patient had cardiovascular drugs or diuretics.
received
any
Acute study Patients were admitted directly to the ward from the out-patient clinic. A Swan-Ganz catheter was inserted. Pressures were measured and related to the sternal angle. Cardiac output was measured by thermodilution, the value being the mean of three measurements. Systemic and pulmonary vascular resistance were calculated using standard formulae. Following 1 hour of rest, baseline measurements were made and the patients swallowed a tablet of enalapril (10 mg). Measurements were repeated at 4 and 6 hours. A light meal was allowed after the measurements at 4 hours. Body fluid volumes and renal function were measured using standard isotope dilution techniques [13]. All radioactive substances were obtained from Amersham International. The total dose of radiation for each subject was 2.6 mSv. Samples of blood were obtained for hormones after the patient had been resting in bed quietly for 30 minutes [14]. Plasma catecholamines were measured by high pressure liquid chromatography and all other hormones by radioimmunoassay. Chronic study Three patients were treated with enalapril 10 mg b.d. for a period of 1 month. After a week in hospital they were considered sufficiently well to return home and were studied again after 1 month. Statistics Results are expressed as mean + 1 SD. Where only 2 values were available only the mean has been given. Formal statistical analysis with a Student’s t-test was only performed where data were available on all 5 patients.
Results The baseline characteristics of the patients are shown in Table 1. Mean pulmonary wedge pressure was 29 + 4 mm Hg and cardiac index 1.8 k 0.2
343
l/min/m2. Plasma adrenaline was not raised. Plasma noradrenaline and atria1 natriuretic peptide were elevated in all patients. Renin activity and plasma aldosterone were raised in 1. Cortisol and growth hormone were raised in all and vasopressin in only 1. Plasma volume and extracellular volume were increased in all patients. Glomerular filtration rate and effective renal plasma flow were reduced. The total body exchangeable sodium and total body water were increased. These findings were compatible with the diagnosis of severe congestive heart failure and fluid overload [12].
TABLE
The acute effects of enalapril are shown in Table 1. Small falls were observed in pulmonary wedge pressure and mean aortic pressure at 4 hours. Cardiac index and stroke volume index rose. Two patients, treated acutely with enalapril, were judged to have responded insufficiently well to continue treatment with enalapril alone. They were withdrawn from the study and treated conventionally with diuretics (frusemide 40 mg b.d.). In these two patients weight fell by 7 and 6 kg over two months. Peripheral oedema, ascites and
1
Acute effects of enalaptil
(10 mg orally)
alone in patients
with severe chronic n
Initial
Heart rate (beats/mm) Right atria1 pressure (mm Hg) Mean pulmonary artery pressure (mm Hg) Mean pulmonary wedge pressure (mm Hg) Mean arterial pressure (mm Hg) Cardiac index (I/mm/m’) Stroke volume index (ml/m2) Pulmonary resistance index (dynes/s/cm-‘/m2) Systemic resistance index (dynes/s/cm-‘/m’)
5 5 5 5 5 5 5 5 5
104 13 43 29 99 1.8 18 709 3835
Adrenaline (pg/mf) Noradrenaline (pg/ml) Renin (ng/ml/h) Atria1 natriuretic peptide (pg/rnl) Cortisol (ng/ml) Growth hormone (ng/ml) Aldosterone (pg/ml) Vasopressin (pg/ml)
3 3 4 4 4 4 4 4
Extracellular volume (ml/kg) Plasma volume (ml/kg) Packed cell volume (%) Blood volume (ml/kg) Glomerular filtration rate (ml/min/1.73 m2) Effective renal plasma flow (ml/mm/l.73 m’) Total body exchangeable sodium (mmol/kg) Total body water (ml/kg) Body weight (kg) Sodium (mmol/l) Potassium (mmol/l) Urea (mg’dl) Creatinine (mg/dl) Haemoglobin (g/d])
4 4 4 2 4 4 4 4 5 5 5 5 5 5
heart
failure.
Mean f 1 SD. * P < 0.05.
4h
6h
f 18 f 4 f 7 + 4 f 13 i 0.2 + 4 *121 +400
101 12 41 26 94 2.2 24 553 3030
97 841 2.9 265 170 8+ 192 24
f 94 f381 + 6 i120 *loo 8 +340 + 20
110 + 45 1092 +603 4.5* 8 284 5166 170 * 40 10 + 2 153 +25 2 18 _+ 24
287 55 39 80 65 151 57 597 55 134 4.1 48 1.6 11.9
f f *
70 4.8 4
k i * + f * f f + +
26 60 12 60 8 4 0.6 14 0.4 1.6
* 13 + 4 & 9 + 7 + 20 * 0.2 * + 7* * 92 k288 *
104 k 16 13 + 4 39 * 11 26 F 7 99 * 18 1.9 f 0.2 19 f 2 568 & 94 3596 1208 Normal range 20 -130 160 -370 0.21.6 9 - 70 30 -130 0.21.0 25 -120 2 - 11 Normal values (mean f 1 SD) 227 513 43 + 3 46 + 1 62 + 7 99 f 3 479 119 45 i 2 536 +20 133 -145 3.55.0 15 -39 0.61.4 13 - 17
344
pulmonary oedema resolved. The other 3 patients were treated with enalapril(10 mg b.d. orally) and after 1 week were discharged from the hospital. They were readmitted after 1 month for reassessment. The findings in these patients are shown in Table 2. NYHA functional classification was judged to have improved by 1 class in each patient. All patients initially had pedal oedema which resolved in 1. Two patients had ascites and in 1 patient this resolved. Basal creps cleared in 1
TABLE Effects
patient. All patients lost more than 4 kg in weight. The mean pulmonary wedge pressure, right atria1 pressure and cardiac index did not change. The blood pressure was marginally reduced. There was a reduction in the pulmonary resistance index. Plasma hormones were unchanged apart from a small increase in plasma renin and a fall in plasma aldosterone. The patients showed a reduction in the extracellular volume, total body exchangeable sodium, total body water, and body weight. Effective renal plasma flow was unchanged and glomer-
2 of enalapril(10
mg b.d.) alone for 1 month
in patients
with severe chronic
heart
failure.
1 Month
Initial Heart rate (beats/mm) Right atrial pressure (mm Hg) Mean pulmonary artery pressure (mm Hg) Mean pulmonary wedge pressure (mm Hg) Mean arterial pressure (mm Hg) Cardiac index (l/min/m2) Stroke volume index (ml/m2) Pulmonary resistance index (dynes/s/cm-‘/m*) Systemic resistance index (dynes/s/cm-‘/m2) 3 3 3 3 3 3 3 2
Adrenaline (pg/ml) Noradrenaline (pg/ml) Renin (mg/ml/h) Atria1 natriuretic peptide (pg/ml) Cortisol (ng/ml) Growth hormone (ng/ml) Aldosterone (pg/ml) Vasopressin (pg/ml) Extracellular volume (ml/kg) Plasma volume (ml/kg) Packer cell volume (%) Blood volume (ml/kg) Glomerular filtration rate (ml/min/1.73 Effective renal plasma flow (ml/mm/l.73 Total body sodium (mmol/kg) Total body water (ml/kg) Weight (kg) Sodium (mmol/l) Potassium (mmol/l) Urea (mg/dl) Creatinine (mg/dl) Haemoglobin (g/dl)
m’) m2)
3 3 3 3 3
Mean + 1 SD.
99 14 47 31 107 1.9 20 640 3984
-, 21 + 2.8 + 7 f 2 + 10 f 0.2 + 5 +102 +112
93 14 39 30 106 1.9 21 396 3742
* 12 f 2 + 2 f 2.6 f 10 + 0.2 * 5 f185 +729
77 794 0.5 222 120 4.6 112 2.4
+ 42 +461 * 0.2 + 99 + 52 + 2 +147
63 515 0.8 94 120 10 43 2.2
* 16 k152 + 0.3 f 59 + 17 * 2 + 45
330 53 39 80
274 52 _ _
72 195 62 591 56
+ + +
61 204 53 529 51
137 4.4 36 1.6 11.1
* 7 + 0.3 f 17 + 0.3 + 1.2
16 52 10
* f f
136 + 4.3 + 42 + 1.3 + 11.2*
9 43 10 7 0.3 9 0.3 0.9
345
ular filtration rate had fallen. In view of the limited response to enalapril all patients were ultimately treated with diuretics. Discussion This paper does not report a controlled clinical trial with patients randomised to active treatment or placebo. Rather we describe our experience with enalapril, an angiotensin converting enzyme inhibitor, given as the initial and sole treatment to patients with severe chronic heart failure and fluid retention. A controlled and randomised trial was not considered appropriate in these ill patients until more information on the effects of enalapril was available. Having obtained that information it is our judgement that the results are not sufficiently encouraging to justify a formal trial. ACE inhibitors are widely used for the control of hypertension and the treatment of chronic congestive heart failure. The use of these agents in many other cardiovascular disorders [3-51 is currently under investigation. Severe chronic heart failure with sodium retention is currently treated with diuretics and in selected patients with digoxin. Nitrates and ACE inhibitors are often prescribed in addition. ACE inhibitors might be expected to be of value in chronic heart failure because of haemodynamic effects, renal actions, suppression of hormonal activation, and other effects on the kinin system, the prostaglandins, remodelling and the tissue renin-angiotensin system. The benefit of ACE inhibition is not well related to the initial plasma renin concentration [7,8]. The 5 patients investigated had severe chronic heart failure with the expected [12] haemodynamic changes, sodium and water retention, reduced renal blood flow and glomerular filtration rate. The initial dose of enalapril (10 mg) was high compared to the initial dose in recent large trials. Three patients were continued on treatment with enalapril (10 mg b.d. orally) alone for a period of 1 month. This is the dose currently recommended by the drug manufacturers. However after the initial treatment two patients we:: withdrawn from the study and at the end of one month the three remaining patients still had evidence ?f sodium and water retention and were begun on diuretics.
Thus, treatment with enalapril alone in these 5 patients was not sufficient to control sodium and water retention. The study was terminated because the investigators could not justify continuing with treatment which was less effective than conventional treatment and would not be shown to be advantageous unless very different results were found in all further patients. The angiotensin enzyme inhibitors bring about vasodilatation [15-171, sodium loss from the kidney provided blood pressure does not fall [15,16], and inhibit the formation of angiotensin II. In chronic heart failure treated with diuretics plasma renin activity, angiotensin II and aldosterone are often elevated. ACE inhibitors may act partly by counteracting the effects of these hormones. The elevation of plasma hormones is not due solely to heart failure but also to the treatment of heart failure with diuretics. In untreated mild heart failure plasma renin activity and aldosterone are not elevated [9,10] but increase when patients are treated with diuretics. In more severe heart failure the resting values of renin and angiotensin II are variable [12,18], plasma renin activity being increased in only 3 out of 8 patients [12]. In the present study plasma renin activity was increased in only one patient. The haemodynamic response and change in fluid compartments was not different in the single patient with a raised plasma renin activity from that in the other 4 patients. This suggests that the effects of ACE inhibition are not due solely to a reduction of plasma renin activity, a finding suggested by earlier reports [7,8]. Nevertheless it remains a possibility that part of the reason for a lack of response to enalapril was the low resting plasma renin activity. Many questions which arise from the findings in this study remain unresolved. Symptomatic improvement and weight loss was not accompanied by haemodynamic changes, indicating that symptoms are not directly related to resting haemodynamic measurements [19]. Weight loss was associated with a decrease of the extracellular volume but no change of haemodynamics and unimpressive changes in the plasma renin activity and aldosterone. The reasons for these observations are not clear but may relate to effects of ACE inhibitors other than an effect on the plasma
346
renin-angiotensin system. Another finding was a grossly elevated plasma growth hormone concentration approaching that found in acromegaly. This finding has been reported previously [12]. Some of the features of heart disease in acromegaly are similar to those found in chronic congestive heart failure [20]. An earlier study in mild heart failure has shown that in patients with a previous history of sodium and water retention captopril alone is not sufficient to prevent the recurrence of pulmonary oedema [ll]. The present findings show that enalapril given alone in patients with severe chronic heart failure has some effects which might be considered advantageous to patients. But the benefit is small and less than the response to diuretics. The use of ACE inhibitors alone as initial therapy in severe chronic heart failure is not recommended. References 1 The Captopril Multicentre Research Group. A placebo controlled trial of captopril in refractory chronic heart failure. J Am Co11 Cardiol 1983;2:755-763. 2 The CONSENSUS trial study group. Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N Engl J Med 1987;316:1429-1435. 3 Lipkin DP, Frenneaux M, Maseri A. Beneficial effect of captopril in cardiogenic shock. Lancet 1987;2:327. 4 Sharpe N, Murphy J, Smith H, Hannan S. Treatment of patients with symptomless left ventricular dysfunction after myocardial infarction. Lancet 1988;1:255-259. 5 Pfeffer MA, Lamas GA, Vaughan DE, Parisi AF, Braunwald E. Effect of captopril on progressive ventricular dilatation after anterior myocardial infarction. N Engl J Med 1988;319:80-86. 6 Williams GH. Converting enzyme inhibitors in the treatment of hypertension. N Engl J Med 1988;319:1517-1525. 7 Packer M, Medina N, Yushak M, Lee WH. Usefulness of plasma renin activity in predicting haemodynamic and clinical responses and survival during long term converting enzyme inhibition in severe chronic heart failure. Experi-
ence in 100 consecutive patients. Br Heart J 1985;54:298304. 8 Mettauer B, Rouleau J-L, Bichet D, et al. Differential long-term intrarenal and neurohumoral effects of captopril and prazosin in patients with congestive heart failure: importance of initial plasma renin activity. Circulation 1986;73:492-502. 9 Bayliss J, Norell M, Canepa-Anson R, Sutton G, PooleWilson P. Untreated heart failure: clinical and neuroendomine effects of introducing diuretics. Br Heart J 1987; 57~17-22. 10 Fyhrquist F, Tikkanen I. Atria1 natriuretic peptide in congestive heart failure. Am J Cardiol 1988;62:20A_24A. 11 Richardson A, Bayliss J, Striven AJ, Parameshwar J, Poole-Wilson PA, Sutton G. Double-blind comparison of captopril alone against frusemide plus amiloride in mild heart failure. Lancet 1987;2:709-711. 12 Anand IS, Ferrari R, Kalra GS, Wahi PL, Poole-Wilson PA, Harris PC. Edema of cardiac origin: studies of body water and sodium, renal function, hemodynamics and plasma hormones in untreated congestive heart failure. Circulation 1989;80:299-305. 13 Anand IS, Veal1 N, Kalra GS, et al. Treatment of heart failure with diuretics: body compartments, renal function and plasma hormones. Eur Heart J 1989;10:445-450. 14 Ferrari R, Ceconi C, Signorini C, Anand I, Harris P, Albertini A. Sample treatment for long-distance transport of plasma for hormone assay. Clin Chem 1989;35:331-332. 15 Dzau VJ, Colucci WS, Williams GH, Curfman G, Meggs L, Hollenberg NK. Sustained effectiveness of converting enzyme inhibition in patients with severe congestive heart failure. N Engl J Med 1980;302:1373-1379. 16 Creager MA, Halperin JL, Bernard DB, et al. Acute regional circulatory and renal hemodynamic effects of converting enzyme inhibition in patients with congestive heart failure. Circulation 1981;64:483-489. 17 Sharpe DN, Coxon RJ, Douglas JE, Long B. Low-dose captopril in chronic heart failure: acute haemodynamic effects and long-term treatment. Lancet 1980;2:1154-1157. 18 Brown JJ, Davies DL, Johnson VW, Lever AF, Robertson JIS. Renin relationships in congestive cardiac failure, treated and untreated. Am Heart J 1970;80:329-342. 19 Lipkin DP, Poole-Wilson PA. Symptoms limiting exercise in chronic heart failure. Br Med J 1986;292:1030-1031. 20 Rodrigues EA, Caruana MP. Lahiri A, Nabarro JDN, Jacobs HS, Raftery EB. Subclinical cardiac dysfunction in acromegaly: evidence for a specific disease of heart muscle. Br Heart J 1989;62:185-194.