International Elsevier
CARD10
55
Journal of Cardiology, 29 (1990) 55-61
11206
Sustained beneficial effects of enalapril in Africans with congestive heart failure A.A. Ajayi and M.O. Balogun Departmeni
of Medicine,Faculty of Health Sciences, Obajemi Awolowo University, Ile-Ije, Nigeria (Received 16 November 1989; revision accepted 24 April 1990)
Ajayi AA, Balogun MO. Sustained beneficial effects of enalapril in Africans with congestive heart failure. Int J Cardiol 1990;29:55-61. A single blind, placebo controlled, dose-ranging 3 month study of the effects of enalapril on cardiovascu-
lar parameters, clinical status and self-paced exercise capacity was undertaken in 12 Nigerians with chronic heart failure. Enalapril exerted only a modest reduction in blood pressure and heart rate but significantly improved functional capacity (P < O.Ol), and prolonged self-paced exercise thne (P < 0.05) compared to the placebo baseline. The pressure rate product and the double product corrected for exercise time, an index of myocardial oxygen demand, exhibited a significant and sustained reduction on enalapril treatment (P -z0.01). Concentration of sodium in the serum was significantly increased (P < 0.05)but concentrations of potassium and creatinine were unaltered. These results demonstrate the sustained efficacy of enalapril in black Africans with heart failure and indicate no important racial difference in the response to inhibition of angiotensin converting enzyme in congestive heart failure.
Key words: Congestive heart failure; Africans; Enalapril; Self-paced walk test; ACE inhibition
Introduction
Inhibitors of angiotensin converting enzyme are of established value as balanced vasodilators in the therapy of congestive heart failure [l]. Recently, in the Cooperative Northern Scandinavian Enalapril Survival Study [2], enalapril was shown to exert beneficial amelioration of symptoms and to reduce mortality in severe congestive heart failure. The pharmacodynamic effects and the clinical response to converting enzyme inhibition, however, may be dependent on plasma renin activ-
Correspondence to: A.A. Ajayi, M.B., Ph.D., FWACP., Dept. of Medicine, Obafemi Awolowo University, Ile-Ife, Nigeria.
0167~5273/90/$03.50
ity [3], which exhibits interracial differences, and is low in people of African descent [4,5]. There remain, therefore, important unanswered questions regarding the worldwide clinical utility of inhibitors of angiotensin converting enzyme in cardiovascular disease, especially in populations with epidemiologically low renin profile. For example, a poor antihy-pertensive efficacy of enalapril monotherapy has been reported both in North American [6] and African [7,8] black patients with essential hypertension. Compensatory neurohumoral mechanisms in heart failure and concurrent diuretic therapy may, however, in concert, cause activation of the Renin-angiotensin-aldosterone system [9] and render Africans more responsive to inhibition of the converting enzyme.
0 1990 Elsevier Science Publishers B.V. (Biomedical Division)
56
Consistent with this concept is our preliminary finding, in a short term double blind study, of salutary treadmill and clinical effects of enalapril in heart failure in Nigerians [lo]. The aim of the present investigation was to examine the longer term consequence of treatment with enalapril on clinical status, cardiovascular parameters, exercise tolerance, renal and metabolic status in Nigerians with chronic congestive heart failure.
Materials and Methods After informed consent and prior ethical approval, 12 Nigerians with chronic congestive heart failure were entered into a single blind, placebo controlled, dose-ranging study for 3 months. Criteria for inclusion were Nigerians with symptoms of heart failure for more than 3 months, stabilised on digoxin and diuretics. Exclusion criteria were significant hepatic or renal impairment (serum creatinine > 200 pm01 . l-l), Cor pulmonale, or other non-cardiac causes of limitation of exercise. The patients were aged 17-65 years with New York Heart Association functional capacity ranging from IIb-IV. The duration of heart failure ranged from 3 months to 10 years. The baseline clinical and demographic data of the patients completing the study are shown in Table 1. The volunteers were admitted to the wards and received a placebo tablet (identical in appearance to active enalapril tablets) for 2 weeks in conjunction with their conventional treatment. After this initial placebo run-in phase, the patients received active enalapril tablets, 2.5 mg . day-’ for 1 month, with incremental dose titration to 5 mg . day-’ for another month and if indicated to 10 mg . day-’ or left unchanged for yet another month. The patients were studied after the placebo run-in phase and thereafter at 1, 2, 3 months of enalapril treatment on out-patient basis. Baseline investigations prior to the study included a 1Zlead electrocardiogram, chest X-ray, serum biochemistry, 24 hour urine collection for creatinine clearance, and M-mode echocardiography using an ultrasonoscope (Picker LSC 7000) utilising a Cambridge 2.25 mHz transducer. Exercise capacity was assessed using a symptom
TABLE 1 Baseline clinical and demographic data of the heart failure patients who completed the study (n = 9 mean + SD). Parameter Age (years) Sex (M/F) We@ (Kg) Self-paced exercise time (set) New York Heart Association class Cardiothoracic ratio Creatinine clearance (ml.min-‘) Echocardiographic indices Left ventricular diastolic size (mm) Left ventricular systolic size (mm) Fractional fibre shortening (W) Velocity of circumferential fibre shortening (Circ.sec-‘) Cause of heart disease Hypertension Valvar lesion Cardiomyopathy
47
*19
4/5 51 + 16 299 +181 2.57+ 0.53 0.73* 0.12 42 +19 65 54 17 0X2*
+ + +
5 6 7 0.4
4 2 3
limited self-paced corridor walk test [ll-131. Patients were required to walk to and fro along a 30 m corridor at our Electrodiagnostic Unit, at a self selected ‘normal’ pace, which was comfortable and neither fast nor slow. The patients maintained this walking pace until they experienced symptoms of dyspnea, fatigue, dizziness, palpitations, or leg cramps. Erect blood pressure and heart rate were measured by manual sphygmomanometry and cardiac auscultation, before and immediately after the termination of the self-paced walk test by the same observer throughout. The total exercise duration was noted using a stop clock. Throughout the study period, the doses of digoxin and diuretics were held constant. Compliance with enalapril treatment was assessed by counting of pills and by direct questioning for recall of drug intake during each clinic attendance. Adverse effects were evaluated by spontaneous reports or direct questioning and by the response to a standard symptom checklist administered at each outpatient visit.
Statistical Analysis Data are expressed as means f standard deviation. Effect of enalapril treatment was compared
to the placebo baseline value using paired t-tests or by repeated measures analysis of variance utilising a STATVIEW 512 statistical package on a Macintosh Plus Apple Microcomputer. The results were considered significant at P -C0.05.
modest hypotensive action was associated with unchanged heart rate after enalapril. Erect heart rate placebo run in was 100 f 24 beats mirC1, there was a slight fall in heart rate (see Fig. 1) but this was not significant (F = 0.87 not significant).
Results
Clinical status and New York Heart Association functional class
Twelve patients were recruited but only 9 completed the study protocol. Two patients missed their first month appointment and were lost to follow-up. One patient (functional class IV, a 20year-old woman) died of progressive heart failure after 2 weeks of treatment whilst in hospital. Blood pressure and heart rate
Enalapril caused a modest reduction in erect mean blood pressure. Mean blood pressure after the placebo run in was 86 + 21 mm Hg and this was not significantly affected by enalapril treatment (F = 1.42not significant), see Fig. 1. This
Enalapril therapy caused a significant improvement in New York Heart Association Functional capacity (F = 26.2, P < 0.001 ANOVA). Baseline functional class was 2.57 f 0.53, and was 1.86 _t 0.90, 1.57 f 0.53, and 1.57 f 0.53 at 1, 2, and 3 months, respectively (see Fig. 2). The mean weight increased from 51 f 16 kg to 55 k 13 kg (P -c0.05) without increased peripheral edema (see Fig. 3). All patients experienced improved subjective wellbeing. Two patients exhibited reductions in left ventricular systolic size and increased fractional shortening on echocardiography after 3 months of enalapril. Self-paced exercise capacity
r
T
2
1
0 TIME
3
(MONTHS)
Fig. 1. Mean erect blood pressure and erect heart rate, before ( 0) and after (0) enalapril treatment in Nigerians with chronic congestive heart failure. n = 9 mean + SD.
There was a significant and sustained increase in the symptom limited self-paced exercise time following enalapril (F = 3.4, P -e0.05), see Fig. 2. This was associated with a diminished subjective perception of exercise effort. Baseline exercise time increased from 299 &-181 set to 466 f 395 set at 1 months, 557 f 243 set at 2 months, and 573 f 308 set at 3 months. The 95% confidence interval for the difference in exercise time between the placebo baseline and the end of the study was from 182 set to 366 sec. This prolongation of exercise time was unaccompanied by a significant change in the self-paced walking speed, which was 3.2 rf: 0.8 km . h-’ after placebo, and 3.3 + 0.7, 3.5 f 0.9, and 3.3 &-0.9 km. h-t at 1, 2, and 3 months, respectively (F = 0.96, not significant). The pressure rate product (mm Hg beats. rnin-’ X 102) showed a significant and progressive decline with enalapril therapy. (F = 5.71, P = 0.006). At baseline, the double product was 146 t_ 23 and corresponding values after 1, 2, and 3 months of enalapril were 119 f 28, 118 + 19, 105 k 21 mm Hg beats mm’, respectively. The ratio
l-‘and 116 f 36 pmol . l-l, respectively. Serum bicarbonate was 26 f 4 mm01 - 1-l after enalapril therapy. The 24 hour creatinine clearance, at 3 months, could not be accurately determined owing to unreliable urine collection by the subjects on out-patient basis.
ir&/Azy 3-
A_
Dose-response
relationships
The optimal dose requirement of enalapril was 5 mg- day-’ in eight patients and 10 mg - day-’ in one. Five mg * day- ’ consistently exhibited superior efficacy compared to 2.5 mg . day-‘. In one patient, functional class IV, enalapril dose was reduced to 1.25 mg . day-’ owing to acute reversible renal insufficiency. Adverse reaction profile TIME
(MONTHS)
z
Fig. 2. The effect of enalapril treatment on NYHA functional capacity and on self paced exercise time and pressure rate product corrected for exercise time in Nigerians with heart failure. Enalapril significantly improved the parameters relative to placebo baseline (repeated measures ANOVA) n = 9 mean f SD. * P < 0.01 compared to placebo baseline value.
of the double product to exercise time (mm Hg beats min-’ - set-’ ) and indicator of myocardial oxygen demand per unit time, showed a significant and steady reduction with enalapril treatment (F = 4.56, P = 0.015), see Fig. 2. The values were: 70 + 48 after placebo, and 43 + 28, 27 f 17, and 27 f 21 mm Hg beats min-’ . set-’ at 1, 2, and 3 months, respectively. The 95% confidence interval for the difference in the double product/exercise time ratio, between the placebo baseline and after 3 months of enalapril treatment, was from 29.5 mm Hg beats min-’ . set-’ to 56.5 mm Hg beats mm-’ . see-‘. Biochemical
The enalapril regimen was generally tolerated. There was no episode of “first
well dose
+
20-F 14Or
+
16Or
and renal status
The effects of enalapril on biochemical parameters are shown in Fig. 3. Concentration of sodium in the serum rose significantly from 129 f 5 mm01 . 1-l to 135 f 3 mm01 . 1-l at 3 months (P -c 0.01). Serum potassium (3.64 mmol. 1-l) and serum creatinine (124 A-25 pm01 .1-l) before, were unchanged after 3 months, being 3.93 + 0.4 mm01 -
--
0 TIME
3 (MONTHS)
Fig. 3. The biochemical effects of enalapril treatment in Nigerian patients witb congestive heart failure. n = 9 mean* SD. * P -z0.01 compared to placebo baseline value.
59
syncope”, although 2 patients had asymptomatic hypotension (systolic blood pressure -C90 mm Hg). One patient (function class IV), developed acute reversible renal insufficiency, after one week of enalapril dosing but subsequently died of progressive heart failure. One patient with endomyocardial fibrosis developed blisters on the palms and soles and another experienced transient pruritus. There were no haematological or biochemical abnormalities on post-study check. Discussion We have evaluated the long-term effects of enalapril in Nigerians with congestive heart failure. The findings of a significant and sustained improvement in clinical status, New York Heart Association functional capacity and self-paced exercise tolerance confirms and extends our earlier, short-term observation [lo]. It is likely that this beneficial consequence of inhibition of angiotensin converting enzyme is related to the activation of plasma and tissue renin-angiotensin-aldosterone system in heart failure [9]. Both the choice of our study design, and the possibility of a type II error, deserve comment. As we have previously reported the improvement in exercise capacity and salutary clinical effects produced by enalapril in a double blind, placebo controlled, short-term study [lo], the principal aim of the present investigation was the evaluation of the long-term consequence of inhibition of converting enzyme on heart failure in Nigerians. Further, the profound symptomatic subjective amelioration with enalapril in our earlier study posed practical and ethical problems in the placebo blinding of the present follow-up. It is possible that a double blind protocol could have yielded a stronger basis for the validity of our findings. Moreover, the patient population, and the drop-out rate may have limited the power of the study, which is of the order of 48% at the 5% a-level. Nonetheless, the employment of a conservative repeated measures analysis of variance, as well as the quoted confidence intervals for the difference between placebo baseline and the enalapril induced effects, indicates the internal validity of the results.
In the present study, a symptom-limited, selfpaced, walking protocol was employed. The measurement of symptomatic amelioration in heart failure patients is problematic 1131 and it is unlikely that any one method accurately reflects all aspects of symptomatic response to treatment [13]. Maximal treadmill testing in heart failure is unlikely to reflect ideally all the composites of patient status, since patients do not repeatedly exercise to their symptomatic maximum during their daily living activities [13]. The self-paced corridor walk test [ll-131 is based on the familiar daily activity of walking. Since the subjects selected their own pace of walking, it may represent a more physiological evaluation of cardiovascular status, and permit a better appraisal of the improvement that the patients are likely to experience during their daily activities [13]. Furthermore, the self-paced walk test is less likely than the treadmill test to be influenced by a ‘training effect’ consequent upon repeated measurements. It has also been shown to be highly reproducible [l&12]. Enalapril, thus, increased a physiologically relevant, self-paced exercise time and enhanced work capacity at low levels of exercise. This prolongation in exercise time was associated with unchanged walking speed, indicating that the increase in exercise time induced by enalapril was not a consequence of reduced walking speed or exertion. The pressure rate product, and the pressure rate product corrected for exercise time, exhibited a sustained reduction with enalapril treatment. The double product is an index of myocardial oxygen demand, and a fall in this parameter reflects a diminution in myocardial oxygen requirement per unit time. This salutary effect of inhibition of angiotensin converting enzyme on myocardial energy consumption has been reported previously [14,15] and it may be related to reduced exercise blood pressure and heart rate as well as to a direct effect on an endogenous cardiac renin angiotensin aldosterone system [16]. This is also concordant with a suggested cardioprotective effect of inhibitors of the converting enzyme [16]. The modest hypotensive action of enalapril was unassociated with a reflex tachycardia, which is consistent with previous experience [17]. Biochemically, concentrations of both potassium and
60
creatinine in the serum were unchanged, so that converting enzyme inhibition did not significantly impair renal function but mitigated diuretic-induced hypokalemia [18]. Serum sodium was, however, significantly increased. Several studies have reported that inhibition of angiotensin converting enzyme with both enalapril and captopril reversed hyponatremia in severe congestive heart failure [19], possibly reflecting converting enzyme inhibition-induced suppression of arginine-vasopressin levels [20]. An interesting observation was the enalapril-induced significant, oedema-free weight gain. Whether this represents a reversal of ‘cardiac cachexia’ is unclear. The adverse effects of enalapril included the occurrence of acute reversible renal insufficiency [21] during low reual perfusion. One patient experienced blisters on the palms and soles and another had transient pruritus [22] in a patient with severe heart failure (Functional class IV). This is indicative of the loss of postglomerular efferent arteriolar vasoconstriction mediated by angiotensin II [21] during low renal perfusion. One patient experienced plisters on the palms and soles, and another ,had transient pruritus [22] but whether these are related to an alteration in kinin metabolism [23] is unclear. Thus, long term inhibition of angiotensin converting enzyme with enalapril in Africans with congestive heart failure on conventional therapy elicited satisfactory tolerance, caused sustained amelioration in clinical status, exercise tolerance and myocardial energetics while preserving renal function. These findings are largely in accord with results of inhibition of angiotensin converting enzyme in heart failure in Caucasians. There is, thus, no suggestion of important racial differences in the response to inhibition of converting enzyme in patients with congestive heart failure. Acknowledgements We would like to express our immense indebtedness to Miss Debbie Burrows, Merck Sharp & Dohme, Hoddesden Herefordshire, U.K. and thank M.S.D. (U.K.) for the supply of enalapril and placebo tablets. We thank Dr. J.A. Balogun for statistical advice, and Mrs. F.M. Adesida for typing the manuscript.
References
7
8
9
10
11
12
13
14 15
16
17
Edward CR, Padfield, PL. Angiotensin converting enzyme inhibitors: past present and bright future. Lancet 1985;i:30-34. CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure. N Engl J Med 1987;316:1429-1425. Case DB, Wallace JM, Kiem HJ, Sealey JE, Laragh, JH. Possible role of renin in hypertension as suggested by renin-sodium profiling and inhibition of converting enzyme. N Engl J Med 1977;296:640-646. Sever PS. Racial differences in blood pressure: genetic and environmental factors. Postgrad Med J 1981:57,755-759. Osotimehin B, Erasmus RT, Iyun AO, Falase AO, Ahmad Z. Plasma renin activity and plasma aldosterone concentration in untreated Nigerians with essential hypertension. Afr J Med Med Sci 1984;13:139-143. Freier P, Wollam GL, Hall D, Unger DJ, Douglas MB, Bain, RP. Blood pressure, plasma volume and catecholamine levels during enalapril therapy in blacks with hypertension. Clin Pharmacol Ther 1984;36:731-737. Goodman C, Rosendorff C, Coull A. Comparison of the antihypertensive effect of enalapril and propranolol in black South Africans. S Afr Med J 1985;87:672-767. Ajayi AA, Oyewo EA, Ladipo GOA, Akinsola A. Enalapril and hydrochlorothiazide in hypertensive Africans. Eur J Clin Pharmacol1989;36:229-234. Nicholls MG, Espiner EA, Donald RA, Hughes H. Aldosterone and its regulation during diuresis in patients with gross congestive heart failure. Clin Sci Mol Med 1974;47:301-315. Ajayi AA, Balogun MO, Oyewo EA, Ladipo GOA. Enalapril in African patients with congestive cardiac failure. Br J Clin Pharmacol 1989;27:400-403. Bassey EJ, Fentem PH, Macdonal K, Striven PM. Self paced walking as a method for exercise testing in elderly and young men. Clin Sci Mol Med 1976;51:609-612. Bassey EJ, Mcdonald IA, Patrick JM. Factors affecting heart rate during self paced walking. Eur J Appl Physiol 1982;48:105-115. Cowley AJ, Stainer K, Wynne RD, Rowley JM, Hamptor JR. Symptomatic assessment of patients with heart failure: double blind comparison of increasing doses of diuretics and captopril in moderate heart failure. Lancet 1986; ii:770-772. Gomez HJ, Cirillo VJ, Jones KH. The clinical pharmacology of enalapril. J Hypertens 1983; l(supp1 1): 65-70. Davies RO, Gomez HJ, Inin JO, Walker JF. An overview of the clinical pharmacology of enalapril. Br J Clin Pharmacol 1984;18:215s-241s. Lindpaintner K, Jin M, Wilhelm M, Toth M, Ganten D. Aspects of molecular biology and biochemistry of the cardiac renin angiotensin system. Br J Clin Pharmacol 1989;27:159s-165s. Ajayi AA, Campbell BC, Howie CA, Reid JL. Acute and chronic effects of converting enzyme inhibitors, enalapril and lisinopril, on reflex control of heart rate in normotensive man. J Hypertens 1985;3:47-53.
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18 Weinberger MH. Influence of an angiotensin converting enzyme inhibitor on diuretic induced metabolic effects in hypertension. Hypertension 1983;193:132-138. 19 Editorial. Angiotensin converting enzyme inhibitors in treatment of heart failure. Lancet 1985;ii:811-812. 20 Goldsmith SR, Francis GS, Cowley AW, Levine TB, Cohn, JN. Increased plasma arginine vasopressin levels in patients with congestive heart failure. J Am Co11 Cardiol 1983;1:1385-1389. 21 Hricik DE, Browning PJ, Kopelman R, Madias NE, Dzau
VJ. Captopril induced functional renal insufficiency in patients with bilateral renal artery stenoses or renal artery stenosis in a solitary kidney. N Engl J Med 1983;308:373376. 22 Goodfield, MJ, Millard LG. Severe cutaneous reactions to captopril. Ann Intern Med 1984;100:616. 23 Mimram A, Targhetta R, Laroche. The antihypertensive effect of captopril: evidence for an influence of kinins. Hypertension 1980;2:732-737.
CARD10
55
Journal of Cardiology, 29 (1990) 55-61
11206
Sustained beneficial effects of enalapril in Africans with congestive heart failure A.A. Ajayi and M.O. Balogun Departmeni
of Medicine,Faculty of Health Sciences, Obajemi Awolowo University, Ile-Ije, Nigeria (Received 16 November 1989; revision accepted 24 April 1990)
Ajayi AA, Balogun MO. Sustained beneficial effects of enalapril in Africans with congestive heart failure. Int J Cardiol 1990;29:55-61. A single blind, placebo controlled, dose-ranging 3 month study of the effects of enalapril on cardiovascu-
lar parameters, clinical status and self-paced exercise capacity was undertaken in 12 Nigerians with chronic heart failure. Enalapril exerted only a modest reduction in blood pressure and heart rate but significantly improved functional capacity (P < O.Ol), and prolonged self-paced exercise thne (P < 0.05) compared to the placebo baseline. The pressure rate product and the double product corrected for exercise time, an index of myocardial oxygen demand, exhibited a significant and sustained reduction on enalapril treatment (P -z0.01). Concentration of sodium in the serum was significantly increased (P < 0.05)but concentrations of potassium and creatinine were unaltered. These results demonstrate the sustained efficacy of enalapril in black Africans with heart failure and indicate no important racial difference in the response to inhibition of angiotensin converting enzyme in congestive heart failure.
Key words: Congestive heart failure; Africans; Enalapril; Self-paced walk test; ACE inhibition
Introduction
Inhibitors of angiotensin converting enzyme are of established value as balanced vasodilators in the therapy of congestive heart failure [l]. Recently, in the Cooperative Northern Scandinavian Enalapril Survival Study [2], enalapril was shown to exert beneficial amelioration of symptoms and to reduce mortality in severe congestive heart failure. The pharmacodynamic effects and the clinical response to converting enzyme inhibition, however, may be dependent on plasma renin activ-
Correspondence to: A.A. Ajayi, M.B., Ph.D., FWACP., Dept. of Medicine, Obafemi Awolowo University, Ile-Ife, Nigeria.
0167~5273/90/$03.50
ity [3], which exhibits interracial differences, and is low in people of African descent [4,5]. There remain, therefore, important unanswered questions regarding the worldwide clinical utility of inhibitors of angiotensin converting enzyme in cardiovascular disease, especially in populations with epidemiologically low renin profile. For example, a poor antihy-pertensive efficacy of enalapril monotherapy has been reported both in North American [6] and African [7,8] black patients with essential hypertension. Compensatory neurohumoral mechanisms in heart failure and concurrent diuretic therapy may, however, in concert, cause activation of the Renin-angiotensin-aldosterone system [9] and render Africans more responsive to inhibition of the converting enzyme.
0 1990 Elsevier Science Publishers B.V. (Biomedical Division)
56
Consistent with this concept is our preliminary finding, in a short term double blind study, of salutary treadmill and clinical effects of enalapril in heart failure in Nigerians [lo]. The aim of the present investigation was to examine the longer term consequence of treatment with enalapril on clinical status, cardiovascular parameters, exercise tolerance, renal and metabolic status in Nigerians with chronic congestive heart failure.
Materials and Methods After informed consent and prior ethical approval, 12 Nigerians with chronic congestive heart failure were entered into a single blind, placebo controlled, dose-ranging study for 3 months. Criteria for inclusion were Nigerians with symptoms of heart failure for more than 3 months, stabilised on digoxin and diuretics. Exclusion criteria were significant hepatic or renal impairment (serum creatinine > 200 pm01 . l-l), Cor pulmonale, or other non-cardiac causes of limitation of exercise. The patients were aged 17-65 years with New York Heart Association functional capacity ranging from IIb-IV. The duration of heart failure ranged from 3 months to 10 years. The baseline clinical and demographic data of the patients completing the study are shown in Table 1. The volunteers were admitted to the wards and received a placebo tablet (identical in appearance to active enalapril tablets) for 2 weeks in conjunction with their conventional treatment. After this initial placebo run-in phase, the patients received active enalapril tablets, 2.5 mg . day-’ for 1 month, with incremental dose titration to 5 mg . day-’ for another month and if indicated to 10 mg . day-’ or left unchanged for yet another month. The patients were studied after the placebo run-in phase and thereafter at 1, 2, 3 months of enalapril treatment on out-patient basis. Baseline investigations prior to the study included a 1Zlead electrocardiogram, chest X-ray, serum biochemistry, 24 hour urine collection for creatinine clearance, and M-mode echocardiography using an ultrasonoscope (Picker LSC 7000) utilising a Cambridge 2.25 mHz transducer. Exercise capacity was assessed using a symptom
TABLE 1 Baseline clinical and demographic data of the heart failure patients who completed the study (n = 9 mean + SD). Parameter Age (years) Sex (M/F) We@ (Kg) Self-paced exercise time (set) New York Heart Association class Cardiothoracic ratio Creatinine clearance (ml.min-‘) Echocardiographic indices Left ventricular diastolic size (mm) Left ventricular systolic size (mm) Fractional fibre shortening (W) Velocity of circumferential fibre shortening (Circ.sec-‘) Cause of heart disease Hypertension Valvar lesion Cardiomyopathy
47
*19
4/5 51 + 16 299 +181 2.57+ 0.53 0.73* 0.12 42 +19 65 54 17 0X2*
+ + +
5 6 7 0.4
4 2 3
limited self-paced corridor walk test [ll-131. Patients were required to walk to and fro along a 30 m corridor at our Electrodiagnostic Unit, at a self selected ‘normal’ pace, which was comfortable and neither fast nor slow. The patients maintained this walking pace until they experienced symptoms of dyspnea, fatigue, dizziness, palpitations, or leg cramps. Erect blood pressure and heart rate were measured by manual sphygmomanometry and cardiac auscultation, before and immediately after the termination of the self-paced walk test by the same observer throughout. The total exercise duration was noted using a stop clock. Throughout the study period, the doses of digoxin and diuretics were held constant. Compliance with enalapril treatment was assessed by counting of pills and by direct questioning for recall of drug intake during each clinic attendance. Adverse effects were evaluated by spontaneous reports or direct questioning and by the response to a standard symptom checklist administered at each outpatient visit.
Statistical Analysis Data are expressed as means f standard deviation. Effect of enalapril treatment was compared
to the placebo baseline value using paired t-tests or by repeated measures analysis of variance utilising a STATVIEW 512 statistical package on a Macintosh Plus Apple Microcomputer. The results were considered significant at P -C0.05.
modest hypotensive action was associated with unchanged heart rate after enalapril. Erect heart rate placebo run in was 100 f 24 beats mirC1, there was a slight fall in heart rate (see Fig. 1) but this was not significant (F = 0.87 not significant).
Results
Clinical status and New York Heart Association functional class
Twelve patients were recruited but only 9 completed the study protocol. Two patients missed their first month appointment and were lost to follow-up. One patient (functional class IV, a 20year-old woman) died of progressive heart failure after 2 weeks of treatment whilst in hospital. Blood pressure and heart rate
Enalapril caused a modest reduction in erect mean blood pressure. Mean blood pressure after the placebo run in was 86 + 21 mm Hg and this was not significantly affected by enalapril treatment (F = 1.42not significant), see Fig. 1. This
Enalapril therapy caused a significant improvement in New York Heart Association Functional capacity (F = 26.2, P < 0.001 ANOVA). Baseline functional class was 2.57 f 0.53, and was 1.86 _t 0.90, 1.57 f 0.53, and 1.57 f 0.53 at 1, 2, and 3 months, respectively (see Fig. 2). The mean weight increased from 51 f 16 kg to 55 k 13 kg (P -c0.05) without increased peripheral edema (see Fig. 3). All patients experienced improved subjective wellbeing. Two patients exhibited reductions in left ventricular systolic size and increased fractional shortening on echocardiography after 3 months of enalapril. Self-paced exercise capacity
r
T
2
1
0 TIME
3
(MONTHS)
Fig. 1. Mean erect blood pressure and erect heart rate, before ( 0) and after (0) enalapril treatment in Nigerians with chronic congestive heart failure. n = 9 mean + SD.
There was a significant and sustained increase in the symptom limited self-paced exercise time following enalapril (F = 3.4, P -e0.05), see Fig. 2. This was associated with a diminished subjective perception of exercise effort. Baseline exercise time increased from 299 &-181 set to 466 f 395 set at 1 months, 557 f 243 set at 2 months, and 573 f 308 set at 3 months. The 95% confidence interval for the difference in exercise time between the placebo baseline and the end of the study was from 182 set to 366 sec. This prolongation of exercise time was unaccompanied by a significant change in the self-paced walking speed, which was 3.2 rf: 0.8 km . h-’ after placebo, and 3.3 + 0.7, 3.5 f 0.9, and 3.3 &-0.9 km. h-t at 1, 2, and 3 months, respectively (F = 0.96, not significant). The pressure rate product (mm Hg beats. rnin-’ X 102) showed a significant and progressive decline with enalapril therapy. (F = 5.71, P = 0.006). At baseline, the double product was 146 t_ 23 and corresponding values after 1, 2, and 3 months of enalapril were 119 f 28, 118 + 19, 105 k 21 mm Hg beats mm’, respectively. The ratio
l-‘and 116 f 36 pmol . l-l, respectively. Serum bicarbonate was 26 f 4 mm01 - 1-l after enalapril therapy. The 24 hour creatinine clearance, at 3 months, could not be accurately determined owing to unreliable urine collection by the subjects on out-patient basis.
ir&/Azy 3-
A_
Dose-response
relationships
The optimal dose requirement of enalapril was 5 mg- day-’ in eight patients and 10 mg - day-’ in one. Five mg * day- ’ consistently exhibited superior efficacy compared to 2.5 mg . day-‘. In one patient, functional class IV, enalapril dose was reduced to 1.25 mg . day-’ owing to acute reversible renal insufficiency. Adverse reaction profile TIME
(MONTHS)
z
Fig. 2. The effect of enalapril treatment on NYHA functional capacity and on self paced exercise time and pressure rate product corrected for exercise time in Nigerians with heart failure. Enalapril significantly improved the parameters relative to placebo baseline (repeated measures ANOVA) n = 9 mean f SD. * P < 0.01 compared to placebo baseline value.
of the double product to exercise time (mm Hg beats min-’ - set-’ ) and indicator of myocardial oxygen demand per unit time, showed a significant and steady reduction with enalapril treatment (F = 4.56, P = 0.015), see Fig. 2. The values were: 70 + 48 after placebo, and 43 + 28, 27 f 17, and 27 f 21 mm Hg beats min-’ . set-’ at 1, 2, and 3 months, respectively. The 95% confidence interval for the difference in the double product/exercise time ratio, between the placebo baseline and after 3 months of enalapril treatment, was from 29.5 mm Hg beats min-’ . set-’ to 56.5 mm Hg beats mm-’ . see-‘. Biochemical
The enalapril regimen was generally tolerated. There was no episode of “first
well dose
+
20-F 14Or
+
16Or
and renal status
The effects of enalapril on biochemical parameters are shown in Fig. 3. Concentration of sodium in the serum rose significantly from 129 f 5 mm01 . 1-l to 135 f 3 mm01 . 1-l at 3 months (P -c 0.01). Serum potassium (3.64 mmol. 1-l) and serum creatinine (124 A-25 pm01 .1-l) before, were unchanged after 3 months, being 3.93 + 0.4 mm01 -
--
0 TIME
3 (MONTHS)
Fig. 3. The biochemical effects of enalapril treatment in Nigerian patients witb congestive heart failure. n = 9 mean* SD. * P -z0.01 compared to placebo baseline value.
59
syncope”, although 2 patients had asymptomatic hypotension (systolic blood pressure -C90 mm Hg). One patient (function class IV), developed acute reversible renal insufficiency, after one week of enalapril dosing but subsequently died of progressive heart failure. One patient with endomyocardial fibrosis developed blisters on the palms and soles and another experienced transient pruritus. There were no haematological or biochemical abnormalities on post-study check. Discussion We have evaluated the long-term effects of enalapril in Nigerians with congestive heart failure. The findings of a significant and sustained improvement in clinical status, New York Heart Association functional capacity and self-paced exercise tolerance confirms and extends our earlier, short-term observation [lo]. It is likely that this beneficial consequence of inhibition of angiotensin converting enzyme is related to the activation of plasma and tissue renin-angiotensin-aldosterone system in heart failure [9]. Both the choice of our study design, and the possibility of a type II error, deserve comment. As we have previously reported the improvement in exercise capacity and salutary clinical effects produced by enalapril in a double blind, placebo controlled, short-term study [lo], the principal aim of the present investigation was the evaluation of the long-term consequence of inhibition of converting enzyme on heart failure in Nigerians. Further, the profound symptomatic subjective amelioration with enalapril in our earlier study posed practical and ethical problems in the placebo blinding of the present follow-up. It is possible that a double blind protocol could have yielded a stronger basis for the validity of our findings. Moreover, the patient population, and the drop-out rate may have limited the power of the study, which is of the order of 48% at the 5% a-level. Nonetheless, the employment of a conservative repeated measures analysis of variance, as well as the quoted confidence intervals for the difference between placebo baseline and the enalapril induced effects, indicates the internal validity of the results.
In the present study, a symptom-limited, selfpaced, walking protocol was employed. The measurement of symptomatic amelioration in heart failure patients is problematic 1131 and it is unlikely that any one method accurately reflects all aspects of symptomatic response to treatment [13]. Maximal treadmill testing in heart failure is unlikely to reflect ideally all the composites of patient status, since patients do not repeatedly exercise to their symptomatic maximum during their daily living activities [13]. The self-paced corridor walk test [ll-131 is based on the familiar daily activity of walking. Since the subjects selected their own pace of walking, it may represent a more physiological evaluation of cardiovascular status, and permit a better appraisal of the improvement that the patients are likely to experience during their daily activities [13]. Furthermore, the self-paced walk test is less likely than the treadmill test to be influenced by a ‘training effect’ consequent upon repeated measurements. It has also been shown to be highly reproducible [l&12]. Enalapril, thus, increased a physiologically relevant, self-paced exercise time and enhanced work capacity at low levels of exercise. This prolongation in exercise time was associated with unchanged walking speed, indicating that the increase in exercise time induced by enalapril was not a consequence of reduced walking speed or exertion. The pressure rate product, and the pressure rate product corrected for exercise time, exhibited a sustained reduction with enalapril treatment. The double product is an index of myocardial oxygen demand, and a fall in this parameter reflects a diminution in myocardial oxygen requirement per unit time. This salutary effect of inhibition of angiotensin converting enzyme on myocardial energy consumption has been reported previously [14,15] and it may be related to reduced exercise blood pressure and heart rate as well as to a direct effect on an endogenous cardiac renin angiotensin aldosterone system [16]. This is also concordant with a suggested cardioprotective effect of inhibitors of the converting enzyme [16]. The modest hypotensive action of enalapril was unassociated with a reflex tachycardia, which is consistent with previous experience [17]. Biochemically, concentrations of both potassium and
60
creatinine in the serum were unchanged, so that converting enzyme inhibition did not significantly impair renal function but mitigated diuretic-induced hypokalemia [18]. Serum sodium was, however, significantly increased. Several studies have reported that inhibition of angiotensin converting enzyme with both enalapril and captopril reversed hyponatremia in severe congestive heart failure [19], possibly reflecting converting enzyme inhibition-induced suppression of arginine-vasopressin levels [20]. An interesting observation was the enalapril-induced significant, oedema-free weight gain. Whether this represents a reversal of ‘cardiac cachexia’ is unclear. The adverse effects of enalapril included the occurrence of acute reversible renal insufficiency [21] during low reual perfusion. One patient experienced blisters on the palms and soles and another had transient pruritus [22] in a patient with severe heart failure (Functional class IV). This is indicative of the loss of postglomerular efferent arteriolar vasoconstriction mediated by angiotensin II [21] during low renal perfusion. One patient experienced plisters on the palms and soles, and another ,had transient pruritus [22] but whether these are related to an alteration in kinin metabolism [23] is unclear. Thus, long term inhibition of angiotensin converting enzyme with enalapril in Africans with congestive heart failure on conventional therapy elicited satisfactory tolerance, caused sustained amelioration in clinical status, exercise tolerance and myocardial energetics while preserving renal function. These findings are largely in accord with results of inhibition of angiotensin converting enzyme in heart failure in Caucasians. There is, thus, no suggestion of important racial differences in the response to inhibition of converting enzyme in patients with congestive heart failure. Acknowledgements We would like to express our immense indebtedness to Miss Debbie Burrows, Merck Sharp & Dohme, Hoddesden Herefordshire, U.K. and thank M.S.D. (U.K.) for the supply of enalapril and placebo tablets. We thank Dr. J.A. Balogun for statistical advice, and Mrs. F.M. Adesida for typing the manuscript.
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