Cardiology 64: 35-47 (1979)
Postinfarction Exercise Capacity after Lidoflazine Treatment or Physical Training S. Degré, A. Lenaers, R. Messin, P. Vandermoien, Ph. Salhadin, M. Limage and H. Denolin Laboratoire de Recherches cardiologiques; Clinique cardiologique; Département de Cardiologie, and Laboratoire de Physiologie cardio-pulmonaire of the Hôpital Universitaire Saint-Pierre, Brussels
Key Words. Myocardial infarction • Oxygen consumption • Blood pressure • Heart rate Abstract. 44 male postinfarction volunteers were divided into 4 groups and submitted to performance tests. Groups I and II consisted of 24 patients, 12 of whom followed a 2-month physical training program, while the other 12 served as controls. Groups III and IV (10 patients each) were included in a 10-month double-blind crossover study with lido flazine 240 mg/day vs. placebo. The cardiovascular adaptation of the patients treated for 5 months with lidoflazine had two features in common with that observed after 2 months of physical training, namely an increase in maximal exercise capacity and, during submaximal exercise tests, a decrease in heart rate compensated for by an increase in stroke volume. In contrast to physical training, treatment with lidoflazine did not improve the peripheral oxygen consumption by the muscles.
Introduction
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It is generally acknowledged that physical training helps postmyocardial infarction patients by inducing two major effects, i.e. an increase of exercise tolerance and a decrease of heart rate at a given level of submaximal work load (2, 5, 6, 8, 9, 11, 16). These effects are demonstrable when physical condi tioning is compared with no training in properly controlled studies (4, 7, 22). Lidoflazine, a novel synthetic substance [4-||4,4-bis(p-fluorophenyl)-butyl ]|l-piperazine-aceto-2',6'-xylidide], was originally described as a long-acting coro nary vasodilator stimulating the coronary collateral circulation in the dog (14, 24, 25, 28). However, it was later found to lack coronary dilating properties at usual dose levels in pigs (15, 26) as well as in man (23), though such doses
Degré/ Lcnaers/Messin/Vandermoten/Salhadin/Limagc/Dcnolin
36
appear to enhance coronary reactive hyperemia (15, 26). In double-blind studies, this agent was found to be a potent antianginal agent (1), and, accordingly, the drug has been made available in most European countries and is currently under clinical investigation in the US (13, 19—21). Since prolonged treatment with lidoflazine appeared to produce hemodynamic changes similar to those observed after physical training (10, 18, 21), we designed the present study to compare the effects of this new treatment modality with those of physical conditioning.
Material and Methods Patients 44 male patients with a mean age of 52 years, who had suffered a myocardial infarct, volunteered for this study. Criteria for selection were: first myocardial infarct, 2 months before and confirmed by clinical criteria, serum enzymes and ECG, absence of any sign of heart failure and of hypertension: no medical treatment except for anticoagulants and nitroglycerin. The most prominent characteristics of the 35 patients, who have completed the trial, are listed in table 1.
Assessments All patients were submitted to two or three performance tests: (1)2 months after the myocardial infarct, i.e. immediately before starting the study: (2) at the end of the 2-month period, i.e. 4 months after the infarct, of follow-up without treatment (group I: vide infra) or of physical training (group II) or after the first 5-month phase, i.e. 7 months after the infarct, of double-blind medication (groups III and IV), and (3) only for groups III and IV, Table I. Patients’ characteristics Study group
1 II III IV
Patients n
12 12 5 6
Mean age years
Mean weight kg
Mean height cm
Initial mean V0 j max or V(x SL, 1/min
Anginal attacks, n yes
no
51 52 56 50
74 74 74 72
171 170 165 167
1.32 1.44 1.11 1.37
5 4 3 1
7 8 2 5
Downloaded by: Univ. of California Santa Barbara 128.111.121.54 - 4/3/2018 5:32:33 AM
V0 j SL = Symptom-limited maximal oxygen consumption (see text).
Lidoflazine and Physical Training after Infarction
37
at the end of the second 5-month phase of the double-blind crossover study, i.c. 12 months after the myocardial infarction. These performance assessments consisted of a clinical examination, an ECG at rest, and a maximal and a submaximal exercise test. Maximal Exercise Test A gradually increasing work load (increments of 10 W/min) on a Monark bicycle ergometer in the upright position was used; ECG and heart rate were recorded continuously (Mingograf 42B Elema). The systolic blood pressure was measured every second minute from the upper arm by means of the auscultation method. Oxygen consumption was as sessed from minute to minute in an open-circuit system. The exercise test was continued until the plateau of oxygen consumption (Vo, max, or aerobic capacity) had been reached; however, in some cases, the test was stopped because of an anginal attack: in such cases, the maximal exercise capacity was expressed by the oxygen consumption at the moment of angina (Vp, SL, or symptom-limited maximal oxygen consumption). Therefore, both Vq max and Vq , SL are a measure of the maximal working capacity. Submaximal Exercise Test This test was performed in the sitting position on an Elema bicycle ergometer, 1 day after the maximal test; however, as the majority of the patients failed to attend the third exercise session (at 12 months), the small number of data precludes an analysis. 1'or this test, each patient was submitted to two different submaximal work loads, i.e. one at 40% and the other at 70% of the initial maximal working capacity. Each work load was maintained for 6 min and measurements were performed during the last 2 of these minutes. The parameters studied were: oxygen consumption, arterial lactic acid level, intrahumeral blood pressure (Statham), and cardiac output by means of the dye dilution tech nique (Cardio-Green; Gilford densitometer). Front these data, the Katz index (Kl) (17) was calculated as follows: KI = P,\ll x fh, where I'^ ll = mean intrahumeral blood pressure and fit = heart rate.
Treatment Treatment under Evaluation (table II) The patients were randomly subdivided into 4 groups as follows. Group I: Control Group. From the end of the second postinfarction month (start of study) onwards, no particular instructions were given to these patients during the 2 study months, but they were allowed to resume some physical activity gradually.
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Group II: Physical Training. During the 2 study months (time schedule as in group I), these patients were following a physical training program consisting of three exercise sessions, lasting 25 min each, per week on a bicycle ergometer. During the latter sessions, the work load alternated from 70% of the maximal working capacity (periodically reas sessed) for 2 min to 90% of this capacity for 3 min.
Degré/ Lenacrs/Messin/Vandermotcn/Salhadin/Limage/Denolin
38
Table II. Design of the study and number of patients involved (44 male patients; mean age = 52 years) Time after first myocardial infarct months
2 4 7 12
Group 1 (control)
II (training) Ill (L-P)
IV (P-L)
12 10 -
12 10
10
10
-
—
-
5 5
6 4
L-»P = Lidoflazine for 5 months, followed by placebo for the next 5 months; P—L = placebo for 5 months, followed by lidoflazine for the next 5 months.
Table III. Dropouts during double-blind treatment Reason Gastric ulcer New infarction Renal colic Not mentioned Pancreatitis Move to remote area Refusal to perform second exercise test Refusal to perform third exercise test Total
Patients, n 1 1 1 2 1 1 2 2 11*2
Groups III and IV: Double-Blind Treatment. These patients were treated at random with either 240 mg of lidoflazine (group III) or placebo (group IV) per day for 5 months, starting 2 months after the myocardial infarct. At the end of this period, a crossover took place, group 111 patients receiving placebo and group IV patients the same daily dose of lidoflazine for another 5 months.
Downloaded by: Univ. of California Santa Barbara 128.111.121.54 - 4/3/2018 5:32:33 AM
Other Treatments No treatment changes were allowed during the entire duration of the study, the only medications allowed being anticoagulants (as adapted to the individual coagulation status) and nitroglycerin (in case of anginal attacks) as already indicated above.
Lidoflazine and Physical Training after Infarction
39
Table IV. Comparison of maximal exercise test findings in trained patients and in controls (figures are means t SD) Test No.
Parameter1
Before study (2nd month)
After study (4th month)
Change %
1.32 t 0.3 48.8 ± IS 127 * 10
1.27 i 0.3 46.0 i 14 133 ± 12
-4 -6 +4
1.44 t 0.4 56.8 t 17 157 ± 20
1.82 ± 0.5 67.7 ± 20 162 i 21
+ 26 + 19 +3
p value2
Group I: control (n = 10) 1 2 3
Vq , 1/min Vj/, l/min fh, beats/min
n.s. n.s. n.s.
Group II: training (n = 10) 4 5 6
Vq , 1/min Vfci, 1/min fit, beats/min
Postinfarction Exercise Capacity after Lidoflazine Treatment or Physical Training S. Degré, A. Lenaers, R. Messin, P. Vandermoien, Ph. Salhadin, M. Limage and H. Denolin Laboratoire de Recherches cardiologiques; Clinique cardiologique; Département de Cardiologie, and Laboratoire de Physiologie cardio-pulmonaire of the Hôpital Universitaire Saint-Pierre, Brussels
Key Words. Myocardial infarction • Oxygen consumption • Blood pressure • Heart rate Abstract. 44 male postinfarction volunteers were divided into 4 groups and submitted to performance tests. Groups I and II consisted of 24 patients, 12 of whom followed a 2-month physical training program, while the other 12 served as controls. Groups III and IV (10 patients each) were included in a 10-month double-blind crossover study with lido flazine 240 mg/day vs. placebo. The cardiovascular adaptation of the patients treated for 5 months with lidoflazine had two features in common with that observed after 2 months of physical training, namely an increase in maximal exercise capacity and, during submaximal exercise tests, a decrease in heart rate compensated for by an increase in stroke volume. In contrast to physical training, treatment with lidoflazine did not improve the peripheral oxygen consumption by the muscles.
Introduction
Downloaded by: Univ. of California Santa Barbara 128.111.121.54 - 4/3/2018 5:32:33 AM
It is generally acknowledged that physical training helps postmyocardial infarction patients by inducing two major effects, i.e. an increase of exercise tolerance and a decrease of heart rate at a given level of submaximal work load (2, 5, 6, 8, 9, 11, 16). These effects are demonstrable when physical condi tioning is compared with no training in properly controlled studies (4, 7, 22). Lidoflazine, a novel synthetic substance [4-||4,4-bis(p-fluorophenyl)-butyl ]|l-piperazine-aceto-2',6'-xylidide], was originally described as a long-acting coro nary vasodilator stimulating the coronary collateral circulation in the dog (14, 24, 25, 28). However, it was later found to lack coronary dilating properties at usual dose levels in pigs (15, 26) as well as in man (23), though such doses
Degré/ Lcnaers/Messin/Vandermoten/Salhadin/Limagc/Dcnolin
36
appear to enhance coronary reactive hyperemia (15, 26). In double-blind studies, this agent was found to be a potent antianginal agent (1), and, accordingly, the drug has been made available in most European countries and is currently under clinical investigation in the US (13, 19—21). Since prolonged treatment with lidoflazine appeared to produce hemodynamic changes similar to those observed after physical training (10, 18, 21), we designed the present study to compare the effects of this new treatment modality with those of physical conditioning.
Material and Methods Patients 44 male patients with a mean age of 52 years, who had suffered a myocardial infarct, volunteered for this study. Criteria for selection were: first myocardial infarct, 2 months before and confirmed by clinical criteria, serum enzymes and ECG, absence of any sign of heart failure and of hypertension: no medical treatment except for anticoagulants and nitroglycerin. The most prominent characteristics of the 35 patients, who have completed the trial, are listed in table 1.
Assessments All patients were submitted to two or three performance tests: (1)2 months after the myocardial infarct, i.e. immediately before starting the study: (2) at the end of the 2-month period, i.e. 4 months after the infarct, of follow-up without treatment (group I: vide infra) or of physical training (group II) or after the first 5-month phase, i.e. 7 months after the infarct, of double-blind medication (groups III and IV), and (3) only for groups III and IV, Table I. Patients’ characteristics Study group
1 II III IV
Patients n
12 12 5 6
Mean age years
Mean weight kg
Mean height cm
Initial mean V0 j max or V(x SL, 1/min
Anginal attacks, n yes
no
51 52 56 50
74 74 74 72
171 170 165 167
1.32 1.44 1.11 1.37
5 4 3 1
7 8 2 5
Downloaded by: Univ. of California Santa Barbara 128.111.121.54 - 4/3/2018 5:32:33 AM
V0 j SL = Symptom-limited maximal oxygen consumption (see text).
Lidoflazine and Physical Training after Infarction
37
at the end of the second 5-month phase of the double-blind crossover study, i.c. 12 months after the myocardial infarction. These performance assessments consisted of a clinical examination, an ECG at rest, and a maximal and a submaximal exercise test. Maximal Exercise Test A gradually increasing work load (increments of 10 W/min) on a Monark bicycle ergometer in the upright position was used; ECG and heart rate were recorded continuously (Mingograf 42B Elema). The systolic blood pressure was measured every second minute from the upper arm by means of the auscultation method. Oxygen consumption was as sessed from minute to minute in an open-circuit system. The exercise test was continued until the plateau of oxygen consumption (Vo, max, or aerobic capacity) had been reached; however, in some cases, the test was stopped because of an anginal attack: in such cases, the maximal exercise capacity was expressed by the oxygen consumption at the moment of angina (Vp, SL, or symptom-limited maximal oxygen consumption). Therefore, both Vq max and Vq , SL are a measure of the maximal working capacity. Submaximal Exercise Test This test was performed in the sitting position on an Elema bicycle ergometer, 1 day after the maximal test; however, as the majority of the patients failed to attend the third exercise session (at 12 months), the small number of data precludes an analysis. 1'or this test, each patient was submitted to two different submaximal work loads, i.e. one at 40% and the other at 70% of the initial maximal working capacity. Each work load was maintained for 6 min and measurements were performed during the last 2 of these minutes. The parameters studied were: oxygen consumption, arterial lactic acid level, intrahumeral blood pressure (Statham), and cardiac output by means of the dye dilution tech nique (Cardio-Green; Gilford densitometer). Front these data, the Katz index (Kl) (17) was calculated as follows: KI = P,\ll x fh, where I'^ ll = mean intrahumeral blood pressure and fit = heart rate.
Treatment Treatment under Evaluation (table II) The patients were randomly subdivided into 4 groups as follows. Group I: Control Group. From the end of the second postinfarction month (start of study) onwards, no particular instructions were given to these patients during the 2 study months, but they were allowed to resume some physical activity gradually.
Downloaded by: Univ. of California Santa Barbara 128.111.121.54 - 4/3/2018 5:32:33 AM
Group II: Physical Training. During the 2 study months (time schedule as in group I), these patients were following a physical training program consisting of three exercise sessions, lasting 25 min each, per week on a bicycle ergometer. During the latter sessions, the work load alternated from 70% of the maximal working capacity (periodically reas sessed) for 2 min to 90% of this capacity for 3 min.
Degré/ Lenacrs/Messin/Vandermotcn/Salhadin/Limage/Denolin
38
Table II. Design of the study and number of patients involved (44 male patients; mean age = 52 years) Time after first myocardial infarct months
2 4 7 12
Group 1 (control)
II (training) Ill (L-P)
IV (P-L)
12 10 -
12 10
10
10
-
—
-
5 5
6 4
L-»P = Lidoflazine for 5 months, followed by placebo for the next 5 months; P—L = placebo for 5 months, followed by lidoflazine for the next 5 months.
Table III. Dropouts during double-blind treatment Reason Gastric ulcer New infarction Renal colic Not mentioned Pancreatitis Move to remote area Refusal to perform second exercise test Refusal to perform third exercise test Total
Patients, n 1 1 1 2 1 1 2 2 11*2
Groups III and IV: Double-Blind Treatment. These patients were treated at random with either 240 mg of lidoflazine (group III) or placebo (group IV) per day for 5 months, starting 2 months after the myocardial infarct. At the end of this period, a crossover took place, group 111 patients receiving placebo and group IV patients the same daily dose of lidoflazine for another 5 months.
Downloaded by: Univ. of California Santa Barbara 128.111.121.54 - 4/3/2018 5:32:33 AM
Other Treatments No treatment changes were allowed during the entire duration of the study, the only medications allowed being anticoagulants (as adapted to the individual coagulation status) and nitroglycerin (in case of anginal attacks) as already indicated above.
Lidoflazine and Physical Training after Infarction
39
Table IV. Comparison of maximal exercise test findings in trained patients and in controls (figures are means t SD) Test No.
Parameter1
Before study (2nd month)
After study (4th month)
Change %
1.32 t 0.3 48.8 ± IS 127 * 10
1.27 i 0.3 46.0 i 14 133 ± 12
-4 -6 +4
1.44 t 0.4 56.8 t 17 157 ± 20
1.82 ± 0.5 67.7 ± 20 162 i 21
+ 26 + 19 +3
p value2
Group I: control (n = 10) 1 2 3
Vq , 1/min Vj/, l/min fh, beats/min
n.s. n.s. n.s.
Group II: training (n = 10) 4 5 6
Vq , 1/min Vfci, 1/min fit, beats/min
