The Effect of Lidoflazine on Exercise Tolerance in Patients with Angina Pectoris

The Effect of Lidoflazine on Exercise Tolerance in Patients with Angina Pectoris· LeOflllf'd A Nordstrom~ M.D.~ and Fredanck L. Gobel~ M.D.

The died of dIerapJ wItIa ........... _ " aerdie ill tile uprtpt pGIIItIoB was eftllated .. 21 ...... whit _ _ pectoris. TIle ItIIdy COIIIIIIted of tile follow... tIuee c. wti,e periods: (1) • tIIree-aaoatII period of ebo; (2) lib ...... of daerapy with lidoIaiDe; aad (3) • lib...... period .. whidl were raadomIzed to eItIIer daerapy with IIdoftaIDe or placebo. FImdioaaI ..... was IIIOIIitored by ............. of eserdle capacity aad the 8IDOIIId of nltroIIYeerin COlI.-ed. From period 1 to period 2, "e ...... mninwI nerdse time lDcre_ed from 4.4 to 6.5 .mates (48 percellt; P < 0.001), ad tile eDenai workload ~

ncem.a

.-tieIds

Oral therapy with lidoflazine is commonly used for the relief of angina pectoris in Europe but is not yet clinically available in the United States. Administration of lidoflazine (l-[4~4-di( fluorophenyl) butyl]-4-[(2,6-dimethylaniliano-carbonyl)methyI] piperazine) prolongs reactive hyperemia after temporary coronary occlusion in experiments with animals.! Many studies have indicated that therapy with lidoflazine is effective in reducing the incidence and~m~ofangina~mandin~uoogthe

consumption of nitroglycerin;I.1 however, the strong placebo effect from both medical and surgical therapy in patients with angina pectoris indicates the need for objective measurements of functional capacity if a new form of therapy is to be accurately evaluated," When there is adherence to a suitable protocol, the duration of exercise and the rate-pressure product (the product of the heart rate times the peale systolic blood pressure) at the onset of symptoms are reproducible and therefore should be part of the evaluation of any new antianginal therapy.4-8 Very little information is available regarding the effect of therapy with lidoflazine on exercise tolerance in patients with arteriographically proven coronary arterial disease. Improvement in exercise tolerance in the upright position on a bicycle ergometer has been reported during therapy with lidoflazine~ °From the Cardiovascular Section, Department of Medicine~ Veterans Administration Hospital, and the University of Minnesota, M~. Manuscript received November 16; revision accepted January 12. Reprint requem: In. Gobel. !545 ChktJgo A~ South, Mirmeapolu 55404

50 NORDSTROM, SOBEL

by 68 perceIIt (P < 0.001). TIle . . . . IIeIII1 rate .. two . . . . . . of u:erdse decre.ed from 114 to 101 beats per miDate (P < O.Ml) hut ~ UDCIIaDged at symptomtolerated JMYimaI nerd8e. ~ period 3, the p.dents reeeivinl daerapy wi" JicIoIazine .....taIned tIleir iJDproved nerdle toIennce, _d tile redudIon In ..... heart rate at two mimltes of eserdle ........ Patients placebo . . . . . period 3 had. decn8Ie .. eserdse tolerance, ad the mean IIeart rate at two miDutes of es.erdse ~ to CODtnJI I.JdoIazine is dective _ _ - ........ JDedIcatioD, .. pIII1 due to suppressi_ of die IIeart rate ........ nerdle.

ncem.a

.BeL

associated with a reduction in the heart rate during exercise. 7 Previous studies have indicated that changes in the rate-pressure product correlate well with changes in myocardial consumption of oxygen during exercise.8-12 There is a need for further information regarding the effect of therapy with lidoflazine on the rate-pressure product during exercise in patients with angina pectoris. The present study was designed to evaluate the effect of therapy with lidoflazine on the rate-pressure product during exercise and on the exercise tolerance in patients with arteriographically proven coronary arterial disease and to compare the results with those obtained during a control period. MATERIALS AND METHODS

Patienta

The subjects under study consisted of a group of 21 men (mean age. 53 ± 7 yean) with a history of stable angina pectoris for at least one year's duration and with depression

of the S-T segment during exercise. Coronary arteriographic studies in 18 of the 21 patients revealed severe three-vessel disease in 14 patien~ severe two-vessel disease in two patients. and severe disease of the left anterior descending coronary artery in the remaining two patients. The three patients without coronary arteriograms bad electrocardiographic evidence of myocardial infarction. AD were chosen on the basis of sufficient motivation to faithfully take medication. to complete a diary recording consumption of nitroglycerin, and to return for monthly testing. Informed consent was obtained from each subject. and the study was approved by the Minneapolis Veterans Administration Hospital's Subcommittee on Human Studies. During this period of time. there was no change in weight, which averaged 82 ± 9 kg (179 ± 19 lb) at the onset and 82 CHES~

74: 1, JULY, 1978

Period 1 (Placebo)

,

Patient and Group" 1 2 3

Period 2 (Lidoftazine)

,

"

Heart Rate, beats/min

,

• Exercise " At 2 min At STME** Time, min

Period 3 (Placebo or Lidoflazine)

"

"

Heart Rate, beats/min

,

1 Exercise " At 2 min At STME** Time, min

110 143 113

124 145 126

4.1 2.3 3.4

100 111

Group At 4 5 6 7 8 9 10 11 Group mean ± SD

128 131 129 101 122 125 116 91

130 135 136 122 148 139 150 116

3.5 3.8 3.5 4.1 7.8 3.4 6.4 6.3

102 122

Group Bt 12 13 14 15 16 17 18 19 20 21 Group mean ±SD

110 101 92 126 106 107 94 109 103 135

99

96

106 109 107 90 88

134 143 121

5.8 4.4 4.9

124 143 138 136 135 130 135 128

5.6 5.0 5.8 6.7 8.2 5.5 7.5 8.0

Heart Rate, beats/min

,

1 Exercise " At 2 min At STME** Time, min

lOS 116 103 107 109 107 94 86

104±9§

Total mean ±SDII 114±15

116 122 115 122 136 112 114 129 103 161

3.4 4.5 5.3 2.7 5.7 3.8 5.3 5.0 2.5 5.3

111 97 94 109 89 100 84 100 98 115

133 119 144 126 136 130 118 142 110 148

5.7 6.8 8.2 6.2 8.2 7.8 7.2 6.4 5.4 6.7

129±15

4.4 ± 1.4

101 ±10§

132±1O

6.5 ± 1.21

120

lOS

106 117 97 102 95 112 109 120 109±9

120 143 134 114 143 132 124 128 130±10

5.2 5.5 5.7 5.2 9.2 6.0 6.5 7.5 6.4 ± 1.4§

152 125 143 135 142 127 127 136 120 143 135±101

5.8 5.2 4.0 4.2 7.2 7.5 7.5 5.2 3.8 5.5 5.6 ± 1.4§

*Patients 1 to 3 were not included in period 3 (two died, and one was excluded because of poor compliance). • *8TME, Symptom-tolerated maximal exercise. tGroup A received lidoflazine in period 3. :Group B received placebo in period 3. §Significant change (P <0.05) from period l. IITotal mean is mean of a1l21 patients. ±91cg (ISO ± 20 Ib) at the end of the study. Three patients continued to smoke cigarettes during the study. In four patients the resting diastolic blood pressure was between 90 and 100 mm Hg during therapy with diuretic drugs. Excluded were patients with arrhythmias at rest that required suppressive medication. Patients with roentgenographic evidence of cardiomegaly or with a third heart sound (or both) were excluded. No patient had had a myocardial infarction within six months of entrance into the study.

MethocU The study encompassed a 15-month interval and was divided into three periods. Period I consisted of a threemonth period of receiving placebo, followed by six months of therapy with lidoftazine (120 mg given orally three times daily) (period 2). Period 3 consisted of a six-month doubleblind study in which patients were randomized to receive therapy with lidoflazine or placebo. Levels of the drug in the blood were not available. Medication was prepackaged in identical containers, and the code was contained in sealed envelopes. It was not possible for patients to discern a tablet of lidoftazine from a tablet of placebo. Patients completed a monthly diary of the frequency of pain in the chest and of consumption of nitroglycerin.

CHEST, 74: 1, JULY, 1978

Exercise performance was evaluated by a multistage test of exercise capacity in the upright position,18 in which patients exercised to pain of grade 2, which was then interpreted as symptom-tolerated maximum exercise. Patients were instructed to grade the pain in the chest on a scale from 0 to 4, where pain of grade 2 represented about 50 percent of the most severe pain in the chest experienced by the patient and of such a quantity that the patient would usually take nitroglycerin. This grading system has been used successfully in our laboratory, as well as by others.4 , ll ' 12 The electrocardiogram was continuously monitored and was recorded each minute from the lateral precordial lead with the maximum amplitude of the QRS complex (usually lead Vs or V8 and lead aVF. Prior to and immediately following exercise, a seven-lead ECG was recorded. The blood pressure was determined from an external cuff and Korotlcoffs sounds immediately before exercise, each minute during exercise, and for eight minutes in the period after exercise. The heart rate, blood pressure, and ST -segment depression were measured during the SnaI ten seconds of exercise. The total amount of external work performed from the beginning to the end of the test was calculated from the body weight of the patient and the height and distance walked and was expressed as the total number of kilograme meters of work performed.

EFFECT OF UDAfLAZlIIE 011 EXERCISE TOLEUJlCE 51

Routine medications during the study included nitroglycerin, placebo or lidoflazine, and a diuretic drug (in four patients). No patient received digitalis or therapy with {:Jadrenergic blocking agents or took part in a regular program of exercise. Subjects were instructed to take DO nitroglycerin on the morning of the test. During period 1. exercise tests were performed at entrance into the study and at the end of the 6rst and third months. The responsibility of the measurements of heart rate, ratepressure product, and exercise time during administration of the placebo in our laboratory bas been reported.s Three exercise tests were pedormed during the last four months of period 2, and the last test was pedormed just prior to entrance into period 3. During period 3, exercise tests were repeated at the third and sixth months or at evidence of relapse, indicated by increasing frequency of pain in the chest or of consumption of nitroglycerin. H a decrease in exercise tolerance was demonstrated, a second exercise test was pedormed one month later. H the second exercise test demonstrated a continued decrease in exercise tolerance, the envelope was opened. and the code was exposed. H the exercise test demonstrated improvement or no change, the administration of placebo or lidoflazine was continued to the end of period 3. at which time the code was exposed.

'00

eo IJO

~

~

52 NORDSTROM, GOBEL

PERf00 II

70

~

eo

~

50

~ U

~

(

D'l'ERNAl WOM*

40

~

I

!O

....

20

~

I

'0

a

-------

-'0

REsuLTS The results are indicated in Table 1. Of the 21 patients who completed period 2, only 18 completed period 3 (two patients died at the end of period 2, and one patient was excluded from the study because of poor compliance). Both deaths occurred in patients living in other communities, and although autopsies were not performed, clinical circumstances suggested that death occurred from acute myocardial infarction in one instance and from an arrhythmia in the other. Of the 21 patients completing period 2, all were subjectively and objectively improved. During period 2, the mean exercise time increased from a mean value with placebo of 4.4 -+- 1.4 minutes to 6.5 -+- 1.2 minutes (48 percent increase) during therapy with lidoHazine (P < 0.(01) (Fig 1). The mean external workload increased from 4,665 -+- 2,113 kg. meters to 7,825 -+- 2,014 kg e meters (P < 0.(01), which represents a 68 percent increase in external workload (Fig 1). The mean heart rate at two minutes of exercise decreased from 114 -+- 15 beats per minute to 101 ± 10 beats per minute (P < 0.(01). The mean heart rate at symptom-tolerated maximum exercise was unchanged from placebo to therapy with lidoHazine, and there was a small but significant increase in the rate-pressure product (10 percent increase; P < 0.01) ( Fig 1) . There was evidence of subjective improvement as the mean consumption of nitroglycerin dropped from 37 -+- 62 tablets per month to 10± 12 tablets per month. On completion of period 2, treatment was randomized for the 18 patients in period 3. Eight of these 18 patients continued to receive lidoHazine

PERIOD I

-20

*p<

0.0'

1. Effect of therapy with lidoflaziDe on exercise tolerance and on heart rate (HR) and blood pressure (BP) during exercise. Results during period 2 are compared to mean values obtained during period of receiving placebo (period 1). STME. Symptom-tolerated maximal exercise. FIGURE

( group A), and ten patients received placebo ( group B). The severity of coronary arterial disease was essentially the same for the two groups. During period 2, the mean exercise time for group A increased from a value of 4.8 ± 1.7 minutes during Period 1 to 6.5 ± 1.2 minutes (P < 0.(01), and the mean external work increased from 5,324 + 2,647 kg-meters to 7,832 + 2,039 kg-meters (47 percent increase; P < 0.(01) (Fig 2). There was no change ~ EXTERNAl MlfIC •

HRATZ,.

140

-' 0

110

§

100

r:

I

I ...G ~

is

~

GROUP

A

teMTlE"TSJ

GROWS (/0 PATlE".,.J

eo eo 40 20

0 ~

PERIOO II UOClFl.AZINE

PERIOD llC UOOFLAZINE

P£RKJD II UOOFlAZIN£

PERIOD llC PlACSJO

2. Effect of therapy with Udoflazine on external work pedormed at symptom-tolerated maximal exercise during periods 2 and 3. Patients in group A received lidollazine during period 3, and patients in group B received placebo during period 3. FIGURE

CHEST, 74: 1, JULY, 1978

during period 3, as the mean maximal exercise time was maintained at 6.4 ± 1.6 minutes. There was no change in the consumption of nitroglycerin, the mean maximal heart rate, and the rate-pressure product from period 2 to Period 3 (Fig 2). During period 2, the ten patients receiving placebo (group B) in period 3 had an increase in the mean maximal exercise time from 4.4 ± 1.2 to 6.9 ± 1.0 minutes (P < 0.(01), and the mean external work increased from 4,597 ± 1,706 kg-meters to 8,525 ± 1,712 kg - meters (85 percent increase; P < 0.(01). During period 3, the patients in group B had a decrease in exercise time to 5.6 ± 1.4 minutes (P < 0.02), and the heart rate at two minutes of exercise returned to control values. The mean value for exercise time and external work did not decrease to control values, as four of the ten patients maintained their improved status. The heart rate and ratepressure product at symptom-tolerated maximum exercise was unchanged in group B from period 2 (during therapy with lidoflazine) to period 3. Subjectively, there was no evidence of regression, as the consumption of nitroglycerin decreased from 15 tablets per month to eight tablets per month (P < 0.5). No adverse effects from therapy with lido8azine were noted in any patient. DIscuSSION

Results from this study indicate that therapy with lidoflazine results in functional as well as symptomatic improvement in patients with angina pectoris, as suggested by previous studies." The condition of all patients who completed period 2 improved during therapy with lidoHazine; and during period 3, those patients receiving lidoHazine ( group A) maintained their improved exercise tolerance, as manifested by a longer exercise time and an increased external workload at symptom-tolerated maximum exercise. In contrast, those patients receiving placebo in period 3 (group B) had a reduction toward control values of their exercise time and external workload at symptom-tolerated maximum exercise. Lidoflazine appears to be effective, at least in part, by suppressing the heart rate during exercise, as the increase in exercise time and external workload at symptom-tolerated maximum exercise was accomplished at the same heart rate. In addition, at two minutes of exercise, the heart rate during therapy with Iido8azine was 10 percent lower than during the period of receiving placebo (P < 0.(01). Measurement at two minutes of exercise allows evaluation at the same external worldoad during a steady state, since all subjects were able to reach at least that level of work without pain in the chest. A

CHEST, 74: 1, JULY, 1978

similar suppression of the heart rate during exercise was noted by Piessens and DeGeest. 7 The basis for suppression of the heart rate has not been fully elucidated; however, lidollazine has been demonstrated to interfere with the release of adenosine from the myocardium and with uptake of adenosine by red blood cells, thereby prolonging the local action of adenosine.14.u~ When adenosine is injected directly into the sinoatrial nodal artery, bradycardia results." Adenosine is a potent vasodilator compound, and it is possible that therapy with lidoflazine, through potentiation of adenosine at all smooth muscle sites, resulted in a reduction in afterload and therefore in tension of the ventricular wall and consequently in myocardial needs for oxygen. We were unable to measure a reduction in arterial pressure at rest or at two minutes of exercise under the conditions of this study; however, it is possible that more subtle changes in blood pressure may have been overlooked, as our measurements were made with an external coH. Also, peripheral augmentation of the systolic blood pressure increases during exercise and differs among Indivtduals." In addition, we were only able to accurately measure the systolic blood pressure during exercise, and changes in the diastolic and mean blood pressure may have been overlooked. Contractility was not evaluated in this study, but since therapy with lidoflazine suppresses the heart rate during exercise and reduces the frequency of angina pectoris, one might query whether there may have been an effect on contractility similar to that observed with propranolol. There were no changes in the cardiothoracic ratio on the chest x-ray film, no occurrence of a new third heart sound, and no SYmPtoms suggestive of heart failure in any patient in this study. In addition, therapy with propranolol usually results in a decrease in the rate-pressure product at symptom-tolerated maximum exercise, even though external work may be increased.t.l0.18 During therapy with lidoHazine, the rate-pressure product was either unchanged or increased, and thus it is unlikely that there were significant changes in contractility. Previous work demonstrated that the rate-pressure product correlates well with myocardial consumption of oxygen in normal young menl-IO and in patients with ischemic heart disease. u. l ! There appears to be a rather constant relationship between the onset of angina pectoris and the rate-pressure product,8 which is reproducible even over long Periods of time. 4,1 A reduction in the rate-pressure product at two minutes of exercise therefore implies either a reduction in myocardial consumption of oxygen at the same external workload or a shift in

EFFECT OF UDAFWIIIE 011 ElElCISE TOlEIAIICE 53

the relationship between external work and myocardial consumption of oxygen such as one notes during therapy with propranolol. S By the same token the increase in the rate-pressure product at symptomtolerated maximum exercise with therapy with lidoBazine implies that myocardial consumption of oxygen may be increased at the new workload. It has been suggested that therapy with lidoHazine may be effective by increasing the development of collateral blood vessels, and this could account for increased myocardial consumption of oxygen at symptom-tolerated maximum exercise. On the other hand, ventricular volume might be reduced by therapy with lidoHazine; and, hence, the increase in the rate-pressure product at symptom-tolerated maximum exercise noted in this study may be on a basis similar to that observed after therapy with nitroglycerin. 18 The effect of therapy with lidoHazine on the distribution of the intramyocardial How of blood has not been evaluated. The condition of four patients receiving placebo during period 3 did not regress, and the reason for this is unclear. It is possible that coronary collateral circulation was promoted during therapy with lidoHazine and persisted during the subsequent period of receiving placebo. Both hemodynamic and histologic data in dogs indicate that administration of lidoHazine induces an acceleration of the development of coronary collateral circulation, although the final degree of development is not changed. IS ACKNOWLEDGMENT: We thank Mr. Edwin J. Ketola and Ms. Donna Wagner for technical assistance in the preparation of this manuscript.

1 Jageneau ADM, Schaper WKA, Van Gerven W: Enhancement of coronary reactive hyperemia in unanesthetized pigs by an adenosine potentiator ( lidoflazine). Arch Exp Pathol Pharmakol 265: 16-23, 1969 2 Batlouni M, Bertolami V, Duprat R: Lidoflazine in angina pectoris:Double-blind trial Arq Bras Cardio121:321-326, 1968 3 Verhaeghe LK: Treatment of angina pectoris with lidoflazine. Arzneim Forsch 19:1842-1844, 1969 4 Harbnan ICE, Nordstrom LA, Gobel FL: Effect of placebo on exercise response and nitroglycerin consumption. Minn Med 59:839-843,1976

54 NORDSTROM, GOBEL

5 Smokier, PE, MacA1pin RN, Alvaro A, et al: Reproducibility of a multi-stage near maximal treadmill test for exercise tolerance in angina pectoris. Circulation 48:346351, 1973 6 Robinson BF: Relation of heart rate and systolic blood pressure to the onset of pain in angina pectoris. Circo1ation 35:1073-1083, 1967 7 Piessens J, DeGeest H: Long-term evaluation of lidoBazine in angina pectoris based on exercise tolerance. Cardiology 57: 135-149, 1972 8 Kitamura K, Jorgensen CR. Gobel FL, et al: Hemodynamic correlates of myocardial oxygen consumption during upright exercise. J Appl Physiol 32:516-522, 1972 9 Jorgensen CR, Wang K, Gobel FL, et al: Effect of propranolol on myocardial oxygen consumption and its hemodynamic correlates during upright exercise. Circulation 48:1173-1182, 1973 10 Nelson RR. Gobel FL, Jorgensen CR, et at: Hemodynamic predictors of myocardial oxygen consumption during static and dynamic exercise. Circulation 50:11791189,1974 ·11 Holmberg S, Serzysko W, Varnauskas E: Coronary circulation during heavy exercise in control subjects and patients with coronary heart disease. Acta Med Scand 190: 465-480, 1971 12 Gobel FL, Nordstrom LA, Nelson RR. et a1: Hemodynamic predictors of myocardial oxygen consumption during exercise in patients with angina pectoris. Circulation, to be published 13 Bruce RA, Hornsten TR: Exercise stress testing in evaluation of patients with ischemic heart disease. Prog Cardiovase Dis 11:371-390, 1969 14 Afonso S, O'Brien GS, Crumpton CW: Enhancement of coronary vasodi1ating action of ATP and adenosine by Iidoflazine. Circ Res 22:43-48,1968 15 Jageneau AHM, Schaper WKA: Potentiation of adenosine activity by low oral doses of lidoflazine. Nature 221:184-185, 1969 16 James TN: The chronotropic action of ATP and related compounds studied by direct perfusion of the sinus node. J Pharmacol Exp Ther 149:233-247,1965 17 Rowell LB, Brengelmann GL, Blackmon JA, et at: Disparities between aortic and peripheral pulse pressures induced by upright exercise and vasomotor changes in man. Circulation 37 :954-964, 1968 18 Amsterdam EA, Hughes JL, DeMaria AN, et a1: Indirect assessment of myocardial oxygen consumption in the evaluation of mechanisms and therapy of angina pectoris. Am J Cardiol33:737-743, 1974 19 Borgers M, Verheyen A, Xhonneus R, et al: The influence of IidoHazine on the development of coronary collaterals in dogs: a hemodynamic, quantitative histologic and ultrastructural study. In Hochrein H (ed): Second Lidoflazine Symposium. Hamburg, West Germany, Perimed Verlag, 1975, p. 41

CHEST, 74: 1, JULY, 1978