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Nitroglycerin lingual spray: Clinical efficacy and dose-response relation
JANUARY
The
American
Journal
1, 1988
of CARDIOLOGY@ VOLUME
57
NUMBER
1
CORONARY HEART DISEASE
Nitroglycerinlingual Spray: ClinicalEfficacy and Dose-Response Relation JOHN 0. PARKER, MD, KAREN A. VANKOUGHNETT,
Twenty patients with chronic, stable, exercise-induced angina pectorts were studied after receiving lingual sprays that delivered 0.2, 0.4 and 0.8 mg of nitroglycerin (GM). The hemodynamic effects and changes in exercise time to the onset of angina and to the development of moderate angina were compared with those of placebo spray and 0.4 mg of sublingual GlN. A dose-response relation was apparent with the 3 doses of active spray for heart rate at rest but not for standing systolic blood pressure. Sublingual GTN produced effects similar to those with 0.4 and 0.8 mg of GIN spray, but exceeded the response to 0.2 mg of GTN spray.
RN, and BERNICE FARRELL,
RN
Treadmill waikfng time to the onset of angina and to the development of moderate angina was prolonged with each dose of GTN spray and showed a doseresponse relation with significantly greater effects with increasing doses of GTN spray. This study indicates that GlN lingual spray fs effective in the prophylaxis of angfna and should be effective in the therapy of exercise-induced or spontaneous episodes of angina pectoris. The dose of 0.4 or 0.8 mg would appear to be most effective and simfiar to 0.4 mg of sublingual GTN. (Am J Cardioi 1988; 57: 1-5)
T
he organic nitrates are the most frequently used agents in the management of patients with angina pectoris. Sublingual nitroglycerin (GTN) usually relieves angina pectoris and improves exercise tolerance when used prophylactical1y.l GTN is also available for oral
use,2 transmucosal administration by tablet,3 and transdermal application either by ointment4 or patch.5Jj GTN lingual spray has been available in Europe for several years but is not available in North America. This study was undertaken to study the efficacy of GTN lingual spray in patients with chronic stable exertional angina. The study design permitted assessment of the effect of multiple doses on hemody namic variables measured at rest and during exercise, exercise tolerance and electrocardiographic changes. The protocol also permitted comparison with a standard dose of 0.4 mg of sublingual GTN. The study thus permitted examination of the clinical efficacy and dose-response relation of GTN lingual spray in patients with angina pectoris.
From the Division of Cardiology, Department of Medicine, Queen’s University, Kingston, Ontario, Canada. This study was supported in part by grants from the Ontario Heart Foundation and the Medical Research Council, Kingston, Ontario, Canada. Manuscript received January 26, 1985; revised manuscript received May Z&1985, accepted May 22.1985. Address for reprints: John 0. Parker, MD, Division of Cardiology, Etherington Hall, Stuart Street, Queen’s University, Kingston, Ontario, Canada K7L 3N6. 1
2
NITROGLYCERIN
SPRAY
IN ANGINA
Methods Patients: Twenty patients (19 men, 1 woman], aged 49 to 70 years (mean 60), with chronic stable angina pectoris entered this study. Each patient had classic exertional angina pectoris and had a positive result on treadmill exercise testing, which included the development of chest pain and ischemic ST-segment depression (flat or downsloping ST segments of at least 1 mm at 60 ms after the J point]. The diagnosis of coronary artery disease was confirmed by documentation of previous myocardial infarction or by angiographitally significant coronary artery disease in 17 patients. No patient had cardiomegaly, heart failure, valvular disease, systemic hypertension or heart disease other than coronary artery disease. No patient was taking digitalis glycosides, calcium entry blocking agents, or nitrate preparations other than sublingual GTN. Four patients were receiving p-blocking agents and these were continued in the same dose throughout this investigation. Beta-blocking agents were not administered on the study days until the exercise tests were completed. Before entering the definitive study each patient underwent repeated treadmill exercise testing according to the Bruce protocol to familiarize them with the procedure and to determine the reproducibility of the exercise endpoint. The time to the onset of angina (PI) was noted and patients were asked to continue exercising until angina was of moderate severity (P,]. This was defined as the level of discomfort when the patient would normally stop activity and take sublingual GTN. During treadmill testing, systolic blood pressure was recorded at the end of each exercise stage and at PI and PZ. The CASE Marquette system, which provides data relating to heart rate and ST segments, was used. Before entry into the study, patients exercised on 3 or 4 occasions over several days until the endpoint Pz was reproducible within 90 seconds. Patients who demonstrated reproducibility and whose total exercise duration was less than 9 minutes with the Bruce protocol were eligible for this investigation. When reproducibility had been established, exercise testing was carried out 5 minutes after the sublingual administration of 0.4 mg of GTN. Patients were classified as nitrate responders if the time to P2 was increased by 60 seconds after GTN administration. When patients had demonstrated reproducible angina pectoris and nitrate responsiveness, they entered the definitive investigation after giving informed written consent. Definitive investigation: The definitive investigation consisted of a double-blind, randomized, crossover, placebo-controlled trial during which patients received (I] GTN lingual spray* (0.2,0.4 and 0.8 mg of GTN delivered per metered dose], (2) placebo lingual spray, and (31 sublingual GTN tablets (0.4 mg). Each spray delivered an identical volume (50 ~1) and these were administered in random order. The sublingual GTN was always administered last. * Nitrolingual spray@manufactured by G. Pohl-Boskamp (Germany) and supplied by Kremers Urban, Milwaukee, Wisconsin.
On the morning of study, patients came to the laboratory in the fasting state and not having taken sublingual GTN for at least 2 hours. Hemodynamic observations were made at rest and during treadmill exercise testing performed with observations as previously described. After a 30-minute recovery period, the patients received a lingual spray. The dorsal surface of the tongue was dried, a single spray applied and the mouth maintained open until the spray had dried. Hemodynamic observations were carried out after 4 minutes and treadmill exercise testing begun at 5 minutes. After a recovery period of 90 minutes, a second spray was administered and 90 minutes later, a third spray given. Hemodynamic observations were made and exercise testing carried out 5 minutes after each lingual spray. The patient returned to the laboratory the following morning. Control exercise testing was carried out and 30 minutes later, the fourth spray was administered and after 5 minutes, hemodynamic observations and exercise testing carried out. Ninety minutes later, the patients were given 0.4 mg of sublingual GTN and 5 minutes thereafter, hemodynamic observations and treadmill exercise testing were carried out. Analysis of variance was used to compare the effects of the 3 doses of GTN lingual spray and placebo. The dose-response relation was examined by regression analysis treating subjects as replicates.
Results There were no major untoward effects during this study. Only 4 instances of mild headache occurred during the 80 active treatment phases, and all 20 patients completed the investigation. Hemodynamics at rest (Table I, Fig. 1 and 2): The standing heart rate at rest before administration of each spray and sublingual GTN was similar. Each dose of GTN spray and the sublingual GTN produced a significant increase in the standing heart rate over that seen with placebo. An increase of 6, 9 and 13 beats/min was seen with 0.2, 0.4 and 0.8 mg of GTN spray, respectively (all with p values
January
TABLE
I
Hemodynamics
(Standing)
l-m (beatsimin) GTN-S GTN-S GTN-S GTN-S GTN-SL
72 f 74f 71 f 71 f 69f
JOURNAL
Treatment
OF CARDIOLOGY
After
SBP
ST 0-m)
(mm W
12 I2 13 I3 12
* Difference from placebo (p <0.05). GTN-S = nitroglycerin lingual spray; depresslon.
THE AMERICAN
Volume
57
129 126 122 126 I31
GTN-SL
zk 18 f 16 l 13 f 19 zk 16
= nitroglycerin
-0.1 -0.1 -0.1 -0.1 -0.1
sublingual;
0.2,0.4 and 0.8 mg of GTN spray were each significantly greater than that for placebo (p <0.05). There was a dose-response relation: 0.8 mg of GTN spray increased time to PI more than 0.4 mg of GTN spray, and 0.4 mg of GTN spray more than 0.2 mg of GTN spray (p CO.05). Sublingual GTN increased TWT to PI by 174 seconds (p
It: f f f
l
HR (beetslmin! 0.1 0.1 0.2 0.1 0.1
HR = heart
78 a3 84 72f 81
rate;
f f f f
Treatment SBP (mm Hg)
13’ 15’ 15’ 12 15’
120 113 114 128 116f
SBP = standing
systolic
ST
imw
f 20 f 16’ f 18’ f I8 17’
blood
pressure;
-0.1 -0.1 -0.1 0.0 0.0
f f f f f
0.2 0.2 0.1 0.1 0.1
ST = ST-segment
Treadmill exercise to moderate angina (Fig. 4): TWT to the development of Pz after each dose of GTN spray and with sublingual GTN was significantly greater than that seen with placebo. Placebo spray increased TWT above control level by 21 seconds, whereas the increase was 104, 134 and 143 seconds with O.&O.4 and 0.8 mg of GTN spray, and 158 seconds with sublingual GTN (p <0.05). There was an apparent dose-response relation with the GTN sprays (p <0.05]. Sublingual GTN produced an increase in TWT similar to that seen with 0.4 and 0.8 mg of GTN spray, but the effect was greater than that with 0.2 mg of GTN spray (p <0.025). The heart rate at Pz was slightly but not significantly greater than at PI with each GTN spray and sublingual GTN. The heart rate at Pz was significantly greater with each active medication than with the placebo spray (p
70-
65-
I Mean 2 SEM
+5b!h+
3
at Rest Before
0.2 mg 0.4 mg 0.8 mg Placebo 0.4 mg
1. 1986
0.4 (SL)
GTN FIGURE 1. Standing heart rate (HR) at rest increased signlflcantly over the placebo (PI) value with each dose of nitroglycerin (GTN) spray and subllngual (SL) GTN. The increases in HR showed a doseresponse relation with GTN spray because the HR was greater wlth 0.8 than with 0.4 mg of spray and the HR was greater with 0.4 than with 0.2 mg of GTN spray (p
I
I
I
I
PL
0.2
0.4
J 0.6
0.4
(SL
1
GTN FIGURE 2. Standing systolic blood pressure (SBP) decreased significantly over that with placebo (PI) with each dose of nitroglycerin (GTN) spray and with subllngual (SL) GTN. There were no significant differences apparent among the 3 doses of GTN spray, SEM = standard error of the mean. l p
4
NITROGLYCERIN
SPRAY
IN ANGINA
product at Pz significantly (p
I Meon?SEM 1
PL
0.2
I
I
0.4
0.8
I
0.4(SL)
GTN FIGURE 3. Treadmill walking time (TWT) to the onset of angina (P,) was prolonged with each of the doses of nitroglycerin (GIN) spray and with subilnguai (SL) GTN when compared with that seen with placebo (Pi). There was a dose-response relation for the GTN spray as TWT was greater with 0.8 than with 0.4 mg (p
TWT (P,) set
550r
500 450 -
400 350 -
1
’
I
1
I
PL
0.2
0.4
0.8
I 0.4 (SL)
GTN FIGURE 4. Treadmill walking time (TWT) to the development of moderate angina (P2) was significantly prolonged over placebo (Pi) with 0.2,0.4 and 0.8 mg of nitroglycerin (GTN) spray and 0.4 mg of sublingual (SL) GTN. There was a dose-response relation for the GTN spray as treadmill walking time was greater with 0.8 than with 0.4 mg and 0.4 mg exceeded 0.2 mg (p <0.05). SEM = standard error of the mean. l p X0.05.
January
dose of GTN spray, sublingual GTN and placebo. The time to the development of 1 mm of ST-segment depression was increased by each of the GTN sprays and sublingual GTN when compared with that seen with placebo (p
Discussion This investigation assessed the efficacy of GTN lingual spray in the prophylactic treatment of angina pet-m toris. The study was randomized, double-blind, placebo-controlled, and designed to determine clinical efficacy and to assess possible dose-response relations between varying doses of GTN lingual spray. Previous studies of GTN lingual spray that were single-blind showed improvement in exercise tolerance over placebo.7 The 20 patients who entered the present study had reproducible angina during exercise testing and had demonstrated responsiveness to sublingual GTN. Hemodynamic values at rest suggest the presence of a dose-response relation with the 3 strengths of GTN spray. Heart rate at rest increased significantly with each of the 3 active sprays and the increase was different for each dose, with the greatest change occurring with the 0.8-mg dosage. The increase in heart rate at rest with 0.4 mg of sublingual GTN was similar to that with 0.4 and 0.8 mg of GTN spray and greater than that observed with 0.2 mg of GTN spray. On the other hand, each active spray significantly reduced systolic blood pressure over that seen with placebo, but there were no significant differences among the 3 doses. Previous studies of the hemodynamic effects of GTN lingual spray have not explored dose-response relations.7,8 Kimchi et al7 studied GTN lingual spray in a single dose of 0.8 mg and found this to be effective in angina prophylaxis. Chevigne et al8 used 0.8 mg of GTN lingual spray and demonstrated that this significantly reduced wedge pressure, systemic arterial pressure and cardiac output and increased heart rate at rest. They did not assess changes in exercise tolerance. Each of the spray dosages was clinically effective as exercise time to PI and Pz was prolonged over placebo. Exercise times to PI and Pz showed a dose-response relation in that the prolongation of TWT increased more significantly as the dose of GTN spray was increased. The response of sublingual GTN was similar to that seen with 0.4 and 0.8 mg of GTN spray. The extent of ST-segment depression at the end of exercise was similar during each GTN spray, sublingual GTN and placebo. As another indicator of clinical efficacy, the exercise time to 1 mm of ST-segment depression was studied. Each of the lingual sprays and sublingual GTN significantly prolonged exercise time to this degree of ST-segment depression. However, there were no dose-response relations because the 3 spray doses and sublingual GTN were not significantly different. GTN lingual spray is an effective means of nitrate administration in the prophylaxis of exercise-induced angina pectoris. The data suggest that the 0.4- or 0.8-mg dosage would be most effective and comparable to the effect seen with 0.4 mg of sublingual GTN. Although
1, 1986
THE AMERICAN
JOURNAL
OF CARDIOLOGY
Volume
57
5
we did not test this agent in the treatment of episodes of exertionally induced angina, the results suggest that this would be as equally effective as sublingual GTN in the treatment of angina pectoris. However, the onset of action was not assessed in this investigation and the efficacy of this method of GTN administration for treatment of angina1 attacks is not known. Kimchi et al7 studied exercise tolerance 2 minutes after spray administration and found it effective. We did not assess the duration of action and it is uncertain how lingual GTN spray would compare with sublingual GTN in angina1 prophylaxis, The advantage of this method of administration would be that of ready availability and ease of application with prompt absorption. Absorption should occur even more quickly than sublingual GTN, particularly in patients with dry mucous membranes. Stability studies show that GTN in this form is stable and maintains its potency for at least a year.s This offers a distinct advantage over sublingual tablets, which lose their potency within a few weeks after the seal of the bottle has been broken. There is increasing concern over the development of nitrate tolerance during sustained oral nitrate therapy. Hemodynamic and antianginal tolerance have also been demonstrated with oraV’-12 and transdermalls isosorbide dinitrate and with transdermal GTN application.5 Delivery systems that produce steady-state plasma nitrate levels may be undesirable in the management of angina. Thus, intermittent nitrate therapy may be the best approach to nitrate therapy. This could be accomplished by infrequent oral, transdermal or transmucosal therapy. Many patients can be successfully treated with sublingual GTN alone and lingual spray provides an attractive alternate therapy for intermittent treatment.
References 1. Parker JO, Digiorgi S, West RO. A hemodynomic study of acute coronary insufficiency precipitated by exercise. With observations on the effect of nitroglycerin. Am f CardioJ 1966;17:470-483. 2. Winsor T, Berger Hj. Oval nitroglycerin as a prophylactic antianginal drug: clinical, physiologic, and statistical evidence of efficacy based on a threephase design. Am Heart [ 1975;90:611-626. 3. Reichek N, Priest C. Kienzle M. Kleveland JP, Bolton S. St John Sutton M. Angina prophylaxis with buccal synchron nitroglycerin: a rapid onset, Jongacting nitrate. Adv Pharmacother 1982;1:143-145. 4. Reichek N, Goldstein RE, Redwood DR, Epstein SE. Sustained effects of nitroglycerin ointment in patients with angina pectoris. Cir&Jation 2974;50:348-352, 5. Parker JO, Fung HL. Transdermal nitroglycerin in angina pectoris. Am f CardioJ 1984:54:471-476. 6. Reichek G, Priest C. Zimrin D, Chandler T, St John Sutton M. Antianginal effects of nitroglycerin patches. Am f CardioJ 1984;54:1-7. 7. Kimchi A, Lee G, Amsterdam E, Fuji K, Krieg P. Mason DT. Increased exercise tolerance after nitroglycerin oral spray: a new and effective therapeutic modality in angina pectoris. Circulation 1983;67:124-127. 8. Chevigne M, Collignon P. Kulbertus H. Hemodynamic response to glyceryl trinitrate in a spray at rest and during exercise in a sitting position. Cardiology 1982;69:84-90. 9. Data on File. G. Pohl-Boskamp. Gmbh. Hohenlockstedt, Federal Republic of Germany. 10. Thadani U, Fung HL, Darke AC, Parker JO. Oral isosorbide dinitrate in angina pectoris: comparison of duration of action and dose-response relation during acute and sustained therapy. Am r Cardiol 1982;49:411-419. 11. Dalal JJ. Yao L. Parker JO. Nitrate tolerance: influence of isosorbide dinitrate on the hemodynamic and antianginal effects oj nitroglycerin. IACC 1983;2:115-120.
12. Dalal II. Parker
10. Nitrate
dinitrate &d nitroglycerin 1984;54:286-288.
13. Parker JO, VanKoughnett in angina pectoris: effect 1984;54:8-13.
cross-tolerance: during sustained
effect
n&ate
of sublineual therapy.“Am
KA. Fung HL. Transdermal isosorbide of acute and sustained therapy. Am
isosorbide r CardioJ dinitrate
[ CardioJ
The
American
Journal
1, 1988
of CARDIOLOGY@ VOLUME
57
NUMBER
1
CORONARY HEART DISEASE
Nitroglycerinlingual Spray: ClinicalEfficacy and Dose-Response Relation JOHN 0. PARKER, MD, KAREN A. VANKOUGHNETT,
Twenty patients with chronic, stable, exercise-induced angina pectorts were studied after receiving lingual sprays that delivered 0.2, 0.4 and 0.8 mg of nitroglycerin (GM). The hemodynamic effects and changes in exercise time to the onset of angina and to the development of moderate angina were compared with those of placebo spray and 0.4 mg of sublingual GlN. A dose-response relation was apparent with the 3 doses of active spray for heart rate at rest but not for standing systolic blood pressure. Sublingual GTN produced effects similar to those with 0.4 and 0.8 mg of GIN spray, but exceeded the response to 0.2 mg of GTN spray.
RN, and BERNICE FARRELL,
RN
Treadmill waikfng time to the onset of angina and to the development of moderate angina was prolonged with each dose of GTN spray and showed a doseresponse relation with significantly greater effects with increasing doses of GTN spray. This study indicates that GlN lingual spray fs effective in the prophylaxis of angfna and should be effective in the therapy of exercise-induced or spontaneous episodes of angina pectoris. The dose of 0.4 or 0.8 mg would appear to be most effective and simfiar to 0.4 mg of sublingual GTN. (Am J Cardioi 1988; 57: 1-5)
T
he organic nitrates are the most frequently used agents in the management of patients with angina pectoris. Sublingual nitroglycerin (GTN) usually relieves angina pectoris and improves exercise tolerance when used prophylactical1y.l GTN is also available for oral
use,2 transmucosal administration by tablet,3 and transdermal application either by ointment4 or patch.5Jj GTN lingual spray has been available in Europe for several years but is not available in North America. This study was undertaken to study the efficacy of GTN lingual spray in patients with chronic stable exertional angina. The study design permitted assessment of the effect of multiple doses on hemody namic variables measured at rest and during exercise, exercise tolerance and electrocardiographic changes. The protocol also permitted comparison with a standard dose of 0.4 mg of sublingual GTN. The study thus permitted examination of the clinical efficacy and dose-response relation of GTN lingual spray in patients with angina pectoris.
From the Division of Cardiology, Department of Medicine, Queen’s University, Kingston, Ontario, Canada. This study was supported in part by grants from the Ontario Heart Foundation and the Medical Research Council, Kingston, Ontario, Canada. Manuscript received January 26, 1985; revised manuscript received May Z&1985, accepted May 22.1985. Address for reprints: John 0. Parker, MD, Division of Cardiology, Etherington Hall, Stuart Street, Queen’s University, Kingston, Ontario, Canada K7L 3N6. 1
2
NITROGLYCERIN
SPRAY
IN ANGINA
Methods Patients: Twenty patients (19 men, 1 woman], aged 49 to 70 years (mean 60), with chronic stable angina pectoris entered this study. Each patient had classic exertional angina pectoris and had a positive result on treadmill exercise testing, which included the development of chest pain and ischemic ST-segment depression (flat or downsloping ST segments of at least 1 mm at 60 ms after the J point]. The diagnosis of coronary artery disease was confirmed by documentation of previous myocardial infarction or by angiographitally significant coronary artery disease in 17 patients. No patient had cardiomegaly, heart failure, valvular disease, systemic hypertension or heart disease other than coronary artery disease. No patient was taking digitalis glycosides, calcium entry blocking agents, or nitrate preparations other than sublingual GTN. Four patients were receiving p-blocking agents and these were continued in the same dose throughout this investigation. Beta-blocking agents were not administered on the study days until the exercise tests were completed. Before entering the definitive study each patient underwent repeated treadmill exercise testing according to the Bruce protocol to familiarize them with the procedure and to determine the reproducibility of the exercise endpoint. The time to the onset of angina (PI) was noted and patients were asked to continue exercising until angina was of moderate severity (P,]. This was defined as the level of discomfort when the patient would normally stop activity and take sublingual GTN. During treadmill testing, systolic blood pressure was recorded at the end of each exercise stage and at PI and PZ. The CASE Marquette system, which provides data relating to heart rate and ST segments, was used. Before entry into the study, patients exercised on 3 or 4 occasions over several days until the endpoint Pz was reproducible within 90 seconds. Patients who demonstrated reproducibility and whose total exercise duration was less than 9 minutes with the Bruce protocol were eligible for this investigation. When reproducibility had been established, exercise testing was carried out 5 minutes after the sublingual administration of 0.4 mg of GTN. Patients were classified as nitrate responders if the time to P2 was increased by 60 seconds after GTN administration. When patients had demonstrated reproducible angina pectoris and nitrate responsiveness, they entered the definitive investigation after giving informed written consent. Definitive investigation: The definitive investigation consisted of a double-blind, randomized, crossover, placebo-controlled trial during which patients received (I] GTN lingual spray* (0.2,0.4 and 0.8 mg of GTN delivered per metered dose], (2) placebo lingual spray, and (31 sublingual GTN tablets (0.4 mg). Each spray delivered an identical volume (50 ~1) and these were administered in random order. The sublingual GTN was always administered last. * Nitrolingual spray@manufactured by G. Pohl-Boskamp (Germany) and supplied by Kremers Urban, Milwaukee, Wisconsin.
On the morning of study, patients came to the laboratory in the fasting state and not having taken sublingual GTN for at least 2 hours. Hemodynamic observations were made at rest and during treadmill exercise testing performed with observations as previously described. After a 30-minute recovery period, the patients received a lingual spray. The dorsal surface of the tongue was dried, a single spray applied and the mouth maintained open until the spray had dried. Hemodynamic observations were carried out after 4 minutes and treadmill exercise testing begun at 5 minutes. After a recovery period of 90 minutes, a second spray was administered and 90 minutes later, a third spray given. Hemodynamic observations were made and exercise testing carried out 5 minutes after each lingual spray. The patient returned to the laboratory the following morning. Control exercise testing was carried out and 30 minutes later, the fourth spray was administered and after 5 minutes, hemodynamic observations and exercise testing carried out. Ninety minutes later, the patients were given 0.4 mg of sublingual GTN and 5 minutes thereafter, hemodynamic observations and treadmill exercise testing were carried out. Analysis of variance was used to compare the effects of the 3 doses of GTN lingual spray and placebo. The dose-response relation was examined by regression analysis treating subjects as replicates.
Results There were no major untoward effects during this study. Only 4 instances of mild headache occurred during the 80 active treatment phases, and all 20 patients completed the investigation. Hemodynamics at rest (Table I, Fig. 1 and 2): The standing heart rate at rest before administration of each spray and sublingual GTN was similar. Each dose of GTN spray and the sublingual GTN produced a significant increase in the standing heart rate over that seen with placebo. An increase of 6, 9 and 13 beats/min was seen with 0.2, 0.4 and 0.8 mg of GTN spray, respectively (all with p values
January
TABLE
I
Hemodynamics
(Standing)
l-m (beatsimin) GTN-S GTN-S GTN-S GTN-S GTN-SL
72 f 74f 71 f 71 f 69f
JOURNAL
Treatment
OF CARDIOLOGY
After
SBP
ST 0-m)
(mm W
12 I2 13 I3 12
* Difference from placebo (p <0.05). GTN-S = nitroglycerin lingual spray; depresslon.
THE AMERICAN
Volume
57
129 126 122 126 I31
GTN-SL
zk 18 f 16 l 13 f 19 zk 16
= nitroglycerin
-0.1 -0.1 -0.1 -0.1 -0.1
sublingual;
0.2,0.4 and 0.8 mg of GTN spray were each significantly greater than that for placebo (p <0.05). There was a dose-response relation: 0.8 mg of GTN spray increased time to PI more than 0.4 mg of GTN spray, and 0.4 mg of GTN spray more than 0.2 mg of GTN spray (p CO.05). Sublingual GTN increased TWT to PI by 174 seconds (p
It: f f f
l
HR (beetslmin! 0.1 0.1 0.2 0.1 0.1
HR = heart
78 a3 84 72f 81
rate;
f f f f
Treatment SBP (mm Hg)
13’ 15’ 15’ 12 15’
120 113 114 128 116f
SBP = standing
systolic
ST
imw
f 20 f 16’ f 18’ f I8 17’
blood
pressure;
-0.1 -0.1 -0.1 0.0 0.0
f f f f f
0.2 0.2 0.1 0.1 0.1
ST = ST-segment
Treadmill exercise to moderate angina (Fig. 4): TWT to the development of Pz after each dose of GTN spray and with sublingual GTN was significantly greater than that seen with placebo. Placebo spray increased TWT above control level by 21 seconds, whereas the increase was 104, 134 and 143 seconds with O.&O.4 and 0.8 mg of GTN spray, and 158 seconds with sublingual GTN (p <0.05). There was an apparent dose-response relation with the GTN sprays (p <0.05]. Sublingual GTN produced an increase in TWT similar to that seen with 0.4 and 0.8 mg of GTN spray, but the effect was greater than that with 0.2 mg of GTN spray (p <0.025). The heart rate at Pz was slightly but not significantly greater than at PI with each GTN spray and sublingual GTN. The heart rate at Pz was significantly greater with each active medication than with the placebo spray (p
70-
65-
I Mean 2 SEM
+5b!h+
3
at Rest Before
0.2 mg 0.4 mg 0.8 mg Placebo 0.4 mg
1. 1986
0.4 (SL)
GTN FIGURE 1. Standing heart rate (HR) at rest increased signlflcantly over the placebo (PI) value with each dose of nitroglycerin (GTN) spray and subllngual (SL) GTN. The increases in HR showed a doseresponse relation with GTN spray because the HR was greater wlth 0.8 than with 0.4 mg of spray and the HR was greater with 0.4 than with 0.2 mg of GTN spray (p
I
I
I
I
PL
0.2
0.4
J 0.6
0.4
(SL
1
GTN FIGURE 2. Standing systolic blood pressure (SBP) decreased significantly over that with placebo (PI) with each dose of nitroglycerin (GTN) spray and with subllngual (SL) GTN. There were no significant differences apparent among the 3 doses of GTN spray, SEM = standard error of the mean. l p
4
NITROGLYCERIN
SPRAY
IN ANGINA
product at Pz significantly (p
I Meon?SEM 1
PL
0.2
I
I
0.4
0.8
I
0.4(SL)
GTN FIGURE 3. Treadmill walking time (TWT) to the onset of angina (P,) was prolonged with each of the doses of nitroglycerin (GIN) spray and with subilnguai (SL) GTN when compared with that seen with placebo (Pi). There was a dose-response relation for the GTN spray as TWT was greater with 0.8 than with 0.4 mg (p
TWT (P,) set
550r
500 450 -
400 350 -
1
’
I
1
I
PL
0.2
0.4
0.8
I 0.4 (SL)
GTN FIGURE 4. Treadmill walking time (TWT) to the development of moderate angina (P2) was significantly prolonged over placebo (Pi) with 0.2,0.4 and 0.8 mg of nitroglycerin (GTN) spray and 0.4 mg of sublingual (SL) GTN. There was a dose-response relation for the GTN spray as treadmill walking time was greater with 0.8 than with 0.4 mg and 0.4 mg exceeded 0.2 mg (p <0.05). SEM = standard error of the mean. l p X0.05.
January
dose of GTN spray, sublingual GTN and placebo. The time to the development of 1 mm of ST-segment depression was increased by each of the GTN sprays and sublingual GTN when compared with that seen with placebo (p
Discussion This investigation assessed the efficacy of GTN lingual spray in the prophylactic treatment of angina pet-m toris. The study was randomized, double-blind, placebo-controlled, and designed to determine clinical efficacy and to assess possible dose-response relations between varying doses of GTN lingual spray. Previous studies of GTN lingual spray that were single-blind showed improvement in exercise tolerance over placebo.7 The 20 patients who entered the present study had reproducible angina during exercise testing and had demonstrated responsiveness to sublingual GTN. Hemodynamic values at rest suggest the presence of a dose-response relation with the 3 strengths of GTN spray. Heart rate at rest increased significantly with each of the 3 active sprays and the increase was different for each dose, with the greatest change occurring with the 0.8-mg dosage. The increase in heart rate at rest with 0.4 mg of sublingual GTN was similar to that with 0.4 and 0.8 mg of GTN spray and greater than that observed with 0.2 mg of GTN spray. On the other hand, each active spray significantly reduced systolic blood pressure over that seen with placebo, but there were no significant differences among the 3 doses. Previous studies of the hemodynamic effects of GTN lingual spray have not explored dose-response relations.7,8 Kimchi et al7 studied GTN lingual spray in a single dose of 0.8 mg and found this to be effective in angina prophylaxis. Chevigne et al8 used 0.8 mg of GTN lingual spray and demonstrated that this significantly reduced wedge pressure, systemic arterial pressure and cardiac output and increased heart rate at rest. They did not assess changes in exercise tolerance. Each of the spray dosages was clinically effective as exercise time to PI and Pz was prolonged over placebo. Exercise times to PI and Pz showed a dose-response relation in that the prolongation of TWT increased more significantly as the dose of GTN spray was increased. The response of sublingual GTN was similar to that seen with 0.4 and 0.8 mg of GTN spray. The extent of ST-segment depression at the end of exercise was similar during each GTN spray, sublingual GTN and placebo. As another indicator of clinical efficacy, the exercise time to 1 mm of ST-segment depression was studied. Each of the lingual sprays and sublingual GTN significantly prolonged exercise time to this degree of ST-segment depression. However, there were no dose-response relations because the 3 spray doses and sublingual GTN were not significantly different. GTN lingual spray is an effective means of nitrate administration in the prophylaxis of exercise-induced angina pectoris. The data suggest that the 0.4- or 0.8-mg dosage would be most effective and comparable to the effect seen with 0.4 mg of sublingual GTN. Although
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THE AMERICAN
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we did not test this agent in the treatment of episodes of exertionally induced angina, the results suggest that this would be as equally effective as sublingual GTN in the treatment of angina pectoris. However, the onset of action was not assessed in this investigation and the efficacy of this method of GTN administration for treatment of angina1 attacks is not known. Kimchi et al7 studied exercise tolerance 2 minutes after spray administration and found it effective. We did not assess the duration of action and it is uncertain how lingual GTN spray would compare with sublingual GTN in angina1 prophylaxis, The advantage of this method of administration would be that of ready availability and ease of application with prompt absorption. Absorption should occur even more quickly than sublingual GTN, particularly in patients with dry mucous membranes. Stability studies show that GTN in this form is stable and maintains its potency for at least a year.s This offers a distinct advantage over sublingual tablets, which lose their potency within a few weeks after the seal of the bottle has been broken. There is increasing concern over the development of nitrate tolerance during sustained oral nitrate therapy. Hemodynamic and antianginal tolerance have also been demonstrated with oraV’-12 and transdermalls isosorbide dinitrate and with transdermal GTN application.5 Delivery systems that produce steady-state plasma nitrate levels may be undesirable in the management of angina. Thus, intermittent nitrate therapy may be the best approach to nitrate therapy. This could be accomplished by infrequent oral, transdermal or transmucosal therapy. Many patients can be successfully treated with sublingual GTN alone and lingual spray provides an attractive alternate therapy for intermittent treatment.
References 1. Parker JO, Digiorgi S, West RO. A hemodynomic study of acute coronary insufficiency precipitated by exercise. With observations on the effect of nitroglycerin. Am f CardioJ 1966;17:470-483. 2. Winsor T, Berger Hj. Oval nitroglycerin as a prophylactic antianginal drug: clinical, physiologic, and statistical evidence of efficacy based on a threephase design. Am Heart [ 1975;90:611-626. 3. Reichek N, Priest C. Kienzle M. Kleveland JP, Bolton S. St John Sutton M. Angina prophylaxis with buccal synchron nitroglycerin: a rapid onset, Jongacting nitrate. Adv Pharmacother 1982;1:143-145. 4. Reichek N, Goldstein RE, Redwood DR, Epstein SE. Sustained effects of nitroglycerin ointment in patients with angina pectoris. Cir&Jation 2974;50:348-352, 5. Parker JO, Fung HL. Transdermal nitroglycerin in angina pectoris. Am f CardioJ 1984:54:471-476. 6. Reichek G, Priest C. Zimrin D, Chandler T, St John Sutton M. Antianginal effects of nitroglycerin patches. Am f CardioJ 1984;54:1-7. 7. Kimchi A, Lee G, Amsterdam E, Fuji K, Krieg P. Mason DT. Increased exercise tolerance after nitroglycerin oral spray: a new and effective therapeutic modality in angina pectoris. Circulation 1983;67:124-127. 8. Chevigne M, Collignon P. Kulbertus H. Hemodynamic response to glyceryl trinitrate in a spray at rest and during exercise in a sitting position. Cardiology 1982;69:84-90. 9. Data on File. G. Pohl-Boskamp. Gmbh. Hohenlockstedt, Federal Republic of Germany. 10. Thadani U, Fung HL, Darke AC, Parker JO. Oral isosorbide dinitrate in angina pectoris: comparison of duration of action and dose-response relation during acute and sustained therapy. Am r Cardiol 1982;49:411-419. 11. Dalal JJ. Yao L. Parker JO. Nitrate tolerance: influence of isosorbide dinitrate on the hemodynamic and antianginal effects oj nitroglycerin. IACC 1983;2:115-120.
12. Dalal II. Parker
10. Nitrate
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cross-tolerance: during sustained
effect
n&ate
of sublineual therapy.“Am
KA. Fung HL. Transdermal isosorbide of acute and sustained therapy. Am
isosorbide r CardioJ dinitrate
[ CardioJ