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Transdermal nitroglycerin
Volume Number
112 6
mental animals on inotropic mechanisms and atrioventricular (AV) block may not be applicable in postoperative humans. We plan to compare the effects of digoxin versus digitoxin in patients with postoperative ventricular dysfunction to observe whether significant pharmacodynamic differences exist between these compounds in this clinical situation. We appreciate Dr. Runge’s comments and his interest in our common area of research, cardiac glycosides. L. Scott Cook, M.D. Ph.D. Thoracic and Cardiovascular Surgery University of Kansas 39th and Rainbow Blud. Kansas City, KS 66103
TRANSDERMAL
NITROGLYCERIN
To the Editor: Dr. S. Scardi et al. undertook a double-blind, placebocontrolled study to examine the effects of the transdermal reservoir nitroglycerin system (TTS, transdermal therapeutic system).’ They report that a single application improved exercise capacity over a 24-hour period. In their Discussion they point out that “we decided to assess the efficacy of TTS-NTG on the basis of clinical picture only.” Therefore, it would seem that a reasonable end-point for their study should be the development of angina. Table IIA shows that placebo-treated patients all developed moderate angina with ST segment depression exceeding 2 mm during the effort test. On the other hand, those treated with TTS 20 cm1 developed angina at 4 hours in 11 of 15 patients and at 24 hours in 13 of 15 patients, indicating no subjective benefit. Those treated with TTS 40 cm’ had a modest improvement at 4 hours (only 6 of 15 developed angina) with no improvement at 24 hours (13 of 15 developed angina, p < 0.01 by chi-square test with Fisher’s exact correction). Therefore, an alternate interpretation of their study is that very substantial tolerance developed to TTS-20 cm” or that it was not effective, and that for TTS-40 cm’, the benefit was more marked at 4 hours than at 24 hours (p < 0.01). This alternate interpretation is compatible with the concept that transdermal nitrate patches frequently lead to the development of nitrate tolerance. Lionel H. Opie, M.D., Ph.D. Heart Research Unit Uniuersity of Cape Town Medical School Observatory 7925 Cape Town, South Africa REFERENCE
Scardi S. Pivotti F, Fonda F, Pandullo C, Caatelli M, Pollavini G: Effect of a new transdermal therapeutic system containing nitroglycerin on exercise capacity in patients with angina pectoris. AM HEART J 1985;110:546.
REPLY To the Editor: We appreciate very much the interest and the comments of Professor Opie on our paper about the effects of the Transdermal Therapeutic System (TTS) in patients with stable exercise-
induced angina pectoris. We agree with some comments of ProI. Gpie, while upon other issues we have different opinions. Our decision to evaluate this drug on the basis of the clinical picture only was taken because, for technical reasons, we were unahle to make a parallel pharmacokinetic study. Nevertheiess, we appreciate that such a study would have improved ~zur understanding of the clinical results we obtained. Because ours was an acute study, we decided ttl evaluate the effectiveness of TTS with the use of the ergometric test, taking as end points those parameters that are generally considered to be the most objective-i.e., the duration of exercise to 1 mm ST segment depression, the total duration of exercise. and the t.otal work. We do not feel that the development >)I’ angina is a sufficiently reliable parameter, because it ran o ;I? be riut).jrc,tivei! assessed by the patients themselves. In any case, it is not suprising that many patients in our study stopped the exercise test as a resolt of angin.r. No antianginal drug can abolish angina1 pain in all patietith sod therefore, in evaluating the efficacy of a drug, it is 1101 the r!;cmher nf pc~t~nts experiencing angina1 pain that is important iu the ergometric laboratory, the exercise test could be too demailding with respect to everyday activitiesi, but the workload Ir~~~~i ;tt which such paili is experienced. It is clear from Table III of our paper that the t.w~ TTS doses significantly increased exercise tolerance. This means that our patient population was able to withstand higher work. loads during TTS therapy than during placeno, thus showing a delay in the onset of angina1 pain and myocardial ischemla. AS far as the reduction of efficacy at the twvnty-fourth hour is concerned, we agree with Dr. Opie that IhI,, could be doe 1,) nitrate tolerance, even if we do not exclude other hypotheses related to the characteristics of the patch cvstem itself. With regard to this subject, we have recently concluded a cc)mplex work, with the aim of studying the phenomemrn of tolerance. ‘l’be manuscript of this study is being prepared at ! he moment. and we feel that it could contribute to a hettrr umIer\tanding of this particular aspect of nit,rate therap\. S .S;rn rtii h’ f’iLvsttl F k’ortda ! ’ l’andff II0 M. (‘nst‘.+li C
l.Jvpartrn~nt
l+~llal.lni
of Ccrrdid,~~~~
(‘I& Hospital !‘/mza Osprdalv, I i’rr
TIAPAMIL PROTECTION IN AMI To the Editor. Recently, Koredenat and Leasure’ demonstrated that tiapamil has a protective effect on myocardial infarction following thrombotic occlusion of a coronary artery, as well as limiting the resulting myocardial infarction size. In discussing the potential mechanism of this effect, the authors did not comment. on the potential beneficial effects of the antiarrhythmic properties of this new calcium antagonist. It has been shown’ that tiapamil shares its influence on cation movements. partially with the antiarrhythmic drugs of group I and partially with those of group IV. Because tiapamil also prolongs the plateau phase of the ventricular action potential, the drug ever; qrems ttr exer! an
112 6
mental animals on inotropic mechanisms and atrioventricular (AV) block may not be applicable in postoperative humans. We plan to compare the effects of digoxin versus digitoxin in patients with postoperative ventricular dysfunction to observe whether significant pharmacodynamic differences exist between these compounds in this clinical situation. We appreciate Dr. Runge’s comments and his interest in our common area of research, cardiac glycosides. L. Scott Cook, M.D. Ph.D. Thoracic and Cardiovascular Surgery University of Kansas 39th and Rainbow Blud. Kansas City, KS 66103
TRANSDERMAL
NITROGLYCERIN
To the Editor: Dr. S. Scardi et al. undertook a double-blind, placebocontrolled study to examine the effects of the transdermal reservoir nitroglycerin system (TTS, transdermal therapeutic system).’ They report that a single application improved exercise capacity over a 24-hour period. In their Discussion they point out that “we decided to assess the efficacy of TTS-NTG on the basis of clinical picture only.” Therefore, it would seem that a reasonable end-point for their study should be the development of angina. Table IIA shows that placebo-treated patients all developed moderate angina with ST segment depression exceeding 2 mm during the effort test. On the other hand, those treated with TTS 20 cm1 developed angina at 4 hours in 11 of 15 patients and at 24 hours in 13 of 15 patients, indicating no subjective benefit. Those treated with TTS 40 cm’ had a modest improvement at 4 hours (only 6 of 15 developed angina) with no improvement at 24 hours (13 of 15 developed angina, p < 0.01 by chi-square test with Fisher’s exact correction). Therefore, an alternate interpretation of their study is that very substantial tolerance developed to TTS-20 cm” or that it was not effective, and that for TTS-40 cm’, the benefit was more marked at 4 hours than at 24 hours (p < 0.01). This alternate interpretation is compatible with the concept that transdermal nitrate patches frequently lead to the development of nitrate tolerance. Lionel H. Opie, M.D., Ph.D. Heart Research Unit Uniuersity of Cape Town Medical School Observatory 7925 Cape Town, South Africa REFERENCE
Scardi S. Pivotti F, Fonda F, Pandullo C, Caatelli M, Pollavini G: Effect of a new transdermal therapeutic system containing nitroglycerin on exercise capacity in patients with angina pectoris. AM HEART J 1985;110:546.
REPLY To the Editor: We appreciate very much the interest and the comments of Professor Opie on our paper about the effects of the Transdermal Therapeutic System (TTS) in patients with stable exercise-
induced angina pectoris. We agree with some comments of ProI. Gpie, while upon other issues we have different opinions. Our decision to evaluate this drug on the basis of the clinical picture only was taken because, for technical reasons, we were unahle to make a parallel pharmacokinetic study. Nevertheiess, we appreciate that such a study would have improved ~zur understanding of the clinical results we obtained. Because ours was an acute study, we decided ttl evaluate the effectiveness of TTS with the use of the ergometric test, taking as end points those parameters that are generally considered to be the most objective-i.e., the duration of exercise to 1 mm ST segment depression, the total duration of exercise. and the t.otal work. We do not feel that the development >)I’ angina is a sufficiently reliable parameter, because it ran o ;I? be riut).jrc,tivei! assessed by the patients themselves. In any case, it is not suprising that many patients in our study stopped the exercise test as a resolt of angin.r. No antianginal drug can abolish angina1 pain in all patietith sod therefore, in evaluating the efficacy of a drug, it is 1101 the r!;cmher nf pc~t~nts experiencing angina1 pain that is important iu the ergometric laboratory, the exercise test could be too demailding with respect to everyday activitiesi, but the workload Ir~~~~i ;tt which such paili is experienced. It is clear from Table III of our paper that the t.w~ TTS doses significantly increased exercise tolerance. This means that our patient population was able to withstand higher work. loads during TTS therapy than during placeno, thus showing a delay in the onset of angina1 pain and myocardial ischemla. AS far as the reduction of efficacy at the twvnty-fourth hour is concerned, we agree with Dr. Opie that IhI,, could be doe 1,) nitrate tolerance, even if we do not exclude other hypotheses related to the characteristics of the patch cvstem itself. With regard to this subject, we have recently concluded a cc)mplex work, with the aim of studying the phenomemrn of tolerance. ‘l’be manuscript of this study is being prepared at ! he moment. and we feel that it could contribute to a hettrr umIer\tanding of this particular aspect of nit,rate therap\. S .S;rn rtii h’ f’iLvsttl F k’ortda ! ’ l’andff II0 M. (‘nst‘.+li C
l.Jvpartrn~nt
l+~llal.lni
of Ccrrdid,~~~~
(‘I& Hospital !‘/mza Osprdalv, I i’rr
TIAPAMIL PROTECTION IN AMI To the Editor. Recently, Koredenat and Leasure’ demonstrated that tiapamil has a protective effect on myocardial infarction following thrombotic occlusion of a coronary artery, as well as limiting the resulting myocardial infarction size. In discussing the potential mechanism of this effect, the authors did not comment. on the potential beneficial effects of the antiarrhythmic properties of this new calcium antagonist. It has been shown’ that tiapamil shares its influence on cation movements. partially with the antiarrhythmic drugs of group I and partially with those of group IV. Because tiapamil also prolongs the plateau phase of the ventricular action potential, the drug ever; qrems ttr exer! an