JACC Vol. 20, No.5 November I, 1992
LETTERS TO THE EDITOR
Reply
Our study (I) concerned a satellite protocol of the large scale placebo-controlled Anglo-Scandinavian Study of Early Thrombolysis (ASSET) study, which was started in November 1986 (2). Until its termination on February 29, 1988, >S,OOO patients with acute ischemic heart disease were allocated to therapy with placebo or recombinant tissue-type plasminogen activator (rt-PA). Neither we nor the scientific ethical committee of Denmark considered it unethical to conduct a small placebo-controlled satellite study starting on October I, 1987. In evaluating the ethical considerations at that time we assessed all available data including, as mentioned by Geraci, the documentation that thrombolytic therapy with streptokinase or anisoylated plasminogen streptokinase activator complex (APSAC) reduces the mortality rate in patients with acute myocardial infarction (3,4), the risk of serious bleeding complications and, in particular, the absence of knowledge about the clinical efficacy of rt-PA therapy. The results of the ASSET study were published on September 3, 1988 (2) >3 months after we had stopped including patients in our investigation (I,S). The ASSET study was prematurely terminated on February 29, 1988 because the ethical committee of that study considered it unethical to allocate patients with acute myocardial infarction to placebo treatment (2). Having learned of their decision, we stopped allocating patients to placebo treatment on the next day. These ethical aspects of our study are described in detail in a separate investigation (S). We consider the arguments forwarded by Geraci to be somewhat simplistic. His ethical judgments of scientific investigators are based on retrospective considerations and focus only on the dates in the total process of conducting placebo-controlled studies. These dates, and particularly the dates of termination of such studies, are an essential part of the information and should be correct. We suggest that Geraci improve his figure by indicating the premature termination of the ASSET study and our investigation. STEFFEN MUNKVAD, MD J0RGEN JESPERSEN, MD, DSc J0RGEN GRAM, MD, DSc Section of Coagulation and Fibrinolysis Department of Clinical Chemistry Ribe County Hospital in Esbjerg 6700 Esbjerg, Denmark
CORNELIS KLUFT, MSc, DSc Gaubius Institute TNO Leiden, The Netherlands
References 1. Munkvad S, Jespersen J, Gram J, Kluft C. Long·lasting depression of the factor XII-dependent fibrinolytic system in patients with myocardial infarction undergoing thrombol}1ic therapy with recombinant tissue·type plasminogen activator: a randomized placebo-controlled study. J Am Coli Cardiol 1991;17:957-62. 2. Wilcox RG, von der Lippe G, Olsson CG, Jensen G, Skene AM, Hampton JR, for the ASSET Study Group. Trial of tissue plasminogen activator for mortality reduction in acute myocardial infarction. Anglo-Scandinavian Study of Early Thrombolysis (ASSET). Lancet 1988;2:525-30. 3. Gruppo Italiano per 10 Studio della Streptochinasi nelI'lnfarto Miocardico (GlSSI). Effectiveness of intravenous thrombolytic treatment in acute myocardial infarction. Lancet 1986;1:397-402. 4. AIMS Trial Study Group. Effect of intm'enous APSAC on mortality after acute myocardial infarction: preliminary report of a placebo-controlled clinical trial. Lancet 1988;1:545-9. 5. Munkvad S, Gram J, Jespersen J, Grande P. Reduction of infarct size estimated enzymatically in patients with acute myocardial infarction after treatment with recom· binant tissue·type plasminogen activator or after spontaneous coronary recanalisation: a randomised, placebo-controlled study. Fibrinolysis 1990;4:95-9.
1303
Diastolic Function in Hypertrophic Cardiomyopathy Nihoyannopoulos et al. (I) are to be congratulated on their study correlating Doppler indexes of diastolic filling at rest with exercise capacity in patients with hypertrophic cardiomyopathy. The large number of patients involved make this an important contribution. However, several important methodologic considerations limit the ability to draw conclusions regarding the mechanism of exercise intolerance in the study patients. \. Fifty percent of the patients had at least mild mitral regurgitation. With the exercise-induced increase in systolic blood pressure, the degree of mitral regurgitation would be expected to increase. In addition to potentially altering results of Doppler indexes of diastolic left ventricular filling, significant mitral regurgitation would also be expected to limit exercise capacity. 2. It is not stated whether an attempt was made to detect concomitant ischemic heart disease, another possible source of exercise limitation. Up to 20% of patients in another study of hypertrophic cardiomyopathy (2) had associated significant coronary artery disease and the prevalence was greater in older patients. The patients studied by Nihoyannopoulos et al. ranged in age up to 74 years and nearly SO% had exertional chest pain. 3. During data collection, nearly SO% of the patients were taking negative inotropic and chronotropic medications such as verapamil and beta-adrenergic blocking agents, and nearly all were taking amiodarone. Although the effect of amiodarone is less well documented, in normal subjects, beta-blockers significantly limit exercise capacity (3) and calcium channel blockers may significantly alter Doppler filling indexes (4). Because presumably none of the normal subjects had mitral regurgitation, possible concomitant ischemic heart disease or concurrent cardioactive medication use, these factors may have confounded the interpretation of the data. 4. The patient group was quite heterogeneous with respect to age, distribution of hypertrophy and presence of mitral regurgitation and left ventricular outflow tract obstruction; these factors could independently alter Doppler filling indexes, and this heterogeneity could have limited the ability to correlate these indexes with maximal oxygen consumption. S. Because age substantially affects maximal oxygen consumption (S), did the subset of normal subjects who underwent exercise testing represent a close age match for the patient group? Finally, the maximal oxygen consumption levels shown for the normal subjects are those one would expect from well conditioned subjects, particularly if they were age matched to the patients. Unfortunately, the previous study from their laboratory referenced in the Methods section (6) does not describe the physical activity status of the normal subjects. Because degree of physical conditioning is another important independent determinant of maximal oxygen consumption (S), and because it is doubtful that patients who had the symptoms noted in the Methods section were very active, a group of sedentary subjects may have been a more appropriate control group. An additional concern is that of potential overlap of patient data sets. Were any of the patients in their previous study (6) included in the present one? If so, did they undergo separate exercise testing for this present study? If not, because the exercise testing methodology in the previous study included invasive hemodynamic monitoring for the patients, this represents another potential difference from the
1304
LEITERS TO THE EDITOR
JACC Vol. 20. No.5 November 1. 1992
control subjects that could have limited the observed exercise capacity in the patients.
PETROS NIHOYANNOPOULOS, MD, FACC CELIA M. OAKLEY, MD, FRCP, FACC
DALANE W. KITZMAN, MD
Royal Postgraduate Medical School Hammersmith Hospital Du Cane Road London W12 OHS, England
Division of Cardiology Bowman Gray School of Medicine Medical Center Boulel'Qrd Winston·Salem, North Carolina 27157
References I. Tesch PA. Kaiser P. Effect of bela-adrenergic blockade on maximal oxygen uptake in
References I. Nihoyannopoulos P, Karatasakis G. Frenneaux M. McKenna WJ. Oakley CM. Dias·
2. 3. 4. 5. 6.
tolic function in hypertrophic cardiomyopathy: relation to exercise capacity. J Am Coli Cardioll992;19:536-40. Cokkinos DV. Krajcer Z. Leachman RD. Hypertrophic cardiomyopathy and associated coronary artery disease. Tex Heart Inst J 1985;12:147-51. Tesch PA, Kaiser P. Effect of beta-adrenergic blockade on maximal oxygen uptake in trained males. Acta Physiol Scand 1981 ;112:351-3. Plotnick GO. Changes in diastolic function-difficult to measure. harder to interpret. Am Heart J 1989;118:637-41. Higginbotham MB, Morris KG. Williams RS. et aI. Physiologic basis for the age-related decline in aerobic work capacity. Am J CardioI1986;57:1374-9. Frenneaux MP. Porter A. Caforio ALP, Odawara H. Counihan PJ. McKenna WJ. Determinants of exercise capacity in hypertrophic cardiomyopathy. J Am Coli Cardiol 1989;13:1521-6.
Reply
The aim of our study was not to list known potential influences on Doppler diastolic indexes but to relate those indexes to the patient's professed symptomatic status and exercise capacity so that each patient in effect served as his or her own control. Our patient group was closely matched with a normal group for comparison of Doppler indexes and exercise capacity. No patient had significant mitral incompetence and all had normal findings on coronary angiography at a time unrelated to the current study. Although beta-adrenergic blocking agents may have a limiting effect on oxygen uptake in trained men (I), in patients with hypertrophic cardiomyopathy, these agents have a beneficial effect on diastolic function and patient symptoms (2,3). Verapamil is more likely to alter diastolic indexes and has a tendency to normalize them (4). However, only four of our patients were taking verapamil during the study and their inclusion does not influence our results in 40 patients.
trained males. Acta Physiol Scand 1981 ;112:351-3. 2. Swanton RH. Brooksby lAB. Jenkins BS. Webb-Peploe MM. Haemodynamic studies on beta blockade in hypertrophic obstructive cardiomyopathy. Eur J Cardiol 1977;5: 327. 3. Alvarez RP. Goodwin JF. Noninvasive assessment of diastolic function in hypertrophic cardiomyopathy on and off beta adrenergic blocking drugs. Br Heart J 1982;48:204. 4. Bonow RO. Dilsizian V. Rosino DR. et aI. Verapamil·induced improvement in left vent~cular ~iastolic filling and increased exercise tolerance in patients ....ith hypertrophIc cardIomyopathy: short- and long-term effects. Circulation 1985;72:853-64.
Correction A correction should be made to Table 2 in the article by Rihal et al. in the May issue of the Journal (Rihal CS, Gersh BJ, Whisnant JP, et al. Influence of coronary heart disease on morbidity and mortality after carotid endarterectomy: a population-based study in Olmsted County, Minnesota [1970-1988]. J Am Coll Cardiol 1992;19:125460). The numbers in the last line of Table 2 were incorrectly transposed from Table 1. The authors apologize for the error and provide the following corrected version: Table 2: Distribution of All Postoperative Cardiac Events Through July I, 1989 Among Olmsted County Residents Who Underwent Carotid Endarterectomy During the Period 1970 to 1988 Group I
Cardiac death Myocardial infarction CABG orPTCA Pulmonary edema Ventricular tachycardia Patients with ~ I event
Group 2
Group 3
Total
No.
%
No.
%
No.
%
No.
%
8
9 14 4 4 3 23
IS 20 19 7 9 40
23 31 30
6 5 4
30 25 20 5 15 50
29 38 27 12 15 71
16 21 15 7
13 4 4 3 21
Definitions and abbreviations as in 'Table I.
II
14 63
3 10
8
40
LETTERS TO THE EDITOR
Reply
Our study (I) concerned a satellite protocol of the large scale placebo-controlled Anglo-Scandinavian Study of Early Thrombolysis (ASSET) study, which was started in November 1986 (2). Until its termination on February 29, 1988, >S,OOO patients with acute ischemic heart disease were allocated to therapy with placebo or recombinant tissue-type plasminogen activator (rt-PA). Neither we nor the scientific ethical committee of Denmark considered it unethical to conduct a small placebo-controlled satellite study starting on October I, 1987. In evaluating the ethical considerations at that time we assessed all available data including, as mentioned by Geraci, the documentation that thrombolytic therapy with streptokinase or anisoylated plasminogen streptokinase activator complex (APSAC) reduces the mortality rate in patients with acute myocardial infarction (3,4), the risk of serious bleeding complications and, in particular, the absence of knowledge about the clinical efficacy of rt-PA therapy. The results of the ASSET study were published on September 3, 1988 (2) >3 months after we had stopped including patients in our investigation (I,S). The ASSET study was prematurely terminated on February 29, 1988 because the ethical committee of that study considered it unethical to allocate patients with acute myocardial infarction to placebo treatment (2). Having learned of their decision, we stopped allocating patients to placebo treatment on the next day. These ethical aspects of our study are described in detail in a separate investigation (S). We consider the arguments forwarded by Geraci to be somewhat simplistic. His ethical judgments of scientific investigators are based on retrospective considerations and focus only on the dates in the total process of conducting placebo-controlled studies. These dates, and particularly the dates of termination of such studies, are an essential part of the information and should be correct. We suggest that Geraci improve his figure by indicating the premature termination of the ASSET study and our investigation. STEFFEN MUNKVAD, MD J0RGEN JESPERSEN, MD, DSc J0RGEN GRAM, MD, DSc Section of Coagulation and Fibrinolysis Department of Clinical Chemistry Ribe County Hospital in Esbjerg 6700 Esbjerg, Denmark
CORNELIS KLUFT, MSc, DSc Gaubius Institute TNO Leiden, The Netherlands
References 1. Munkvad S, Jespersen J, Gram J, Kluft C. Long·lasting depression of the factor XII-dependent fibrinolytic system in patients with myocardial infarction undergoing thrombol}1ic therapy with recombinant tissue·type plasminogen activator: a randomized placebo-controlled study. J Am Coli Cardiol 1991;17:957-62. 2. Wilcox RG, von der Lippe G, Olsson CG, Jensen G, Skene AM, Hampton JR, for the ASSET Study Group. Trial of tissue plasminogen activator for mortality reduction in acute myocardial infarction. Anglo-Scandinavian Study of Early Thrombolysis (ASSET). Lancet 1988;2:525-30. 3. Gruppo Italiano per 10 Studio della Streptochinasi nelI'lnfarto Miocardico (GlSSI). Effectiveness of intravenous thrombolytic treatment in acute myocardial infarction. Lancet 1986;1:397-402. 4. AIMS Trial Study Group. Effect of intm'enous APSAC on mortality after acute myocardial infarction: preliminary report of a placebo-controlled clinical trial. Lancet 1988;1:545-9. 5. Munkvad S, Gram J, Jespersen J, Grande P. Reduction of infarct size estimated enzymatically in patients with acute myocardial infarction after treatment with recom· binant tissue·type plasminogen activator or after spontaneous coronary recanalisation: a randomised, placebo-controlled study. Fibrinolysis 1990;4:95-9.
1303
Diastolic Function in Hypertrophic Cardiomyopathy Nihoyannopoulos et al. (I) are to be congratulated on their study correlating Doppler indexes of diastolic filling at rest with exercise capacity in patients with hypertrophic cardiomyopathy. The large number of patients involved make this an important contribution. However, several important methodologic considerations limit the ability to draw conclusions regarding the mechanism of exercise intolerance in the study patients. \. Fifty percent of the patients had at least mild mitral regurgitation. With the exercise-induced increase in systolic blood pressure, the degree of mitral regurgitation would be expected to increase. In addition to potentially altering results of Doppler indexes of diastolic left ventricular filling, significant mitral regurgitation would also be expected to limit exercise capacity. 2. It is not stated whether an attempt was made to detect concomitant ischemic heart disease, another possible source of exercise limitation. Up to 20% of patients in another study of hypertrophic cardiomyopathy (2) had associated significant coronary artery disease and the prevalence was greater in older patients. The patients studied by Nihoyannopoulos et al. ranged in age up to 74 years and nearly SO% had exertional chest pain. 3. During data collection, nearly SO% of the patients were taking negative inotropic and chronotropic medications such as verapamil and beta-adrenergic blocking agents, and nearly all were taking amiodarone. Although the effect of amiodarone is less well documented, in normal subjects, beta-blockers significantly limit exercise capacity (3) and calcium channel blockers may significantly alter Doppler filling indexes (4). Because presumably none of the normal subjects had mitral regurgitation, possible concomitant ischemic heart disease or concurrent cardioactive medication use, these factors may have confounded the interpretation of the data. 4. The patient group was quite heterogeneous with respect to age, distribution of hypertrophy and presence of mitral regurgitation and left ventricular outflow tract obstruction; these factors could independently alter Doppler filling indexes, and this heterogeneity could have limited the ability to correlate these indexes with maximal oxygen consumption. S. Because age substantially affects maximal oxygen consumption (S), did the subset of normal subjects who underwent exercise testing represent a close age match for the patient group? Finally, the maximal oxygen consumption levels shown for the normal subjects are those one would expect from well conditioned subjects, particularly if they were age matched to the patients. Unfortunately, the previous study from their laboratory referenced in the Methods section (6) does not describe the physical activity status of the normal subjects. Because degree of physical conditioning is another important independent determinant of maximal oxygen consumption (S), and because it is doubtful that patients who had the symptoms noted in the Methods section were very active, a group of sedentary subjects may have been a more appropriate control group. An additional concern is that of potential overlap of patient data sets. Were any of the patients in their previous study (6) included in the present one? If so, did they undergo separate exercise testing for this present study? If not, because the exercise testing methodology in the previous study included invasive hemodynamic monitoring for the patients, this represents another potential difference from the
1304
LEITERS TO THE EDITOR
JACC Vol. 20. No.5 November 1. 1992
control subjects that could have limited the observed exercise capacity in the patients.
PETROS NIHOYANNOPOULOS, MD, FACC CELIA M. OAKLEY, MD, FRCP, FACC
DALANE W. KITZMAN, MD
Royal Postgraduate Medical School Hammersmith Hospital Du Cane Road London W12 OHS, England
Division of Cardiology Bowman Gray School of Medicine Medical Center Boulel'Qrd Winston·Salem, North Carolina 27157
References I. Tesch PA. Kaiser P. Effect of bela-adrenergic blockade on maximal oxygen uptake in
References I. Nihoyannopoulos P, Karatasakis G. Frenneaux M. McKenna WJ. Oakley CM. Dias·
2. 3. 4. 5. 6.
tolic function in hypertrophic cardiomyopathy: relation to exercise capacity. J Am Coli Cardioll992;19:536-40. Cokkinos DV. Krajcer Z. Leachman RD. Hypertrophic cardiomyopathy and associated coronary artery disease. Tex Heart Inst J 1985;12:147-51. Tesch PA, Kaiser P. Effect of beta-adrenergic blockade on maximal oxygen uptake in trained males. Acta Physiol Scand 1981 ;112:351-3. Plotnick GO. Changes in diastolic function-difficult to measure. harder to interpret. Am Heart J 1989;118:637-41. Higginbotham MB, Morris KG. Williams RS. et aI. Physiologic basis for the age-related decline in aerobic work capacity. Am J CardioI1986;57:1374-9. Frenneaux MP. Porter A. Caforio ALP, Odawara H. Counihan PJ. McKenna WJ. Determinants of exercise capacity in hypertrophic cardiomyopathy. J Am Coli Cardiol 1989;13:1521-6.
Reply
The aim of our study was not to list known potential influences on Doppler diastolic indexes but to relate those indexes to the patient's professed symptomatic status and exercise capacity so that each patient in effect served as his or her own control. Our patient group was closely matched with a normal group for comparison of Doppler indexes and exercise capacity. No patient had significant mitral incompetence and all had normal findings on coronary angiography at a time unrelated to the current study. Although beta-adrenergic blocking agents may have a limiting effect on oxygen uptake in trained men (I), in patients with hypertrophic cardiomyopathy, these agents have a beneficial effect on diastolic function and patient symptoms (2,3). Verapamil is more likely to alter diastolic indexes and has a tendency to normalize them (4). However, only four of our patients were taking verapamil during the study and their inclusion does not influence our results in 40 patients.
trained males. Acta Physiol Scand 1981 ;112:351-3. 2. Swanton RH. Brooksby lAB. Jenkins BS. Webb-Peploe MM. Haemodynamic studies on beta blockade in hypertrophic obstructive cardiomyopathy. Eur J Cardiol 1977;5: 327. 3. Alvarez RP. Goodwin JF. Noninvasive assessment of diastolic function in hypertrophic cardiomyopathy on and off beta adrenergic blocking drugs. Br Heart J 1982;48:204. 4. Bonow RO. Dilsizian V. Rosino DR. et aI. Verapamil·induced improvement in left vent~cular ~iastolic filling and increased exercise tolerance in patients ....ith hypertrophIc cardIomyopathy: short- and long-term effects. Circulation 1985;72:853-64.
Correction A correction should be made to Table 2 in the article by Rihal et al. in the May issue of the Journal (Rihal CS, Gersh BJ, Whisnant JP, et al. Influence of coronary heart disease on morbidity and mortality after carotid endarterectomy: a population-based study in Olmsted County, Minnesota [1970-1988]. J Am Coll Cardiol 1992;19:125460). The numbers in the last line of Table 2 were incorrectly transposed from Table 1. The authors apologize for the error and provide the following corrected version: Table 2: Distribution of All Postoperative Cardiac Events Through July I, 1989 Among Olmsted County Residents Who Underwent Carotid Endarterectomy During the Period 1970 to 1988 Group I
Cardiac death Myocardial infarction CABG orPTCA Pulmonary edema Ventricular tachycardia Patients with ~ I event
Group 2
Group 3
Total
No.
%
No.
%
No.
%
No.
%
8
9 14 4 4 3 23
IS 20 19 7 9 40
23 31 30
6 5 4
30 25 20 5 15 50
29 38 27 12 15 71
16 21 15 7
13 4 4 3 21
Definitions and abbreviations as in 'Table I.
II
14 63
3 10
8
40
