The Influence of CLS 2210 on the Course of Myocardial Infarction: A Pilot Study in Man
Laszlo
Szlavy, M.D., F.I.C.A. Repa, M.D.
Imre
and Hans
Jürg Hachen, M.D., F.I.C.A.*
BUDAPEST, HUNGARY and GENEVA, SWITZERLAND
Abstract To assess the effect of CLS 2210 (a new formulation of calcium dobesilate) on the evolution of acute myocardial infarction, 100 patients presenting their first infarct were distributed, according to their sequential admissions to the hospital, into CLS 2210-treated group (50 patients) or a comparison group (50 patients not receiving CLS 2210). The two groups were similar in age, sex, predisposing factors, and site of infarction. Intravenous infusion of CLS 2210 was begun within six hours of onset of chest pain and continued for seventy-two hours. Thereafter, it was given, as oral capsules, in a dose of 1,000 mg every eight hours throughout the hospitalization. Before and during the trial, blood samples were drawn for the measurements of serum concentrations of creatine kinase (CK), and twelve-lead electrocardiograms (ECGs) were obtained serially in each patient. All objective data were analyzed on a coded basis without reference to the treatment. In the comparison group, thirty-six to forty-eight hours was required for CK to fall to 50% of the baseline value, whereas in the CLS 2210-treated group it reached 50% of the baseline in eighteen to twenty-four hours. For each infarction site, a statistically significant fall was reached earlier in the CLS 2210 group. CK, the ECG index, and the sum of the ST segments showed earlier and more rapid improvement in the CLS 2210 group than in the comparison group.
From the Department of Diagnostic Radiology, National Institute for Vascular State University Hospital, Geneva, Switzerland
Surgery, Budapest, Hungary;
639
Downloaded from ang.sagepub.com at UNIV OF MICHIGAN on June 12, 2015
and the *Geneva
640 The consumption of narcotic analgesic agents and nitroglycerin was substantially less in the CLS 2210 group than in the comparison group. Similarly, lidocaine infusion was employed for 1.2 ± 0.03 days in the CLS 2210-treated patients, whereas the comparison group received lidocaine for 5.7 ± 0.23 days because of continuing cardiac arrhythmias. The agent was well tolerated and no untoward side effects were recorded during the trial. The findings so obtained with CLS 2210, in this pilot study, could have important clinical implications in designing protocols for further trials.
Introduction Acute myocardial infarction (MI) is a major cause of mortality and morbidity in much of the world. Because the volume of myocardium destroyed during the acute process is a major determinant of outcome, substantial effort has been made to develop regimens suitable for reducing the size of the MI. Although a number of maneuvers have shown success in animal models,3-5 none have come into wide clinical use today. Indeed, the recent emphasis in clinical studies has been toward opening the occluded coronary artery by the infusion of thrombolytic agents , 6-1 often directly into the coronary artery, a maneuver that has met with some success but that does not preclude, at least in theory, the use of alternative maneuvers to reduce the volume of myocardium injured. In many situations, moreover, the resources required for coronary arteriography are not available. The use of hyaluronidase has been among the most successful maneuvers in animal models of MI3,9,1O and has shown some efficacy in man, although mixed results have been reported. 11,12 Certainly its use has not become widespread or routine in the clinical situation. During an investigation into the mechanisms by which hyaluronidase might be effective, evidence was found to suggest a major action on the myocardial lymphatics.’~ A survey, designed to uncover alternative agents that might have an impact on myocardial lymphatic drainage, identified CLS 2210, a new formulation of calcium dobesilate. CLS 2210 in animal models has a dramatic influence on the normal coronary lymphatic vascular tree14 and preserved viable myocardium and its lymphatic drainage after coronary occlusion in the dog.1S-17 Because the drug is free of serious cardiovascular risk and does not induce hypotension or risk of hemorrhage, cardiac arrhythmias, or reduced myocardial contractility, it seemed an excellent candidate for therapeutic trial. For these reasons a trial was conducted with CLS 2210 in patients having their first acute MI. As a pilot study, a double-blind, placebo-controlled trial was not undertaken; rather, patients fulfilling the entry criteria were randomized into a CLS 2210 or comparison group. For this report only objective data, analyzed on a coded basis without reference to the treatment, have been employed.
Methods Patients The 100
patients represent sequential admissions to one of two hospitals in Budapest,
Downloaded from ang.sagepub.com at UNIV OF MICHIGAN on June 12, 2015
641 TABLE I Pretreatment Characteristics
of Patients
*Hypotension has been defined as a systolic arterial blood pressure < 90 mmHg. In patients with pretreatment hypertension with a systolic blood pressure over 180 mm Hg, an additional definition included a fall in systolic arterial blood pressure to
Laszlo
Szlavy, M.D., F.I.C.A. Repa, M.D.
Imre
and Hans
Jürg Hachen, M.D., F.I.C.A.*
BUDAPEST, HUNGARY and GENEVA, SWITZERLAND
Abstract To assess the effect of CLS 2210 (a new formulation of calcium dobesilate) on the evolution of acute myocardial infarction, 100 patients presenting their first infarct were distributed, according to their sequential admissions to the hospital, into CLS 2210-treated group (50 patients) or a comparison group (50 patients not receiving CLS 2210). The two groups were similar in age, sex, predisposing factors, and site of infarction. Intravenous infusion of CLS 2210 was begun within six hours of onset of chest pain and continued for seventy-two hours. Thereafter, it was given, as oral capsules, in a dose of 1,000 mg every eight hours throughout the hospitalization. Before and during the trial, blood samples were drawn for the measurements of serum concentrations of creatine kinase (CK), and twelve-lead electrocardiograms (ECGs) were obtained serially in each patient. All objective data were analyzed on a coded basis without reference to the treatment. In the comparison group, thirty-six to forty-eight hours was required for CK to fall to 50% of the baseline value, whereas in the CLS 2210-treated group it reached 50% of the baseline in eighteen to twenty-four hours. For each infarction site, a statistically significant fall was reached earlier in the CLS 2210 group. CK, the ECG index, and the sum of the ST segments showed earlier and more rapid improvement in the CLS 2210 group than in the comparison group.
From the Department of Diagnostic Radiology, National Institute for Vascular State University Hospital, Geneva, Switzerland
Surgery, Budapest, Hungary;
639
Downloaded from ang.sagepub.com at UNIV OF MICHIGAN on June 12, 2015
and the *Geneva
640 The consumption of narcotic analgesic agents and nitroglycerin was substantially less in the CLS 2210 group than in the comparison group. Similarly, lidocaine infusion was employed for 1.2 ± 0.03 days in the CLS 2210-treated patients, whereas the comparison group received lidocaine for 5.7 ± 0.23 days because of continuing cardiac arrhythmias. The agent was well tolerated and no untoward side effects were recorded during the trial. The findings so obtained with CLS 2210, in this pilot study, could have important clinical implications in designing protocols for further trials.
Introduction Acute myocardial infarction (MI) is a major cause of mortality and morbidity in much of the world. Because the volume of myocardium destroyed during the acute process is a major determinant of outcome, substantial effort has been made to develop regimens suitable for reducing the size of the MI. Although a number of maneuvers have shown success in animal models,3-5 none have come into wide clinical use today. Indeed, the recent emphasis in clinical studies has been toward opening the occluded coronary artery by the infusion of thrombolytic agents , 6-1 often directly into the coronary artery, a maneuver that has met with some success but that does not preclude, at least in theory, the use of alternative maneuvers to reduce the volume of myocardium injured. In many situations, moreover, the resources required for coronary arteriography are not available. The use of hyaluronidase has been among the most successful maneuvers in animal models of MI3,9,1O and has shown some efficacy in man, although mixed results have been reported. 11,12 Certainly its use has not become widespread or routine in the clinical situation. During an investigation into the mechanisms by which hyaluronidase might be effective, evidence was found to suggest a major action on the myocardial lymphatics.’~ A survey, designed to uncover alternative agents that might have an impact on myocardial lymphatic drainage, identified CLS 2210, a new formulation of calcium dobesilate. CLS 2210 in animal models has a dramatic influence on the normal coronary lymphatic vascular tree14 and preserved viable myocardium and its lymphatic drainage after coronary occlusion in the dog.1S-17 Because the drug is free of serious cardiovascular risk and does not induce hypotension or risk of hemorrhage, cardiac arrhythmias, or reduced myocardial contractility, it seemed an excellent candidate for therapeutic trial. For these reasons a trial was conducted with CLS 2210 in patients having their first acute MI. As a pilot study, a double-blind, placebo-controlled trial was not undertaken; rather, patients fulfilling the entry criteria were randomized into a CLS 2210 or comparison group. For this report only objective data, analyzed on a coded basis without reference to the treatment, have been employed.
Methods Patients The 100
patients represent sequential admissions to one of two hospitals in Budapest,
Downloaded from ang.sagepub.com at UNIV OF MICHIGAN on June 12, 2015
641 TABLE I Pretreatment Characteristics
of Patients
*Hypotension has been defined as a systolic arterial blood pressure < 90 mmHg. In patients with pretreatment hypertension with a systolic blood pressure over 180 mm Hg, an additional definition included a fall in systolic arterial blood pressure to
