Effects Platelet
of Nitroglycerin at Therapeutic Doses on Aggregation In Unstable Angina Pectoris and Acute Myocardial Infarction
Jean Diodati, MD, Pierre Thbroux, MD, Jean-Gilles Latour, PhD, Lucie Lacoste, BSc, Jules Y.T. Lam, MD, and David Waters, MD
The platelet aggregation response to adenosine diphosphate (ADP) and to thrombin was quantified in 10 patients, 5 with unstable angina pectoris and 5 with acute myocardial infarction, before, during and after a 45-minute infusion of nitroglycerin. An impedance aggregometer allowing rapid bedside studies in whole blood was used. The reproducibility of the methods was documented to be within 10%. Doses of nitroglycerin were titrated for a 10 mm Hg decrease in mean arterial blood pressure with mean doses being 1.2 f 0.2 (standard error of the mean) rcglkglmin. Nitroglycerin decreased the area under the aggregation curve induced by ADP from 43 f 3.6 to 30 f 6.3 cm* (p = 0.007) and by thrombin from 8.9 f 1.7 to 4.1 f 0.9 cm* (p = 0.003). Peak responses to ADP were decreased from 13.3 f 1 to 9.1 f 1.7 ohms (p = 0.005) and to thrombin from 9.3 f 2 to 5.0 f 1.2 ohms (p = 0.003). All patients had 250% inhibition with 1 agent or the other and the inhibition was >SO% with each of the 2 aggregating agents in 6 patients. Analyses performed on blood withdrawn 15 minutes after the discontinuation of nitroglycerin showed a return to baseline before nitroglycerin resutts. When analyses were delayed and performed on blood preserved at room temperature for 30 minutes, no effect of nitroglycerin could be detected. Thus, bedside platelet aggregation studies document a significant and reversible effect of nitroglycerin at therapeutic doses on platelet function. (Am J Cardiol 1990;66:683-688)
the Department of Medicine and the Labomtoq of Experimental Pathology, Montreal Heart Institute, and the Department of Pathology, Universitt de Montrtal, Montreal, Quebec. Canada. This study was supported by Grant MT4478 of the Medical Research Council of Canada: J. G. Latour is a career investigator of the Fonds de la Recherche en Santi du Qwkbec. Manuscript received April 9, 1990; revised manuscript received and accepted May 8, 1990. Address for reprints: Pierre Thkoux. MD, Montreal Heart Institute. 5000 Belanger Street East, Montreal, Quebec. HIT 1C8. Canada. From
itroglycerin has played an important role in medical practice for more than a century.’ Its usefulness has stimulated continuous research on its mechanisms of action, which have improved understanding of the pathophysiology of angina pectoris. Nitroglycerin decreases myocardial oxygen consumption by its peripheral vasodilating effects.* The drug also increases myocardial oxygen supply through dilatation of the large coronary arteries.3 Other possible beneficial effects include an increase in coronary collateral flow4 and favorable redistribution of regional flowe5 Nitroglycerin is also widely used in unstable angina and acute myocardial infarction6.’ clinical syndromes in which platelet aggregation and thrombus formation play a major ro1e.s Attempts to document an effect of nitroglycerin on these processes have generally failed”-‘* or yielded controversial results.13 Although in vitroi and in vivo experimental studiesi have shown that nitroglycerin could inhibit platelet aggregation, this effect has not been confirmed in man at therapeutic doses.9,‘h,‘7 The aim of this study was to reassess the effects of nitroglycerin on platelet aggregation in patients with acute ischemic syndromes. For this purpose, we used a new method allowing rapid, bedside determination of platelet aggregation in whole blood.‘s
N
METHODS Population: Ten patients (8 men, 2 women) with documented coronary artery disease were studied. Mean age was 58 years (range 38 to 76). The patients were selected from the coronary care unit population of our institution; 5 had unstable angina and were studied shortly after admission; the other 5 had acute myocardial infarction and were studied 5 to 7 days after the acute phase. Concomitant medications included a calcium antagonist in 5 patients, captopril in 1 and digoxin in 1. Exclusion criteria were use of nitrates, aspirin, nonsteroidal antiinflammatory agents, heparin and fibrinolytic agents in the 10 days before the study, difficult venous puncture access or refusal by the patient to participate in the study. Perfusion of nitroglycerin: Tests were carried out in the fasting state, without recent tobacco use and with a previously installed intravenous line with dextrose 5% in water running at a minimum rate. The blood pressure and heart rate were measured every 5 minutes for 15 minutes or until stable baseline values were recorded. Nitroglycerin infusion (30 mg in 250 cc of dextrose 5% in water) was started at 10 cc/hr and increased by in-
THE AMERICAN
JOURNAL
OF CARDIOLOGY
SEPTEMBER
15.
1990
683
crements of 10 cc/hr every 5 minutes until a 10% decrease in mean arterial blood pressure was seen. Dose titration was stopped before reaching this end point in 3 patients because of side effects. The solution of nitroglycerin was prepared by the pharmacist of the hospital just before the study without addition of any preservatives; specifically, no ethanol was added. The infusion of nitroglycerin was terminated after 45 minutes. Venous blood samplings for the determination of platelet aggregation were obtained by the same well-trained person using a 19-gauge butterfly needle inserted in an antecubital vein with minimal trauma and stasis. Different puncture sites were used for each sampling. Blood samples were obtained just before the start and before the end of the 45minute perfusion of nitroglycerin and again in 6 patients, 15 minutes after discontinuation of the drug. Platelet aggregation studies: Platelet aggregation was tested at 37°C on whole blood diluted I:1 in sterile
TABLE
I Changes
in Heart
Rate and Blood Pressure HR
ape (YW
Sex
Unstable Angina 76 M M 68 63 M F 41 F 49 Myocardial Infarction M 61 38 M 53 M 62 M M 68 Mean f SEM
Mean BP (mm W
Dose of Nitroglycerin (pg/kg/min)
Before
During
Before
During
1.69 1.540 0.57 0.74* 1.90’
64 55 63 74 60
83 64 61 84 61
103 93 83 73 92
93 87 70 70 94
1.23 0.86 1.82 1.11 0.44 1.19f0.2
73 80 80 71 70 69f3
66 86 86 80 76 75f3
(beats/min)
of Nitroglycerin at Therapeutic Doses on Aggregation In Unstable Angina Pectoris and Acute Myocardial Infarction
Jean Diodati, MD, Pierre Thbroux, MD, Jean-Gilles Latour, PhD, Lucie Lacoste, BSc, Jules Y.T. Lam, MD, and David Waters, MD
The platelet aggregation response to adenosine diphosphate (ADP) and to thrombin was quantified in 10 patients, 5 with unstable angina pectoris and 5 with acute myocardial infarction, before, during and after a 45-minute infusion of nitroglycerin. An impedance aggregometer allowing rapid bedside studies in whole blood was used. The reproducibility of the methods was documented to be within 10%. Doses of nitroglycerin were titrated for a 10 mm Hg decrease in mean arterial blood pressure with mean doses being 1.2 f 0.2 (standard error of the mean) rcglkglmin. Nitroglycerin decreased the area under the aggregation curve induced by ADP from 43 f 3.6 to 30 f 6.3 cm* (p = 0.007) and by thrombin from 8.9 f 1.7 to 4.1 f 0.9 cm* (p = 0.003). Peak responses to ADP were decreased from 13.3 f 1 to 9.1 f 1.7 ohms (p = 0.005) and to thrombin from 9.3 f 2 to 5.0 f 1.2 ohms (p = 0.003). All patients had 250% inhibition with 1 agent or the other and the inhibition was >SO% with each of the 2 aggregating agents in 6 patients. Analyses performed on blood withdrawn 15 minutes after the discontinuation of nitroglycerin showed a return to baseline before nitroglycerin resutts. When analyses were delayed and performed on blood preserved at room temperature for 30 minutes, no effect of nitroglycerin could be detected. Thus, bedside platelet aggregation studies document a significant and reversible effect of nitroglycerin at therapeutic doses on platelet function. (Am J Cardiol 1990;66:683-688)
the Department of Medicine and the Labomtoq of Experimental Pathology, Montreal Heart Institute, and the Department of Pathology, Universitt de Montrtal, Montreal, Quebec. Canada. This study was supported by Grant MT4478 of the Medical Research Council of Canada: J. G. Latour is a career investigator of the Fonds de la Recherche en Santi du Qwkbec. Manuscript received April 9, 1990; revised manuscript received and accepted May 8, 1990. Address for reprints: Pierre Thkoux. MD, Montreal Heart Institute. 5000 Belanger Street East, Montreal, Quebec. HIT 1C8. Canada. From
itroglycerin has played an important role in medical practice for more than a century.’ Its usefulness has stimulated continuous research on its mechanisms of action, which have improved understanding of the pathophysiology of angina pectoris. Nitroglycerin decreases myocardial oxygen consumption by its peripheral vasodilating effects.* The drug also increases myocardial oxygen supply through dilatation of the large coronary arteries.3 Other possible beneficial effects include an increase in coronary collateral flow4 and favorable redistribution of regional flowe5 Nitroglycerin is also widely used in unstable angina and acute myocardial infarction6.’ clinical syndromes in which platelet aggregation and thrombus formation play a major ro1e.s Attempts to document an effect of nitroglycerin on these processes have generally failed”-‘* or yielded controversial results.13 Although in vitroi and in vivo experimental studiesi have shown that nitroglycerin could inhibit platelet aggregation, this effect has not been confirmed in man at therapeutic doses.9,‘h,‘7 The aim of this study was to reassess the effects of nitroglycerin on platelet aggregation in patients with acute ischemic syndromes. For this purpose, we used a new method allowing rapid, bedside determination of platelet aggregation in whole blood.‘s
N
METHODS Population: Ten patients (8 men, 2 women) with documented coronary artery disease were studied. Mean age was 58 years (range 38 to 76). The patients were selected from the coronary care unit population of our institution; 5 had unstable angina and were studied shortly after admission; the other 5 had acute myocardial infarction and were studied 5 to 7 days after the acute phase. Concomitant medications included a calcium antagonist in 5 patients, captopril in 1 and digoxin in 1. Exclusion criteria were use of nitrates, aspirin, nonsteroidal antiinflammatory agents, heparin and fibrinolytic agents in the 10 days before the study, difficult venous puncture access or refusal by the patient to participate in the study. Perfusion of nitroglycerin: Tests were carried out in the fasting state, without recent tobacco use and with a previously installed intravenous line with dextrose 5% in water running at a minimum rate. The blood pressure and heart rate were measured every 5 minutes for 15 minutes or until stable baseline values were recorded. Nitroglycerin infusion (30 mg in 250 cc of dextrose 5% in water) was started at 10 cc/hr and increased by in-
THE AMERICAN
JOURNAL
OF CARDIOLOGY
SEPTEMBER
15.
1990
683
crements of 10 cc/hr every 5 minutes until a 10% decrease in mean arterial blood pressure was seen. Dose titration was stopped before reaching this end point in 3 patients because of side effects. The solution of nitroglycerin was prepared by the pharmacist of the hospital just before the study without addition of any preservatives; specifically, no ethanol was added. The infusion of nitroglycerin was terminated after 45 minutes. Venous blood samplings for the determination of platelet aggregation were obtained by the same well-trained person using a 19-gauge butterfly needle inserted in an antecubital vein with minimal trauma and stasis. Different puncture sites were used for each sampling. Blood samples were obtained just before the start and before the end of the 45minute perfusion of nitroglycerin and again in 6 patients, 15 minutes after discontinuation of the drug. Platelet aggregation studies: Platelet aggregation was tested at 37°C on whole blood diluted I:1 in sterile
TABLE
I Changes
in Heart
Rate and Blood Pressure HR
ape (YW
Sex
Unstable Angina 76 M M 68 63 M F 41 F 49 Myocardial Infarction M 61 38 M 53 M 62 M M 68 Mean f SEM
Mean BP (mm W
Dose of Nitroglycerin (pg/kg/min)
Before
During
Before
During
1.69 1.540 0.57 0.74* 1.90’
64 55 63 74 60
83 64 61 84 61
103 93 83 73 92
93 87 70 70 94
1.23 0.86 1.82 1.11 0.44 1.19f0.2
73 80 80 71 70 69f3
66 86 86 80 76 75f3
(beats/min)
