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Prevention of left ventricular mural thrombus
Prevention of Left Ventricular Mural Thrombus Alexander G.G. Turpie, MD
Acute myocardial infarction is associated with a high incidence of left ventricular mural thrombosis, which causes most of the systemic emboli. A double-blind trial was undertaken in patients with anterior transmural myocardial infarction to evaluate the ability of a high-dose heparin regimen to prevent left ventricular mural thrombosis. The high dose consisted of 12,500 U of calcium heparin subcutaneously every 12 hours for 10 days, which was compared with a low dose consisting of 5,000 U every 12 hours. The formation of left ventricular mural thrombosis was assessed by means of 2-dimensional ochocardiography on day 10 after infarcUon. The high-dose group had a significantly lower incidence of left ventricular mural thrombosis than did the low-dose group. This was achieved without increasing the incidence of bleeding. The benefits of high-dose heparin were associated with maintaining plasma heparin concentrations at 0.2 U/ml and activated partial thromboplastin time between 50 and 60 seconds. (Am J Cardiol 1 9 8 9 ; 6 4 : 4 | B - 4 3 B )
From the Hamilton General Hospital, Hamilton, Ontario, Canada. This study was supported by Grant AN 755 from the Heart and Stroke Foundation of Ontario, Toronto, and the Hamilton Civic Hospitals Research Fund, Hamilton, Ontario. Address for reprints: Alexander G.G. Turpie, MD, HGH-McMaster Clinic, Hamilton General Hospital, 237 Barton Street East, Hamilton, Ontario L8L 2X2, Canada.
he principal reasons for administering anticoagulants to patients with myocardial infarction are to (1) prevent systemic embolism, (2) prevent clinically important venous thromboembolism, (3) prevent reinfarction, and (4) reduce mortality. Despite the evidence that anticoagulant therapy achieves these goals, 1-4 there is no consensus on the use of these agents in patients with acute myocardial infarction. Consider, e.g., the data from the Second International Study of Infarct Survival trial, 5 with regard to use of intravenous heparin in acute myocardial infarction. The extent of planned use ranged from none in Denmark to 6% in Canada, 37% in the United States, 70% in West Germany and 89% in Austria. One way to induce physicians to use anticoagulants would be through large clinical trials assessing the impact of such therapy on the important clinical outcomes, namely, death, stroke and pulmonary embolism. If such studies were performed according to current methodologic standards, however, they would need to include many thousands of patients. The question arises whether another end point could be substituted. It has been shown that most of systemic emboli in patients with acute myocardial infarction stem from left ventricular mural thrombi. 6,7We also know that these thrombi can be realiably detected by means of 2dimensional (2-D) echocardiography. 8 Left ventricular mural thrombosis is a frequent event in patients with acute myocardial infarction. It has been seen at autopsy in 20 to 60% of patients dying of their disease9 and has been detected by 2-D echocardiography in 20 to 46% of patients. 8,~° Certain subsets of patients, notably those with large anterior transmural myocardial infarctions, are particularly likely to have left ventricular mural thrombosis. The foregoing observations prompted the undertaking of a clinical trial at McMaster University to assess the ability of heparin to prevent or reduce the frequency of left ventricular mural thrombosis in patients with acute anterior myocardial infarction.~
T
METHODS A double-blind trial design was used to compare 2 regimens of calcium heparin in patients with anterior transmural myocardial infarction. Through randomization, patients received either a high dose, consisting of 12,500 U of calcium heparin subcutaneously every 12 hours, or a low dose consisting of 5,000 U injected subcutaneously every 12 hours. The low dose is routinely used to prevent deep vein thrombosis, The choice of 12,500 U for the high dose was based on a preliminary pharmacologic study in which it was demonstrated that this dose every 12 hours maintained plasma heparin concentrations of about 0.2 U/ml, which is just below the standard therapeutic level. THE AMERICAN JOURNAL OF CARDIOLOGY JULY 18, 1989
41B
A SYMPOSIUM: M Y O C A R D I A L I N F A R C T I O N ~ I R E C T I O N
T A B L E I Incidence of Left Ventricular Mural Thrombosis 10 Days After Infarction
Heparin
No. of patients Positive2-D echocardiogram Negative2-D echocardiogram
High-Dose
Low-Dose
95 10 (10.5%) 85 (89.5%)
88 28 (31.8%) 60 (68.2%)
2-D = 2-dimensional.
Patients admitted to the trial had typical myocardial ischemic pain that lasted more than 20 minutes. Evidence of anterior myocardial ischemia was based on electrocardiographic findings of Q waves in 1 aVL or in 2 adjacent leads, VI to V6, or of ST-segment elevations greater than 1.5 mm in these leads. Patients had to be enrolled within 24 hours of assessment and to have signed an informed consent document. The principal outcome analyzed in this study was the detection by 2-D echocardiography of left ventricular mural thrombosis on day 10 after infarction. RESULTS Of 233 patients enrolled in the trial, 12 were subsequently declared ineligible. Nine did not have confirmatory evidence of infarction, 1 had undergone major surgery and was thus ineligible, 1 did not begin treatment for 11 days after the onset of infarction, and 1 refused to participate after having signed the consent form. Of 221 patients remaining, 183 underwent 2-D echocardiography on day 10. Twenty-four of the 38 who did not had died in the interim. Of the 183 patients analyzed, 171 began treatment within 36 hours of the infarct and 12 began treatment between 36 and 72 hours. The 2 treat-
FOR THE '90s
ment groups--95 patients in the high-dose group and 88 patients in the low-dose group--were virtually identical with respect to baseline characteristics. A highly significant reduction in the incidence of left ventricular mural thrombosis was achieved with the use of high-dose subcutaneous heparin (Table I). There was no difference between treatments with respect to mortality, namely, 13 deaths in the low-dose group and 11 deaths in the high-dose group. There was also no difference in the causes of death. The single fatal pulmonary embolism occurred in a patient given low-dose heparin. The frequency of hemorrhage, major or minor, did not differ significantly between the 2 groups. An interesting observation, although one that could not be appropriately analyzed statistically, was a reduction in the incidence of nonhemorrhagic stroke in patients treated with high-dose heparin. Four patients in the lowdose group and only 1 patient in the high-dose group had such strokes (suspected to be embolic in origin) within 10 days of the myocardial infarction. Specimens of blood obtained midway between doses were analyzed at the end of the study for plasma heparin concentration and activated partial thromboplastin time. In the patients given high-dose heparin, consistent plasma heparin concentrations were maintained at about 0.2 U / ml, whereas concentrations were barely detectable in those given the low dose. Activated partial thromboplastin time was prolonged about 1.5 times in the high-dose group and was only minimally increased in the low-dose group (Fig. 1). A subset analysis of results in the high-dose group showed that patients in whom left ventricular mural thrombosis was seen on echocardiograms had plasma heparin concentrations that were statistically and clinically significantly lower than heparin concentrations in patients with no left ventricular mural thrombosis. This
60-
{i}___{I{---{
50-
40i/i~i----.-i~l |-"~
FIGURE 1. Mean activated partial thromboplasUn time (APTr) in the high-dose heparin group (circles) and in the low-dose heparin group (squares). (Reprinted with
30-
permission from N £ngl J Med. 11) ~/~ 20-
10-
r 1
i 2
i 3
[ 4
[ 5
I
I
I
I
I
6
7
8
9
10
DAY 42B
THE AMERICANJOURNALOF CARDIOLOGY VOLUME64
finding also relates to the significant lower prolongation of activated partial thromboplastin time in such patients. A l-year follow-up of the patients in this study revealed no differences between high- and low-dose heparin with respect to subsequent events, such as nonhemorrhagic stroke, peripheral arterial embolism, transient ischemic attacks and pulmonary embolism. Thus, patients who have anterior transmural infarction continue to be at risk for embolic events and probably should continue to receive anticoagulants for at least 3 months after discharge. CONCLUSION The reSults of the foregoing study support the conclusion that a high-dose regimen of subcutaneous calcium heparin significantly reduces the incidence of left ventricular mural thrombosis in patients with acute anterior transmural myocardial infarction. This therapy is not associated with increased bleeding. The dosage used in this study was 12,500 U every 12 hours. It is recommended that the heparin dosage be one that maintains the plasma heparin concentration between 0.2 and 0.3 U/ml and the activated partial thromboplastin time between 50 and 60 seconds for the duration of the patient's stay in the hospital.
REFERENCES 1. Report of the Working Party on Anticoagulant Therapy in Coronary Thrombosis to the Medical Research Council. Assessment of short-anticoagulant administration after cardiac infarction. Br Med J 1969;1:335-342. 2 . Veterans Administration Hospital Investigators. Anticoagulants in acute myocardial infarction. Results of a cooperative clinical trial. JAMA 1973;225:724729. 3. Drapkin A, Merskey C. Anticoagulant therapy after acute myocardial infarction. Relation of therapeutic benefit to patient's age, sex and severity of infarction. JAMA 1972;222:541-548. 4. Chalmers TC, Matta R J, Smith H Jr, Kunzler A-M. Evidence favoring the use of anticoagulants in the hospital phase of acute myocardial infarction. N Engl J Med 1977;297:1091-1096. 5. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. JACC 1988;12.'3.4-12,4. 6. Visser CA, Kan G, Meltzer RS, Dunning A J, Roelandt J. Embolic potential of left ventricular thrombus after myocardial infarction: a two-dimensional echocardiographic study of 119 patients. JACC 1985;5,'1276-1280. 7. Stratton JR, Resnick AD. Increased embolic risk in patients with left ventricular thrombi. Circulation 1987;75:1004-1011. 8. Asinger RW, Mikell FL, Elsperger J, Hedges M. Incidence of left-ventricular thrombosis after acute transmiaral myocardial infarction: serial evaluation by twodimensional echocardiography. N Engl J Med 1981;305:297-302. 9. Jordan RA, Miller RD, Edwards JE, Parker RL. Thrombo-embolism in acute and in healed myocardial infarction. Circulation 1952;6.'1-6. 10. Lamas GA, Vaughan DE, Pfeffer MA. Left ventricular thrombus formation after first anterior wall acute myocardial infarction. Am J Cardiol 1988,~52:31-35. l !. Turpie AGG, Robinson JG, Doyle D J, Mulji AS, Mishkel G J, Sealey BJ, Cairns JA, Hirsh J, Skingley L, Gent M. Prevention of left ventricular mural thrombosis in acute transmural anterior myocardial infarction: a double blind trial comparing high dose wiih low dose subcutaneous calcium heparin. N Engl J Med 1989;320:352-357.
THE AMERICANJOURNALOF CARDIOLOGY JULY 18, 1989 43B
Acute myocardial infarction is associated with a high incidence of left ventricular mural thrombosis, which causes most of the systemic emboli. A double-blind trial was undertaken in patients with anterior transmural myocardial infarction to evaluate the ability of a high-dose heparin regimen to prevent left ventricular mural thrombosis. The high dose consisted of 12,500 U of calcium heparin subcutaneously every 12 hours for 10 days, which was compared with a low dose consisting of 5,000 U every 12 hours. The formation of left ventricular mural thrombosis was assessed by means of 2-dimensional ochocardiography on day 10 after infarcUon. The high-dose group had a significantly lower incidence of left ventricular mural thrombosis than did the low-dose group. This was achieved without increasing the incidence of bleeding. The benefits of high-dose heparin were associated with maintaining plasma heparin concentrations at 0.2 U/ml and activated partial thromboplastin time between 50 and 60 seconds. (Am J Cardiol 1 9 8 9 ; 6 4 : 4 | B - 4 3 B )
From the Hamilton General Hospital, Hamilton, Ontario, Canada. This study was supported by Grant AN 755 from the Heart and Stroke Foundation of Ontario, Toronto, and the Hamilton Civic Hospitals Research Fund, Hamilton, Ontario. Address for reprints: Alexander G.G. Turpie, MD, HGH-McMaster Clinic, Hamilton General Hospital, 237 Barton Street East, Hamilton, Ontario L8L 2X2, Canada.
he principal reasons for administering anticoagulants to patients with myocardial infarction are to (1) prevent systemic embolism, (2) prevent clinically important venous thromboembolism, (3) prevent reinfarction, and (4) reduce mortality. Despite the evidence that anticoagulant therapy achieves these goals, 1-4 there is no consensus on the use of these agents in patients with acute myocardial infarction. Consider, e.g., the data from the Second International Study of Infarct Survival trial, 5 with regard to use of intravenous heparin in acute myocardial infarction. The extent of planned use ranged from none in Denmark to 6% in Canada, 37% in the United States, 70% in West Germany and 89% in Austria. One way to induce physicians to use anticoagulants would be through large clinical trials assessing the impact of such therapy on the important clinical outcomes, namely, death, stroke and pulmonary embolism. If such studies were performed according to current methodologic standards, however, they would need to include many thousands of patients. The question arises whether another end point could be substituted. It has been shown that most of systemic emboli in patients with acute myocardial infarction stem from left ventricular mural thrombi. 6,7We also know that these thrombi can be realiably detected by means of 2dimensional (2-D) echocardiography. 8 Left ventricular mural thrombosis is a frequent event in patients with acute myocardial infarction. It has been seen at autopsy in 20 to 60% of patients dying of their disease9 and has been detected by 2-D echocardiography in 20 to 46% of patients. 8,~° Certain subsets of patients, notably those with large anterior transmural myocardial infarctions, are particularly likely to have left ventricular mural thrombosis. The foregoing observations prompted the undertaking of a clinical trial at McMaster University to assess the ability of heparin to prevent or reduce the frequency of left ventricular mural thrombosis in patients with acute anterior myocardial infarction.~
T
METHODS A double-blind trial design was used to compare 2 regimens of calcium heparin in patients with anterior transmural myocardial infarction. Through randomization, patients received either a high dose, consisting of 12,500 U of calcium heparin subcutaneously every 12 hours, or a low dose consisting of 5,000 U injected subcutaneously every 12 hours. The low dose is routinely used to prevent deep vein thrombosis, The choice of 12,500 U for the high dose was based on a preliminary pharmacologic study in which it was demonstrated that this dose every 12 hours maintained plasma heparin concentrations of about 0.2 U/ml, which is just below the standard therapeutic level. THE AMERICAN JOURNAL OF CARDIOLOGY JULY 18, 1989
41B
A SYMPOSIUM: M Y O C A R D I A L I N F A R C T I O N ~ I R E C T I O N
T A B L E I Incidence of Left Ventricular Mural Thrombosis 10 Days After Infarction
Heparin
No. of patients Positive2-D echocardiogram Negative2-D echocardiogram
High-Dose
Low-Dose
95 10 (10.5%) 85 (89.5%)
88 28 (31.8%) 60 (68.2%)
2-D = 2-dimensional.
Patients admitted to the trial had typical myocardial ischemic pain that lasted more than 20 minutes. Evidence of anterior myocardial ischemia was based on electrocardiographic findings of Q waves in 1 aVL or in 2 adjacent leads, VI to V6, or of ST-segment elevations greater than 1.5 mm in these leads. Patients had to be enrolled within 24 hours of assessment and to have signed an informed consent document. The principal outcome analyzed in this study was the detection by 2-D echocardiography of left ventricular mural thrombosis on day 10 after infarction. RESULTS Of 233 patients enrolled in the trial, 12 were subsequently declared ineligible. Nine did not have confirmatory evidence of infarction, 1 had undergone major surgery and was thus ineligible, 1 did not begin treatment for 11 days after the onset of infarction, and 1 refused to participate after having signed the consent form. Of 221 patients remaining, 183 underwent 2-D echocardiography on day 10. Twenty-four of the 38 who did not had died in the interim. Of the 183 patients analyzed, 171 began treatment within 36 hours of the infarct and 12 began treatment between 36 and 72 hours. The 2 treat-
FOR THE '90s
ment groups--95 patients in the high-dose group and 88 patients in the low-dose group--were virtually identical with respect to baseline characteristics. A highly significant reduction in the incidence of left ventricular mural thrombosis was achieved with the use of high-dose subcutaneous heparin (Table I). There was no difference between treatments with respect to mortality, namely, 13 deaths in the low-dose group and 11 deaths in the high-dose group. There was also no difference in the causes of death. The single fatal pulmonary embolism occurred in a patient given low-dose heparin. The frequency of hemorrhage, major or minor, did not differ significantly between the 2 groups. An interesting observation, although one that could not be appropriately analyzed statistically, was a reduction in the incidence of nonhemorrhagic stroke in patients treated with high-dose heparin. Four patients in the lowdose group and only 1 patient in the high-dose group had such strokes (suspected to be embolic in origin) within 10 days of the myocardial infarction. Specimens of blood obtained midway between doses were analyzed at the end of the study for plasma heparin concentration and activated partial thromboplastin time. In the patients given high-dose heparin, consistent plasma heparin concentrations were maintained at about 0.2 U / ml, whereas concentrations were barely detectable in those given the low dose. Activated partial thromboplastin time was prolonged about 1.5 times in the high-dose group and was only minimally increased in the low-dose group (Fig. 1). A subset analysis of results in the high-dose group showed that patients in whom left ventricular mural thrombosis was seen on echocardiograms had plasma heparin concentrations that were statistically and clinically significantly lower than heparin concentrations in patients with no left ventricular mural thrombosis. This
60-
{i}___{I{---{
50-
40i/i~i----.-i~l |-"~
FIGURE 1. Mean activated partial thromboplasUn time (APTr) in the high-dose heparin group (circles) and in the low-dose heparin group (squares). (Reprinted with
30-
permission from N £ngl J Med. 11) ~/~ 20-
10-
r 1
i 2
i 3
[ 4
[ 5
I
I
I
I
I
6
7
8
9
10
DAY 42B
THE AMERICANJOURNALOF CARDIOLOGY VOLUME64
finding also relates to the significant lower prolongation of activated partial thromboplastin time in such patients. A l-year follow-up of the patients in this study revealed no differences between high- and low-dose heparin with respect to subsequent events, such as nonhemorrhagic stroke, peripheral arterial embolism, transient ischemic attacks and pulmonary embolism. Thus, patients who have anterior transmural infarction continue to be at risk for embolic events and probably should continue to receive anticoagulants for at least 3 months after discharge. CONCLUSION The reSults of the foregoing study support the conclusion that a high-dose regimen of subcutaneous calcium heparin significantly reduces the incidence of left ventricular mural thrombosis in patients with acute anterior transmural myocardial infarction. This therapy is not associated with increased bleeding. The dosage used in this study was 12,500 U every 12 hours. It is recommended that the heparin dosage be one that maintains the plasma heparin concentration between 0.2 and 0.3 U/ml and the activated partial thromboplastin time between 50 and 60 seconds for the duration of the patient's stay in the hospital.
REFERENCES 1. Report of the Working Party on Anticoagulant Therapy in Coronary Thrombosis to the Medical Research Council. Assessment of short-anticoagulant administration after cardiac infarction. Br Med J 1969;1:335-342. 2 . Veterans Administration Hospital Investigators. Anticoagulants in acute myocardial infarction. Results of a cooperative clinical trial. JAMA 1973;225:724729. 3. Drapkin A, Merskey C. Anticoagulant therapy after acute myocardial infarction. Relation of therapeutic benefit to patient's age, sex and severity of infarction. JAMA 1972;222:541-548. 4. Chalmers TC, Matta R J, Smith H Jr, Kunzler A-M. Evidence favoring the use of anticoagulants in the hospital phase of acute myocardial infarction. N Engl J Med 1977;297:1091-1096. 5. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. JACC 1988;12.'3.4-12,4. 6. Visser CA, Kan G, Meltzer RS, Dunning A J, Roelandt J. Embolic potential of left ventricular thrombus after myocardial infarction: a two-dimensional echocardiographic study of 119 patients. JACC 1985;5,'1276-1280. 7. Stratton JR, Resnick AD. Increased embolic risk in patients with left ventricular thrombi. Circulation 1987;75:1004-1011. 8. Asinger RW, Mikell FL, Elsperger J, Hedges M. Incidence of left-ventricular thrombosis after acute transmiaral myocardial infarction: serial evaluation by twodimensional echocardiography. N Engl J Med 1981;305:297-302. 9. Jordan RA, Miller RD, Edwards JE, Parker RL. Thrombo-embolism in acute and in healed myocardial infarction. Circulation 1952;6.'1-6. 10. Lamas GA, Vaughan DE, Pfeffer MA. Left ventricular thrombus formation after first anterior wall acute myocardial infarction. Am J Cardiol 1988,~52:31-35. l !. Turpie AGG, Robinson JG, Doyle D J, Mulji AS, Mishkel G J, Sealey BJ, Cairns JA, Hirsh J, Skingley L, Gent M. Prevention of left ventricular mural thrombosis in acute transmural anterior myocardial infarction: a double blind trial comparing high dose wiih low dose subcutaneous calcium heparin. N Engl J Med 1989;320:352-357.
THE AMERICANJOURNALOF CARDIOLOGY JULY 18, 1989 43B