- Email: [email protected]
A comparison of heparin strategies after thrombolytic therapy
A compmison~ of ‘heparin @rategiSes after thrombotytic therapy Richard C. Becker, MD, Jeanne M. Corrao, RN, MS, Steven P. Ball, RN, and Joel M. Gore, MD Worcester, Muss.
Thrombolytic therapy has emerged as the treatment of choice for a majority of patients with acute myocardial infarction (MI). Currently tissue plasminogen activator (TPA) is the thrombolytic agent used most commonly in the United States. Its short circulating half-life and limited impact on plasma fibrinogen, however, predispose patients being treated to coronary arterial reocclusion, with a rate approaching 15% in the first 24 to 48 h0urs.l Three clinical trials have shown that intravenous heparin after TPA administration significantly reduces the incidence of early reocclusion.2-4 They have also shown that a therapeutic state of systemic anticoagulation is required for the beneficial effects to become apparent.5-7 Despite the importance of achieving and maintaining a therapeutic state of anticoagulation, few guidelines for heparin use are available. In addition, existing information has been derived almost exclusively from patients with venous thromboembolic disease,8-10 rather than from patients with MI treated with thrombolytic therapy. The requirements for heparin in arterial thromboembolic disease may be unique, and furthermore, the effect of thrombolytic therapy on standard laboratory or bedside tests for assessment of the anticoagulant effects of heparin may have a significant impact. Methods. Two heparin strategies were compared in 276 patients receiving thrombolytic therapy for acute MI for whom information was available from the University of Massachusetts Thrombolysis data base. All patients received heparin as a 5000 U intravenous bolus followed by a continuous infusion beginning at a rate of 1000 U/hr. A target activated partial thromboplastin time (aPTT) that was two to three times the control value was sought. For patients in group 1 heparin adjustments were based entirely on physiFrom the Thrombosis ical School. Received
Research
for publication
AM HEARTJ
Jan.
Center,
University
15, 1993;
accepted
1993;126:750-752
Copyright Q 1993 0002..8703/93/$1.00
by Mosby-Year Book, + .lO 4/l/47694
Inc.
of Massachusetts March
1, 1993.
Med-
Table 1. Mean activated partial thromboplastin
time levels at designated time points between heparin strategy groups Time
point ihr) 6 12 24 48
*aPTT
Group I* (N= 164) 82.2 71.8 61.8 59.5
f + k +
38.7 32.9 27.3 25.9
Group 2* (N = 112) 117.7 94.5 96.3 63.8
+ + + +
46.6 44.6 41.3 28.2
p Value 0.06 0.001 0.001
0.33
f SD in seconds.
cian preference (physician-guided heparin strategy), whereas in group 2 a standard heparin nomogram was followed (nomogram-guided heparin strategy). Serial aPTTs were determined according to a specific coronary care unit protocol at 6,12,24, and 48 hours after heparin was initiated. Results. Mean aPTT values during the 48-hour observation period are shown in Table I. Overall the aPTT was higher in group 2 at all time points; on average, values were 24 seconds higher. The relatively high level of anticoagulation among patients in group 2 is reflected in the higher percentage of these persons being above the target aPTT range (Table II). However, less than 50 % of patients in group 1 and an even smaller number in group 2 had therapeutic levels of anticoagulation. Considering each time point individually, more than 50 % of patients in both heparin strategy groups had one to two aPTTs below the therapeutic range, and nearly 20% of patients in group 2 had three or more subtherapeutic aPTTs (Table III). In essence, these persons were inadequately anticoagulated during the entire observation period. Comments. Heparin is amucopolysaccharide, which after interacting with antithrombin III, neutralizes several coagulation proteins including thrombin and activated factors IX, X, XI, and XII. Commercial preparations of heparin are heterogeneous with molecular weights varying from 3,000 to 30,000. Only one third of heparin molecules bind to antithrombin III, and this fraction is responsible for the anticoag-
Volume 126, Number 3, Part 1 American Heart Journal
Becker
Table II. Comparison of activated partial thromboplastin heparinization
Below therapeutic Therapeutic level Above therapeutic
*p
<0.005 tp = 0.05
comparing designated
level (%) level
(% ) (% )
751
time values between physician- and nomogram-guided
Group 1 (N = 164) Time (hr) Heparinization
et al.
Group 2 (N = 112) Time (hr)
6
12
24
48
18.3 41.3* 46.4
23.5 49.7* 26.8
36.1 47.6* 16.3
43.9 45.9t 10.0
6
12
24
48
15.6 13.8 70.6*
32.1 28.3 35.6
29.8 17.5 52.6
59.0 28.0 13.0
groups at time points.
ulant effect.lll I2 In addition to being a heterogeneous compound, heparin has complex pharmacokinetics, that can best be described as a combination of saturable and first-order kinetics. As a result, the doseanticoagulant response relationship is nonlinear, increasing disproportionately in both intensity and duration as the intravenous dose is increased.13 The anticoagulant response after heparin administration varies widely among patients. This observation is poorly understood but is believed to be the end result of compound heterogeneity, varying pharmacokinetics influenced by age, sex, body weight, smoking status, thrombotic stimulus, renal and hepatic function, I4 drug interactions,15 nonstandardized testing practices,l” and binding to the vascular endthelium.17* l8 Despite the well-known and widely recognized challenge of intravenous heparin use, Iimited information is available for practicing clinicians. We reviewed our experience with two heparin adjustment strategies that are used routinely in patients with MI receiving thrombolytic therapy. To our surprise, we observed a less than 50 % success rate in maintaining a therapeutic level of anticoagulation, even with the assistance of a standardized nomogram. A review of the literature, however, suggests that our experience is probably not unique. In the HART study,5 which utilized a physician-guided heparin strategy, only 58% of patients achieved an aPTT greater than 1.5 times the control value, both 8 and 12 hours after treatment was initiated. Only one third achieved an aPTT greater than 2.0 times the control value, and 25 % of patients had subtherapeutic levels at 12 hours. The European Cooperative Study Group” used a fixed-dose heparin strategy consisting of a 5000 U bolus followed by 1000 U/hr. Adjustments were not permitted during the study period. Sixty percent of patients had either suboptimal or inadequate anticoagulation. More recently the GUSTO investigators reported their findings.14 Among more than 5000 patients in whom a standardized heparin
Table III. Frequency of subtherapeutic during 48-hour observation period Observation Subtherapeutic Subtherapeutic Subtherapeutic Subtherapeutic
period aPTT aPTTs aPTTs aPTTs
(% ) (%) (%)
anticoagulation
Group 1 (N = 164)
Group 2 (N = 112)
39.6 23.8 4.9 3.0
43.8 17.0 10.7 7.1
p
Value 0.54 0.22 0.03 0.11
nomogram was used, a majority (52 % ) was found to have subtherapeutic levels at 24 hours. Among patients weighing more than 80 kg, 60% had subtherapeutic levels at 24 hours. The heparin nomogram used in the GUSTO trial, as well as the nomogram used previously at our institution, was derived from a study of patients with venous thro~boemboIism.10 Although it may offer distinct advantages to physician-based, unstandardized heparin strategies, several shortcomings were noted in the initial experience. First, one third of patients remained inadequately anticoagulated 24 hours after treatment was initiated. Second, fewer than one third remained within a therapeutic range over several days. Third, 60% of patients in whom adequate anticoagulation was achieved initially had one or more subtherapeutic aPTTs over the ensuing days of heparin treatment. Fourth, the adjustment schedule was based on heparin levels yielding aPTT values for a specific laboratory reagent, raising serious questions about the direct applicability of the nomogram to other thromboplastins. Improved nomograms have been developed recently,lg and preliminary results of a study performed at our institution using a new weight-adjusted heparin nomogram (unpublished data) suggest that therapeutic aPTTs can be achieved and maintained 80% to 90% of the time, particularly when bedside coagulation monitoring is utilized. Additional experience among patients with arterial thromboembolic disease receiving thrombolytic therapy, however, is required.
Rodriguez,
Froning,
and Froelicher
American
In conclusion, heparin is the most widely used anticoagulant in clinical practice. It has assumed a central role in the primary and adjunctive treatment of patients with venous and arterial thromboembolism. Although most clinicians feel comfortable and confident using, monitoring, and adjusting intravenous heparin, our findings raise several serious concerns. We advocate an immediate reassessment of heparin strategies, particularly for patients receiving thrombolytic therapy, and recommend that specific nomograms be developed in which body weight, thromboembolic disease state, and thrombolytic agent(s) are primary considerations.
7. Rapold
8.
9.
10.
11.
12.
REFERENCES 1. Becker
2.
3.
4.
5.
6.
RC. Repeat thrombolysis for early coronary arterial reocclusion. Coronary Artery Dis 1992;3:499-512. Hsia J, Hamilton WP, Kleiman N, Roberts R, Chaitman BR, Ross AM, for the HART Investigators. A comparison between heparin and low-dose aspirin as adjunctive therapy with tissue plasminogen activator for acute myocardial infarction. N Engl J Med 1990;323:1433-7. Bleich SD, Nichols TC, Schumacher RR, Cooke DH, Tate DA, Teichman SL. Effect of heparin on coronary arterial patency after thrombolysis with tissue plasminogen activator in acute myocardial infarction. Am J Cardiol 1990;66:1412-7. de Bono DP, Simoons ML, Tijssen J, Arnold AER, Betriu A, Burgersdijk C, Lopez Bescos L, Mueller E, Pfisterer M, Van de Werf F, Zijlstra F, Verstraete M. Effect of early intravenous heparin on coronary patency, infarct size, and bleeding complications after alteplase thrombolysis: results of a randomised double blind European Cooperative Study Group trial. Br Heart J 1992;67:122-8. Hsia J, Kleiman N, Aguirre F, Chaitman BR, Roberts R, Ross AM, for the HART Investigators. Heparin-induced prolongation of partial thromboplastin time and thrombolysis: relation to coronary artery patency. J Am Co11 Cardiol 1992;20:31-5. Arnout J, Simoons M, de Bono D, Rapold HJ, Cohen D, Verstraete M. Correlation between level of heparinization and patency of the infarct-related coronary artery after treatment of acute myocardial infarction with alteplase (rt-PA). J Am Co11 Cardiol 1992;20:513-9.
September 1933 Heart Journal
13.
14.
15.
16.
17.
18. 19.
HJ, de Bono D, Arnold AER. Plasma fibrinopeptide A levels in patients with acute myocardial infarction treated with alteplase. Circulation 1992;85:928-34. Basu D, Callus A, Hirsh J, Cade J. A prospective study of the value of monitoring heparin treatment with the activated partial thromboplastin time. N Engl J Med 1972;287:324-7. Hull RD, Raskdb GE, Hirsh 3, Jay RM, Leclerc JR, Geerts WH. Rosenbloom D. Sackett DL. Anderson C. Harrison L. Gent M. Continuous’ intravenous heparin compared with in: termittent subcutaneous heparin in the initial treatment of proximal-vein thrombosis. N Engl J Med 1986;315:1109-14. Cruickshank MK. Levine MN. Hirsh J. Roberts R. Sieuenza M. A standard heparin nomogram for the management of heparin therapy. Arch Intern Med 1991;151:333-37. Lam LH, Silbert JE, Rosenberg RD. The separation of active and inactive forms of heparin. Biochem Biophys Res Commun 1976;69:570-7. Andersson LO, Barrowcliffe TW, Holmer E, Johnson EA, Sims GEC. Anticoagulant properties of heparin fractioned by affinity chromatography on matrix-bound antithrombin III and by gel filtration. Thromb Res 1976;9:575-83. de Swart CAM, Nijmeyer B, Roelofs JMM, Sixma JJ. Kinetics of intravenously administered heparin in normal humans. Blood 1982;60:1251-8. Granger CB, Califf RM, Hirsh J, Woodlief CH, Top01 EJ. aPTT’s after thrombolysis and standard intravenous heparin are often low and correlate with body weight, age, and sex: exaerience from the GUSTO trial IAbstractl. Circulation i992;86(suppl l):l-259. Becker RC, Corrao JM, Bovill EG, Gore JM, Baker SP, Miller ML, Lucas FV, Alpert JS. Intravenous nitroglycerin-induced heparin resistance: a qualitative antithrombin III abnormality. AM HEART J 1990;119:1254-61. Shapiro GA, Huntzinger SW, Wilson JE. Variation among commercial activated partial thrombaplastin time reagents in response to heparin. Am J Clin Path01 1977;67:477-80. Glimelius B, Busch C, Hook M. Binding of heparin on the surface of cultured human endothelial cells. Thromb Res 1982;31:773-82. Mahadoo J, Heibert L, Jaques LB. Vascular sequestration of heparin. Thromb Res 1977;12:79-90. Hull RD. Raskob GE. Rosenbloom D. Lamaire J. Pineo GF. Baylis B; Ginsberg JS, Panju AA, Brill-Edwards P, Brant RI Optimal therapeutic level of heparin therapy in patients with venous thrombosis. Arch Intern Med 1992;152:1589-95.
ST0 or ST60 Michael
Rodriguez,
MD, Jeffrey Froning,
MA, and Victor F. Froelicher,
MD
Long Beach, Calif.
From the Department of Cardiology, Long Beach Veterans Affairs Medical Center. Received for publication Jan. 22, 1993; accepted March 1, 1993. Reprint requests: Michael Rodriguez, MD, Cardiology Division (lllC), Long Beach VA Medical Center, 5901 East Seventh St., Long Beach, CA 90822.
AMHEARTJ 411147695
1993;126:752-754
Exercise-induced ST depression is an accepted predictor of coronary artery disease and is frequently used in deciding whether to perform coronary angi0graphy.l Some investigators have demonstrated improvement in the diagnostic accuracy of ST depression by means of heart rate adjustment schemes2-I2 whereas others have not.2, 5$6 8pl2 A recent report by Okin et a1.13 adjusting the suggested
Thrombolytic therapy has emerged as the treatment of choice for a majority of patients with acute myocardial infarction (MI). Currently tissue plasminogen activator (TPA) is the thrombolytic agent used most commonly in the United States. Its short circulating half-life and limited impact on plasma fibrinogen, however, predispose patients being treated to coronary arterial reocclusion, with a rate approaching 15% in the first 24 to 48 h0urs.l Three clinical trials have shown that intravenous heparin after TPA administration significantly reduces the incidence of early reocclusion.2-4 They have also shown that a therapeutic state of systemic anticoagulation is required for the beneficial effects to become apparent.5-7 Despite the importance of achieving and maintaining a therapeutic state of anticoagulation, few guidelines for heparin use are available. In addition, existing information has been derived almost exclusively from patients with venous thromboembolic disease,8-10 rather than from patients with MI treated with thrombolytic therapy. The requirements for heparin in arterial thromboembolic disease may be unique, and furthermore, the effect of thrombolytic therapy on standard laboratory or bedside tests for assessment of the anticoagulant effects of heparin may have a significant impact. Methods. Two heparin strategies were compared in 276 patients receiving thrombolytic therapy for acute MI for whom information was available from the University of Massachusetts Thrombolysis data base. All patients received heparin as a 5000 U intravenous bolus followed by a continuous infusion beginning at a rate of 1000 U/hr. A target activated partial thromboplastin time (aPTT) that was two to three times the control value was sought. For patients in group 1 heparin adjustments were based entirely on physiFrom the Thrombosis ical School. Received
Research
for publication
AM HEARTJ
Jan.
Center,
University
15, 1993;
accepted
1993;126:750-752
Copyright Q 1993 0002..8703/93/$1.00
by Mosby-Year Book, + .lO 4/l/47694
Inc.
of Massachusetts March
1, 1993.
Med-
Table 1. Mean activated partial thromboplastin
time levels at designated time points between heparin strategy groups Time
point ihr) 6 12 24 48
*aPTT
Group I* (N= 164) 82.2 71.8 61.8 59.5
f + k +
38.7 32.9 27.3 25.9
Group 2* (N = 112) 117.7 94.5 96.3 63.8
+ + + +
46.6 44.6 41.3 28.2
p Value 0.06 0.001 0.001
0.33
f SD in seconds.
cian preference (physician-guided heparin strategy), whereas in group 2 a standard heparin nomogram was followed (nomogram-guided heparin strategy). Serial aPTTs were determined according to a specific coronary care unit protocol at 6,12,24, and 48 hours after heparin was initiated. Results. Mean aPTT values during the 48-hour observation period are shown in Table I. Overall the aPTT was higher in group 2 at all time points; on average, values were 24 seconds higher. The relatively high level of anticoagulation among patients in group 2 is reflected in the higher percentage of these persons being above the target aPTT range (Table II). However, less than 50 % of patients in group 1 and an even smaller number in group 2 had therapeutic levels of anticoagulation. Considering each time point individually, more than 50 % of patients in both heparin strategy groups had one to two aPTTs below the therapeutic range, and nearly 20% of patients in group 2 had three or more subtherapeutic aPTTs (Table III). In essence, these persons were inadequately anticoagulated during the entire observation period. Comments. Heparin is amucopolysaccharide, which after interacting with antithrombin III, neutralizes several coagulation proteins including thrombin and activated factors IX, X, XI, and XII. Commercial preparations of heparin are heterogeneous with molecular weights varying from 3,000 to 30,000. Only one third of heparin molecules bind to antithrombin III, and this fraction is responsible for the anticoag-
Volume 126, Number 3, Part 1 American Heart Journal
Becker
Table II. Comparison of activated partial thromboplastin heparinization
Below therapeutic Therapeutic level Above therapeutic
*p
<0.005 tp = 0.05
comparing designated
level (%) level
(% ) (% )
751
time values between physician- and nomogram-guided
Group 1 (N = 164) Time (hr) Heparinization
et al.
Group 2 (N = 112) Time (hr)
6
12
24
48
18.3 41.3* 46.4
23.5 49.7* 26.8
36.1 47.6* 16.3
43.9 45.9t 10.0
6
12
24
48
15.6 13.8 70.6*
32.1 28.3 35.6
29.8 17.5 52.6
59.0 28.0 13.0
groups at time points.
ulant effect.lll I2 In addition to being a heterogeneous compound, heparin has complex pharmacokinetics, that can best be described as a combination of saturable and first-order kinetics. As a result, the doseanticoagulant response relationship is nonlinear, increasing disproportionately in both intensity and duration as the intravenous dose is increased.13 The anticoagulant response after heparin administration varies widely among patients. This observation is poorly understood but is believed to be the end result of compound heterogeneity, varying pharmacokinetics influenced by age, sex, body weight, smoking status, thrombotic stimulus, renal and hepatic function, I4 drug interactions,15 nonstandardized testing practices,l” and binding to the vascular endthelium.17* l8 Despite the well-known and widely recognized challenge of intravenous heparin use, Iimited information is available for practicing clinicians. We reviewed our experience with two heparin adjustment strategies that are used routinely in patients with MI receiving thrombolytic therapy. To our surprise, we observed a less than 50 % success rate in maintaining a therapeutic level of anticoagulation, even with the assistance of a standardized nomogram. A review of the literature, however, suggests that our experience is probably not unique. In the HART study,5 which utilized a physician-guided heparin strategy, only 58% of patients achieved an aPTT greater than 1.5 times the control value, both 8 and 12 hours after treatment was initiated. Only one third achieved an aPTT greater than 2.0 times the control value, and 25 % of patients had subtherapeutic levels at 12 hours. The European Cooperative Study Group” used a fixed-dose heparin strategy consisting of a 5000 U bolus followed by 1000 U/hr. Adjustments were not permitted during the study period. Sixty percent of patients had either suboptimal or inadequate anticoagulation. More recently the GUSTO investigators reported their findings.14 Among more than 5000 patients in whom a standardized heparin
Table III. Frequency of subtherapeutic during 48-hour observation period Observation Subtherapeutic Subtherapeutic Subtherapeutic Subtherapeutic
period aPTT aPTTs aPTTs aPTTs
(% ) (%) (%)
anticoagulation
Group 1 (N = 164)
Group 2 (N = 112)
39.6 23.8 4.9 3.0
43.8 17.0 10.7 7.1
p
Value 0.54 0.22 0.03 0.11
nomogram was used, a majority (52 % ) was found to have subtherapeutic levels at 24 hours. Among patients weighing more than 80 kg, 60% had subtherapeutic levels at 24 hours. The heparin nomogram used in the GUSTO trial, as well as the nomogram used previously at our institution, was derived from a study of patients with venous thro~boemboIism.10 Although it may offer distinct advantages to physician-based, unstandardized heparin strategies, several shortcomings were noted in the initial experience. First, one third of patients remained inadequately anticoagulated 24 hours after treatment was initiated. Second, fewer than one third remained within a therapeutic range over several days. Third, 60% of patients in whom adequate anticoagulation was achieved initially had one or more subtherapeutic aPTTs over the ensuing days of heparin treatment. Fourth, the adjustment schedule was based on heparin levels yielding aPTT values for a specific laboratory reagent, raising serious questions about the direct applicability of the nomogram to other thromboplastins. Improved nomograms have been developed recently,lg and preliminary results of a study performed at our institution using a new weight-adjusted heparin nomogram (unpublished data) suggest that therapeutic aPTTs can be achieved and maintained 80% to 90% of the time, particularly when bedside coagulation monitoring is utilized. Additional experience among patients with arterial thromboembolic disease receiving thrombolytic therapy, however, is required.
Rodriguez,
Froning,
and Froelicher
American
In conclusion, heparin is the most widely used anticoagulant in clinical practice. It has assumed a central role in the primary and adjunctive treatment of patients with venous and arterial thromboembolism. Although most clinicians feel comfortable and confident using, monitoring, and adjusting intravenous heparin, our findings raise several serious concerns. We advocate an immediate reassessment of heparin strategies, particularly for patients receiving thrombolytic therapy, and recommend that specific nomograms be developed in which body weight, thromboembolic disease state, and thrombolytic agent(s) are primary considerations.
7. Rapold
8.
9.
10.
11.
12.
REFERENCES 1. Becker
2.
3.
4.
5.
6.
RC. Repeat thrombolysis for early coronary arterial reocclusion. Coronary Artery Dis 1992;3:499-512. Hsia J, Hamilton WP, Kleiman N, Roberts R, Chaitman BR, Ross AM, for the HART Investigators. A comparison between heparin and low-dose aspirin as adjunctive therapy with tissue plasminogen activator for acute myocardial infarction. N Engl J Med 1990;323:1433-7. Bleich SD, Nichols TC, Schumacher RR, Cooke DH, Tate DA, Teichman SL. Effect of heparin on coronary arterial patency after thrombolysis with tissue plasminogen activator in acute myocardial infarction. Am J Cardiol 1990;66:1412-7. de Bono DP, Simoons ML, Tijssen J, Arnold AER, Betriu A, Burgersdijk C, Lopez Bescos L, Mueller E, Pfisterer M, Van de Werf F, Zijlstra F, Verstraete M. Effect of early intravenous heparin on coronary patency, infarct size, and bleeding complications after alteplase thrombolysis: results of a randomised double blind European Cooperative Study Group trial. Br Heart J 1992;67:122-8. Hsia J, Kleiman N, Aguirre F, Chaitman BR, Roberts R, Ross AM, for the HART Investigators. Heparin-induced prolongation of partial thromboplastin time and thrombolysis: relation to coronary artery patency. J Am Co11 Cardiol 1992;20:31-5. Arnout J, Simoons M, de Bono D, Rapold HJ, Cohen D, Verstraete M. Correlation between level of heparinization and patency of the infarct-related coronary artery after treatment of acute myocardial infarction with alteplase (rt-PA). J Am Co11 Cardiol 1992;20:513-9.
September 1933 Heart Journal
13.
14.
15.
16.
17.
18. 19.
HJ, de Bono D, Arnold AER. Plasma fibrinopeptide A levels in patients with acute myocardial infarction treated with alteplase. Circulation 1992;85:928-34. Basu D, Callus A, Hirsh J, Cade J. A prospective study of the value of monitoring heparin treatment with the activated partial thromboplastin time. N Engl J Med 1972;287:324-7. Hull RD, Raskdb GE, Hirsh 3, Jay RM, Leclerc JR, Geerts WH. Rosenbloom D. Sackett DL. Anderson C. Harrison L. Gent M. Continuous’ intravenous heparin compared with in: termittent subcutaneous heparin in the initial treatment of proximal-vein thrombosis. N Engl J Med 1986;315:1109-14. Cruickshank MK. Levine MN. Hirsh J. Roberts R. Sieuenza M. A standard heparin nomogram for the management of heparin therapy. Arch Intern Med 1991;151:333-37. Lam LH, Silbert JE, Rosenberg RD. The separation of active and inactive forms of heparin. Biochem Biophys Res Commun 1976;69:570-7. Andersson LO, Barrowcliffe TW, Holmer E, Johnson EA, Sims GEC. Anticoagulant properties of heparin fractioned by affinity chromatography on matrix-bound antithrombin III and by gel filtration. Thromb Res 1976;9:575-83. de Swart CAM, Nijmeyer B, Roelofs JMM, Sixma JJ. Kinetics of intravenously administered heparin in normal humans. Blood 1982;60:1251-8. Granger CB, Califf RM, Hirsh J, Woodlief CH, Top01 EJ. aPTT’s after thrombolysis and standard intravenous heparin are often low and correlate with body weight, age, and sex: exaerience from the GUSTO trial IAbstractl. Circulation i992;86(suppl l):l-259. Becker RC, Corrao JM, Bovill EG, Gore JM, Baker SP, Miller ML, Lucas FV, Alpert JS. Intravenous nitroglycerin-induced heparin resistance: a qualitative antithrombin III abnormality. AM HEART J 1990;119:1254-61. Shapiro GA, Huntzinger SW, Wilson JE. Variation among commercial activated partial thrombaplastin time reagents in response to heparin. Am J Clin Path01 1977;67:477-80. Glimelius B, Busch C, Hook M. Binding of heparin on the surface of cultured human endothelial cells. Thromb Res 1982;31:773-82. Mahadoo J, Heibert L, Jaques LB. Vascular sequestration of heparin. Thromb Res 1977;12:79-90. Hull RD. Raskob GE. Rosenbloom D. Lamaire J. Pineo GF. Baylis B; Ginsberg JS, Panju AA, Brill-Edwards P, Brant RI Optimal therapeutic level of heparin therapy in patients with venous thrombosis. Arch Intern Med 1992;152:1589-95.
ST0 or ST60 Michael
Rodriguez,
MD, Jeffrey Froning,
MA, and Victor F. Froelicher,
MD
Long Beach, Calif.
From the Department of Cardiology, Long Beach Veterans Affairs Medical Center. Received for publication Jan. 22, 1993; accepted March 1, 1993. Reprint requests: Michael Rodriguez, MD, Cardiology Division (lllC), Long Beach VA Medical Center, 5901 East Seventh St., Long Beach, CA 90822.
AMHEARTJ 411147695
1993;126:752-754
Exercise-induced ST depression is an accepted predictor of coronary artery disease and is frequently used in deciding whether to perform coronary angi0graphy.l Some investigators have demonstrated improvement in the diagnostic accuracy of ST depression by means of heart rate adjustment schemes2-I2 whereas others have not.2, 5$6 8pl2 A recent report by Okin et a1.13 adjusting the suggested