Antithrombotic therapy in acute coronary syndromes: Key notes from ESSENCE and TIMI 11B

Antithrombotic Therapy in Acute Coronary Syndromes: Key Notes From ESSENCEand TIM1 11B Keith A.A. Fox Platelet activation and thrombus formation are key events in the pathogenesis of acute coronary syndromes (unstable angina and non-Q-wave myocardiai infarction). Therefore, current management of these conditions consists of antithrombotic and antiplatelet therapy, principally heparin and oral aspirin. However, such treatment is unsuccessful in a significant proportion of patients. Two recent large studies with the low-molecular-weight heparin (LMWH) enoxaparin have shown that this agent significantly reduces the risk of major ischemic events compared with unfractionated heparin. In the Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-Wave Coronary Events (ESSENCE) study, treatment with enoxaparin for 2 to 8 days reduced the risk of death, myocardial infarction, or recurrent angina by 20% at 14 days compared with treatment with unfractionated heparin. in the Thrombolysis in Myocardiai infarction (TIMI) 11B study, enoxaparin was associated with a significant reduction in the risk of death, myocardial infarction, or urgent revascularization compared with unfractionated heparin, which became apparent within 48 hours: this benefit was maintained during outpatient treatment for 5 weeks. A meta-analysis of these two studies showed that the risk of death or myocardial infarction was consistently approximately 20% lower in enoxaparin-treated patients than in heparin-treated patients. in contrast, studies with other LMWHs have not shown consistent superiority over unfractionated heparin. This may reflect the pharmacologic heterogeneity of LMWH and/or differences in trial design. Semin Hematol38(suppl5):67-74. Copyright 0 2001 by W.B. Saunders Company.

U

NSTABLE ANGINA (UA) and non-Qwave myocardial infarction (NQWMI) without ST-segment elevation share similar pathophysiologies and clinical presentations, and thus, together with Q-wave myocardial infarction, are collectively termed acute coronary (or ischemic) syndromes (ACS).l These conditions are common, accounting for up to 2.5 million hospitalizations per year worldwide, and the prevalence is increasing.lJ Indeed, recent European data suggest that non-STsegment elevation ACS (UA with or without CK and troponin release) are more common than myocardial infarction.3 Furthermore, UA and NQWMI are associated with substantial mortality and morbidity. Data from the Organization to AssessStrategies for Ischemic Syndromes (OASIS) registry, which includes approximately 8,000 patients from six countries, show that the incidence of myocardial infarction or death of cardiovascular causeswithin 6 months is 10.5% in patients with UA or suspected acute myocardial ischemia without STsegment elevation, regardless of whether revascularization is performed promptly.* Moreover, there is a 22% risk of death, myocardial infarction, or refractory angina within the same time. Seminars

in Hematology,

UA/NQWMI thus represents a major problem in cardiology practice. Rupture of an atherosclerotic plaque and subsequent thrombus formation are key elements in the pathophysiology of ACS.> Plaque rupture exposes tissue factor in the lipid core of the plaque to circulating factor VIIa, and the resulting tissue factor-factor VIIa complex then promotes formation of factor Xa.6,7 This in turn leads to activation of the coagulation cascade, with thrombin formation, fibrin deposition, and platelet activation.a,9 Plaque disruption, superimposed thrombosis, and impairment of perfusion determine the severity of the resulting clinical syndrome. l Extensive thrombosis can lead to complete occlusion of the coronary From the Department of Medical and Radiological Sciences, Cardiology, The Royal Infirmary, Edinburgh, Scotland. Based on a presentation delivered at a symposium to the 1999 meeting of the International Society on Thrombosis and Haemostasis. Address reprint requests to Keith A. A. Fox, MBCLB, Department of Cardiology, Royal Injrmary ofEdinburgh, Lauriston Place, Edinburgh, EH3 9YW, UK. Copyright 0 2001 by W.B. Saundws Company 0037-1963/01!3802-5009$35.00/O doi:10.1053/shem.2001.25191

Vol 38, No 2, Suppl 5 (April),

2001:

pp 67-74

67

68

Keith A.A. Fox

artery, resulting in persistent angina1 pain with ST-segment elevation and ultimately in most casesto a Q-wave myocardial infarction.lOJ1

Current Management of Acute Coronary Syndromes Because platelet activation and thrombus formation are key events in the development of ACS, there is a clear rationale for the use of antiplatelet drugs and antithrombotics in the treatment of these conditions. Both aspirin and heparin have been shown to reduce the risk of death or myocardial infarction in patients with non-ST ACS,12-15 and there is evidence that a combination of the two is more effective than aspirin alone.16,17A meta-analysis of published trials in patients with UA, for example, showed that the risk of myocardial infarction or death was reduced by 33% in patients receiving aspirin plus heparin, compared with those receiving aspirin alone. I7 As a result, current management of ACS consists of a combination of intravenous unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH) and oral aspirin. Glycoprotein IIb/IIIa inhibitors and revascularization are generally reserved for higher-risk patients (for example, elevated troponins or recurrent ischemia despite treatment, or ischemia on risk-stratifying tests before discharge).zJs Treatment with UFH may be unsuccessful in a significant proportion of patients. This may be because of difficulties in achieving effective antithrombin activity, l9 lability of activated partial thromboplastin time responses (resulting from inhibition of heparin by activated platelets and binding to plasma proteins).20J1 A rebound increase in thrombin generation after discontinuation of heparin treatment,22 may be associated with an increased incidence of clinical events.23 Prolonged treatment with UFH is associated with a risk of thrombocytopenia.24 LMWHs offer a number of potential advantages over UFH. They have a higher ratio of anti-Xa to anti-IIa activity and a more predictable anticoagulant effect,25 they are resistant to inhibition by activated platelets,20,21 and they are associated with a lower risk of thrombocy-

topenia.25 Furthermore, in contrast to UFH, LMWHs do not necessitate monitoring of anticoagulant activity during treatment. Recent studies with the LMWH enoxaparin have shown that in contrast to other LMWHs, this agent is significantly more effective than UFH in reducing the incidence of cardiac ischemic events in patients with ACS.26-28

Clinical

Trials With Enoxaparin

Two large randomized prospective studies, the Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-Wave Coronary Events (ESSENCE) study26 and the Thrombolysis in Myocardial Infarction (TIMI) 11B study,27 have compared the efficacy and safety of enoxaparin with that of UFH in patients with ACS who were receiving oral aspirin. The designs of these studies are summarized in Table 1.

The ESSENCE study The ESSENCE study involved a total of 3,17 1 patients with angina at rest or NQWMI, who were randomized to receive either enoxaparin, 1 mg/kg (100 anti-Xa U/mg) every 12 hours, or UFH, given as an initial intravenous bolus of 5,000 U followed by a continuous infusion at a dose adjusted according to the activated partial thromboplastin time. In addition, all patients received oral aspirin at daily dosesbetween 100 mg and 325 mg. Study treatment was continued for at least 48 hours, to a maximum of 8 days. The primary endpoint was death, myocardial infarction (or reinfarction), or recurrent angina. After 14 days, the risk of patients experiencing death, myocardial infarction, or recurrent angina was reduced by 20% for the enoxaparin group (P = .019): 19.8% for those receiving UFH compared with 16.6% for those receiving enoxaparin. The benefit of enoxaparin was maintained over time, in that the incidence of the composite endpoint at 30 days was significantly lower in the enoxaparin group than in the UFH group (19.8% 2, 23.3%; P = .016). The proportion of patients requiring coronary revascularization was also significantly lower in the enoxaparin group at this time (27% *

69

Antithrombotic Thvapy in Acute Coronary Syndromes

Table

1. Patient

Populations

and Design

of the ESSENCE

and TIMI IlB

ESSENCE=

Inclusion criteria Rest angina within 24 hours Additional supportive criteria (at least one of the following required) ST deviation History of coronary artery disease

Elevated serum cardiac markers Major exclusion criteria Planned revascularization 524 hours Correctable cause of angina Contraindications to anticoagulation Dose of study drug in acute phase IV UFH

Dose of study Placebo

Required

20.1 mV Acceptable

Acceptable

20.05 mV Acceptable initially, but later dropped as sole supportive criterion Acceptable

Yes Yes Yes

Yes Yes Yes

5,000

U bolus, followed

X control (median days) No initial intravenous SC every 12 hours duration 2.6 days) drug in outpatient

Enoxaparin

Abbreviation: SC, subcutaneous; Reprinted with permission.*a

TIMI 11627

Required

(1,000 U/h) adjusted

Enoxaparin

Studies

by infusion to 1.5 to 2.5 duration 2.6 bolus; (median

1 mg/kg

70 U/kg bolus, followed by infusion (15 U/kg/hour) adjusted to 1.52.5 X control (median duration 3.0 days) 30 mg IV bolus, followed by 1 mg/ kg SC every 12 hours (median duration 4.6 days)

phase None

Matched volume of injections to active treatment 40 mg SC every 12 hours if <65 60 mg SC every 12 hours if ~65

None

IV, intravenous;

UFH, unfractionated

32.2%; P = ,001). Further subgroup analyses showed that enoxaparin was significantly more effective than UFH in a number of patient subgroups, particularly patients over 65 years of age, those who had previously undergone percutaneous transluminal coronary angioplasty, and those with ST-segment depression at baseline. There was no significant difference in the incidence of serious hemorrhagic complications between the enoxaparin and UFH groups (6.5 % and 7 .O%, respectively); hemorrhagic complications (principally minor ecchymoses at the injection site) occurred within 30 days in 18.4% of enoxaparin-treated patients, compared with 14.2% of patients receiving UFH (P = .OOl). Analysis of health-economic data from the ESSENCE study has shown that enoxaparin treatment is cost saving.29 The use of hospital resources, such as diagnostic catheterization and coronary angioplasty, was significantly lower in enoxaparin-treated patients than in those receiving UFH, both during the initial hospitalization and at 30 days, and this was associated

kg kg

heparin.

with significant cost savings. On the basis of these findings, the authors concluded that enoxaparin could be considered a “dominant” therapy in health-economic terms: one that both improves clinical outcome and reduces costs compared with standard treatment.29J0

The TIM1

11B Study

The TIMI 11B study was similar in design to the ESSENCE study, except that enoxaparin was given as an initial 30 mg intravenous bolus, followed by injections of 1 mg/kg every 12 hours. In this study, however, the acute treatment phase was followed by a 5-week outpatient phase to determine the long-term efficacy of enoxaparin because activation of the coagulation cascade can persist for several weeks or months after the index event.3i In the outpatient phase of the study, patients originally randomized to receive enoxaparin in the acute treatment phase received twice-daily injections of 40 mg of enoxaparin if they weighed less

70

Keith

than 65 kg or 60 mg if they weighed 65 kg or above; patients originally randomized to receive UFH received placebo injections. A total of 3,910 patients took part in this study; 2,364 continued into the outpatient phase. After 48 hours’ treatment, the primary endpoint of death, myocardial infarction, or urgent revascularization had been reached in 7.3% of patients receiving UFH and 5.5% of enoxaparin-treated patients, corresponding to a risk reduction of 23.8% (P = .026). After 8 days, the corresponding figures were 14.5% and 12.4%, respectively, with a risk reduction of 17% (P = .048). These figures suggest that 2 1 events could be prevented for every 100 patients treated with enoxaparin. Similarly, the incidence of death or myocardial infarction at 8 days was reduced from 5.9% in patients receiving UFH to 4.6% in the enoxaparin group (P = .073). At 14 days, the incidence of the triple endpoint was 16.7% in patients receiving UFH and 14.2% in the enoxaparin group (P = .029). This difference persisted during outpatient treatment: by 43 days, the corresponding ligures were 19.7% and 17.3%, respectively (P = .048). This indicates that the beneficial effect of enoxaparin seen during the acute phase persisted during long-term treatment, but continued treatment up to one year provided no additional benefit (P = .12). There was no significant difference between the groups in major bleeding complications during the initial hospitalization. During the outpatient phase, major hemorrhages occurred in 2.9% of enoxaparin-treated patients and 1.5% of placebo-treated patients (P = .02 1); the incidence of minor hemorrhagic complications was higher in the enoxaparin group than in the UFH group throughout the trial, mainly as a result of injection-site bruising.

A.A.

Fox

specific endpoints; although only the TIM1 11B trial included an outpatient treatment period, the data could be pooled because long-term follow-up was performed in the ESSENCE study at 3 months and 1 year after randomization.3* Statistical tests for heterogeneity showed no significant differences between the two studies. This meta-analysis showed that the incidence of death or nonfatal myocardial infarction was consistently about 20% lower in enoxaparintreated patients than in those receiving UFH (Fig 1). Statistical significance was observed at day 8 and persisted until day 43. The absolute difference in event rates between the two groups increased from 1.2% at 8 days to 1.5 % at 43 days. Enoxaparin significantly reduced the incidence of the composite endpoint of death, nonfatal myocardial infarction, or urgent revascularization on day 2, and the effect was maintained until day 43 (Fig 2); the absolute difference in event rates increased from 1.4% to 3.2% between these times. Analysis of the pooled event rates showed that it would be necessary to treat 31 patients with enoxaparin to prevent one event by day 43. Mortality rates tended to be approximately 20% lower in enoxaparin-treated patients than in those receiving UFH from day 8 onward. However, this effect did not reach statistical significance. The pooled incidence of major hemorrhagic

Meta-Analysis: Enoxaparin v Unfractionated Heparin ESSENCE and TIMI I 1B Death

Odds Ratio & 95% CI Day 2 -Es-

Day 8

Meta-analysis of the ESSENCE and TIM1 11B Data To detect significant effects of enoxaparin on endpoints other than the composite endpoints specified in the individual trials, the data from both ESSENCE and TIM1 11B were combined in a meta-analysis28 to provide statistically robust estimates of the effects of enoxaparin on

or Myocardial

Day 14 Day 43

---(I ~

0.5

Enoxaparin better

1 .o

Infarction OR

i-i- Cl

(95) Enoxaparin

UFH

0.80 (0.55-1.16)

1.4

1.8

0.77 (0.62-0.95)

4.1

5.3*

0.79(0.65-0.96)

5.2

6.S*

0.82

7.1

8.6*

(0.69-0.97) 2.0

UFH better

*P=0.02

circubrion ,w9;w0:,6o~-s

Figure 1. Meta-analysis of the effects of enoxaparin and UFH on death and nonfatal myocardial infarction in the ESSENCE and TIMI IIB studies. Results are presented as point estimates of the odds ratios (OR), with 95% confidence intervals (Cl). Adapted and reprinted with permission.28

Antitbronzbotic

Therapy

in Acute

Meta-Analysis: Enoxapann 11Unfiactionated Heparin ESSENCE and TIMI 11B -.. ~. Death Odds

or

MIor Urgent

Revascularization

(96)

Ratio& 95% CI

05 Enoxapar’in

I.0 better

Figure 2. Meta-analysis UFH on death, nonfatal revascularization in the Results are presented as (OR), with 95% confidence printed with permission.28

2.0 UFH better

*P=o.oz to 0.0005 circu,amn 19~1oo:i 602-a

of the effects of enoxaparin and myocardial infarction, or urgent ESSENCE and TIM1 116 studies. point estimates of the odds ratios intervals (Cl). Adapted and re-

complications during acute treatment was 1.3% in the enoxaparin group and 1.1% in the UFH group (P = .35). The incidence of minor hemorrhages during the acute phase was 10.0% and 4.3%, respectively (P < .OOOl). In summary, the results of the ESSENCE and TIM1 I 1B studies and the meta-analysis of the combined data show that compared with UFH, enoxaparin reduces the risk of major cardiac ischemic events by approximately 20% when added to oral aspirin treatment in patients with ACS. The effect was consistent across multiple endpoints, which suggests that the difference between enoxaparin and UFH was not attributable to a predominant effect on a single endpoint. The beneficial effect of enoxaparin became apparent within 2 days and was maintained during long-term follow-up. However, the observed benefit was obtained entirely during the acute treatment phase; subsequent outpatient treatment maintained the level of risk reduction achieved previously. The risk- benefit ratio was in favor of enoxaparin. The incidence of major bleeding complications in enoxaparintreated patients was similar to that in patients receiving UFH, although the incidence of minor hemorrhages (mainly injection-site ecchymoses) was higher.

Studies With Other LMWHs LMWHs are a heterogeneous group of compounds that differ markedly in their mean

Coronary

71

Syndrames

molecular weight, polysaccharide chain composition and distribution, anti-Xa-anti-IIa activity ratio, ability to releasetissue factor pathway inhibitor, and potential to cause bleeding in experimental models33 (Table 2). As a result, findings from studies with a given preparation cannot be directly extrapolated to other preparations.28 Several studies have investigated the use of the LMWHs nadroparin and dalteparin in patients with ACS. One study compared the efficacy of nadroparin with that of UFH and aspirin in 219 patients with UA.a4 Nadroparin was given at a dose of 2 14 units Institute Choay (UIC)/kg (85.5 IUikg) for 5 to 7 days or until a major endpoint (death, acute myocardial infarction, recurrent angina, urgent revascularization, or major bleeding) occurred. The incidence of endpoints was significantly reduced, from 63% in the group receiving aspirin and UFH to 22% in the group receiving aspirin plus nadroparin (P = .OOOOl>. In the Fraxiparin in Ischemic Syndromes (FRAXIS) trial, 3,468 patients with UAI NQWMI were randomly allocated to one of three study groups; to receive UFH for 6 days, or nadroparin for either 6 or 14 days (those receiving nadroparin for only 6 days, were adminstered placebo during days 7-14).35 Patients receiving nadroparin were given an initial dose of 86 IU anti-Xa/kg, followed by the same dose twice daily. All patients were followed up until 3 months after randomization. At no point in the trial did nadroparin show superiority over UFH for the endpoints of death, recurrent angina, or revascularization. Studies with dalteparin have provided less consistent results. The Fragmin during Insta-

Table

2. Angiotensin

Ill-Mediated

Anti-Xa (IU) Enoxaparin Nadroparin Dalteparin Parnaparin Tinzaparin Certoparin UFH Abbreviations: unfractionated

102.8 103.6 167.2 81.7 99.6 106.4

193 LMWH, heparin.

LMWH Anti-Ha

Activity

(IU)

Ratio

24.9 29.9 64.2 41.7 53.7 57.2 193

low-molecular-weight

4.1 3.5 2.4 2.0 1.9 1.8 1.0 heparin;

UFH,

72

Keith A.A. Fox

bility in Coronary Artery Disease (FRISC) study investigated the efficacy of dalteparin in comparison with placebo in 1,506 aspirin-treated patients with UA or NQWMI.s6 Dalteparin was given at an initial dose of 120 IU/kg twice daily for 6 days, followed by 7,500 IU once daily for 35 to 45 days. The incidence of the composite endpoint of death, myocardial infarction, revascularization, or need for intravenous heparin during the first 6 days was reduced in dalteparin-treated patients (P < .OOl), but there was no significant difference in event rates between dalteparinand placebo-treated patients 4 to 5 months after the end of treatment. The subsequent Fragmin in Unstable Coronary Artery Disease (FRIC) study compared dalteparin and UFH.3’ Dalteparin was given twice daily at a dose of 120 IU/kg for the first 6 days, and thereafter once daily at a dose of 7,500 IU until day 45. Randomization for each treatment phase was carried out at the start of this study. The incidence of death, myocardial infarction, or recurrent angina was not different in dalteparin-treated patients from that in patients originally randomized to receive UFH during the acute phase, whereas the incidence for those in the dalteparin group was equivalent to that for the placebo group in the long-term treatment phase. Differences in pharmacologic properties between different LMWHs and differences in trial design may contribute to the apparent inconsistency between the results of the ESSENCE and TIM1 11B studies and those of some other trials.28 Anti-Xa activities observed with dalteparin and enoxaparin in the FRIC study and TIM1 11A trial, respectively, showed that enoxaparin treatment was associated with higher trough values of anti-Xa (0.5 to 0.6 anti-Xa IU/mL) than dalteparin (0.35 to 0.37 anti-Xa IU/mL). This difference may indicate a suboptimal anticoagulant effect in the FRIC study, possible contributing to the failure to demonstrate superiority over UFH. Compared with both dalteparin and nadroparin, enoxaparin has a higher ratio of anti-Xa-anti-IIa activity; a lower average molecular weight, resulting in higher XC,, values for thrombin inhibition; and a higher proportion of glycosaminoglycans with molecular weights below 2,000, resulting in

better angiotensin III binding and thus a greater ability to inhibit thrombin generation 38,39 Furthermore, differences in trial design may also have influenced the outcome of previous studies. In the FRIC study, for example, patients were enrolled up to 72 hours after the onset of angina and the patient population included patients with exacerbations of exercise-induced angina;3’ moreover, only 16% of patients had an NQWMI. In contrast, the ESSENCE and TIM1 11B studies restricted inclusion to patients with resting angina during the previous 24 hours and included a higher proportion of patients with NQWMI. Enrolment was also more swift in the FRAXIS trial than in the FRIC study, with patients receiving treatment for UA or NQWMI within 48 hours of their symptoms. 35 Thus, the patients in the FRIC study may have been at lower risk of ischemic events.

Conclusions The results of the ESSENCE and TIM1 11B studies show that enoxaparin is significantly more effective than UFH in reducing the risk of ischemic events in aspirin-treated patients with non-ST-segment elevation ACS and that enoxaparin treatment is highly cost effective. Additional data are needed to determine the benefits of enoxaparin treatment in patients undergoing percutaneous coronary interventions and stenting. In addition, studies are needed to investigate the effect of combination therapy with enoxaparin and glycoprotein IIb/IIIa receptor antagonists. Glycoprotein IIb/IIIa antagonists represent a potentially valuable approach to platelet inhibition in ACS, especially in those undergoing percutaneous coronary interventions, because of the key role of platelet activation in the pathogenesis of these conditions. Indeed, several large-scale recent studies have shown significant reductions in ischemic events in patients with ACS treated with glycoprotein IIb/IIIa antagonists.*O-** In contrast, in medically treated patients with ACS, glycoprotein IIB/IIIa antagonists and UFH may not have an important role, as demonstrated in the GUSTO IV ACS trial (European Society of Cardiology

Antithrombotic Therapy in Acute Coronay Syndromes

Hotline 2000). The combination of enoxaparin and a glycoprotein IIb/IIIa antagonist thus appears to be a promising potential strategy for the future management of ACS.

References 1. Cannon angina. 2. Braunwald angina: Guideline Health

3.

4.

5.

6.

7.

8.

9.

10.

11.

12.

13.

14.

CP: Optimizing the treatment of unstable J Thromb Thrombolysis 2:205-218, 1995 E, Mark DB, Jones RH, et al: Unstable Diagnosis and management. Clinical Practice Number 10, Rockville MD: Agency for Care Policy and Research and the National

Heart, Lung, and Blood Institute, Public Health Service, US Department of Health and Human Services, 1994 Fox KAA, Cokkinos DV, Deckers J, et al: The ENACT study: A pan-European survey of acute coronary syndromes. Eur Heart J 21:1440-1449, 2000 Piegas LS, Flather M, Pogue J, et al: The Organization to Assess Strategies for Ischemic Syndromes (OASIS) registry in patients with unstable angina. Am J Cardiol 84:7M-12M, 1999 (suppl 5A) Fuster V, Badimon L, Badimon JJ, et al: The pathogenesis of coronary artery disease and the acute coronary syndromes. N Engl J Med 326:242-250, 1992 Ardissino D, Merlini PA, Ariens R, et al: Tissuefactor antigen and activity in human coronary atherosclerotic plaques. Lancet 349:769-771, 1997 Toschi V, Gallo R, Lettino M, et al: Tissue factor modulates the thrombogenicity of human atherosclerotic plaques. Circulation 95:594-599, 1997 Weitz JI: Activation of blood coagulation by plaque rupture: mechanisms and prevention. Am J Cardiol 75~23-25, 1995 Antman EM, Handin R: Low-molecular-weight heparins: An intriguing new twist with profound implications. Circulation 98:287-289, 1998 DeWood MA, Spores J, Notske R, et al: Prevalence of total coronary occlusion during the early hours of transmural myocardial infarction. N Engl J Med 303:897-902, 1980 TIM1 Study Group: The Thrombolysis in Myocardial Infarction (TIMI) Trial: Phase I findings. N Engl J Med 312:932-936, 1985 Lewis HD Jr, Davis JW, Archibald DG, et al: Protective effects of aspirin against acute myocardial infarction and death in men with unstable angina. Results of a Veterans Administration Cooperative Study. N Engl J Med 309:396-403, 1983 Theroux P, Ouimet H, McCans J, et al: Aspirin, heparin, or both to treat unstable angina. N Engl J Med 319:1105-1111, 1988 Theroux P, Waters D, Qiu S, et al: Aspirin versus heparin to prevent myocardial infarction during the

acute

phase of unstable

73

angina.

Circulation

88:2045-

2048, 1993 15.

The RISC Group: Risk of myocardial infarction and death during treatment with low dose aspirin and intravenous heparin in men with unstable coronary artery disease. Lancet 336:827-830, 1990 16. Cohen M, Adams PC, Parry G, et al: Combination antithrombotic therapy in unstable rest angina and non-Q-wave infarction in nonprior aspirin users. Primary endpoints analysis from the ATACS Trial. Circulation 89:81-88, 1994 17. Oler A, Whooley MA, Oler J, et al: Adding heparin to aspirin reduces the incidence of myocardial infarction and death in patients with unstable angina. A meta-analysis. JAMA 276:X11-815, I996 18. Stone PH, Thompson B, Zaret BL, er al: Factors associated with failure of medical therapy in patients with unstable angina and non-Q wave myocardial infarction. A TIMI-IIIB database study. Eur Heart J 20:1084-1093, 1999 19. Hirsh J, Fuster V: Guide to anticoagulant therapy, part 1: Heparin. Circulation 89:1449-1468, 1994 20. Hirsh J, Levine MN: Low molecular weight heparin. Blood 79:1-17, 1992 21. Melandri G, Semprini F, Cervi V, et al: Comparison of efficacy of low molecular weight heparin (parnaparin) with that of unfractionated heparin in the presence of activated platelets in healthy subjects. Am J Cardiol 72:450-454, 1993 22. Granger CB, Miller JM, Bovill EG, et al: Rebound increase in thrombin generation and activity after cessation of intravenous heparin in patients with acute coronary syndromes. Circulation 91:1929-

1935, 1995 23.

24.

25.

26.

27.

28.

Theroux P, Waters D, Lam J, et al: Reactivation of unstable angina after the discontinuation of heparin. N Engl J Med 327:141-145, 1992 Samama MM, Bara L, Gerotziafas GT: Mechanisms for the antithrombotic activity in man of low molecular weight heparin (LMWHs). Haemostasis 24:105117, 1994 Warkentin TE, Levine MN, Hirsh J, et al: Heparininduced thrombocytopenia in patients treated with low-molecular-weight heparin or unfractionated heparin. N Engl J Med 332:1330-1335, 1995 Cohen M, Demers C, Gurfinkel EP, et al: A comparison of low-molecular weight heparin with unfractionated heparin for unstable coronary artery disease. N Engl J Med 337:447-452, 1997 Antman EM, McCabe CH, Gurfinkel EP, et al: Enoxaparin prevents death and cardiac ischemic events in unstable angina/non-Q-wave myocardial infarction. Results of the Thrombolysis in Myocardial Infarction (TIMI) 11B trial. Circulation 100: 1593-1601, 1999 Antman EM, Cohen M, Radley D, et al: Assessment of the treatment effect of enoxaparin for unstable

74

Keith A.A. Fox

angina/non-Q-wave 1 lB/ESSENCE 29.

30.

31.

32.

33.

34.

35.

36.

37.

myocardial infarction. TIM1 meta-analysis. Circulation 100:1602-

1608, 1999 Mark DB, Cowper PA, Berkowitz SD, et al: Economic assessment of low-molecular-weight heparin (enoxaparin) versus unfractionated heparin in acute coronary syndrome patients. Results from the ESSENCE randomized trial. Circulation 97:1702-1707, 1998 Fox K, Bosanquet N: Economic assessment of LMWH (enoxaparin) versus UFH in acute coronary syndrome patients: Results from the ESSENCE randomized trial. Br J Cardiol 5:92-105, 1998 Merlini PA, Bauer KA, Olcrona L, et al: Persistent activation of coagulation mechanism in unstable angina and myocardial infarction. Circulation 90:6168, 1994 Cohen M, Bigonzi F, Lelouer V, et al: One-year follow-up of the ESSENCE trial (enoxaparin versus heparin in unstable angina and non-Q-wave myocardial infarction). J Am Co11 Cardiol 31:79A, 1998 (abstr) Fareed J, Jeske W, Hoppensteadt D, et al: Lowmolecular-weight heparins: Pharmacologic profile and product differentiation. Am J Cardiol 82:3LlOL, 1998 Gurfinkel EP, Manos EJ, Mejail RI, et al: Low molecular weight heparin versus regular heparin or aspirin in the treatment of unstable angina and silent ischemia. J Am Co11 Cardiol 26:313-318, 1995 Cohen M: Low molecular weight heparins in the management of unstable angina/non-Q-wave myocardial infarction. Semin Thromb Hemost 25: 113121, 1999 (suppl 3) Fragmin During Instability in Coronary Artery Disease (FRISC) Study Group: Low-molecular-weight heparin during instability in coronary artery disease. Lancet 347:561-568, 1996 Klein W, Buchwald A, Hillis SE, et al: Comparison of low-molecular-weight heparin with unfractionated

38.

39.

40.

41.

42.

43.

44.

heparin acutely and with placebo for 6 weeks in the management of unstable coronary artery disease. Fragmin in Unstable Coronary Artery Disease Study (FRIC). Circulation 96:61-68, 1997 Beguin S, Lindhout T, Hemker HC: The mode of action of heparin in plasma. Thromb Haemost 60: 457-462, 1988 Beguin S, Mardiguian J, Lindhout T, et al: The mode of action of low molecular weight heparin preparation (PK10169) and two of its major components on thrombin generation in plasma. Thromb Haemost 61:30-34, 1989 The CAPTURE Investigators: Randomised placebocontrolled trial of abciximab before and during coronary intervention in refractory unstable angina: The CAPTURE study. Lancet 349:1429-1435, 1997 Lincoff AM, Califf RM, Anderson KM, et al: Evidence for prevention of death and myocardial infarction with platelet membrane glycoprotein IIbiIIIa receptor blockade by abciximab (c7E3 Fab) among patients with unstable angina undergoing percutaneous coronary revascularization. J Am Co11 Cardiol 30:149-156, 1997 The Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS) Study Investigators: Inhibition of the platelet glycoprotein IIb/IIIa receptor with tirofiban in unstable angina and nonQ-wave myocardial infarction. N Engl J Med 338: 1488-1497, 1998 The PURSUIT Trial Investigators: Inhibition platelet glycoprotein IIbiIIIa with eptifibatide patients with acute coronary syndromes. N J Med 339:436-443, 1998 The Platelet Receptor Inhibition in Ischemic drome Management (PRISM) Study Investigators: comparison of aspirin plus tirofiban with aspirin heparin for unstable angina. N Engl J Med 1498-1505, 1998

of in Engl SynA plus 338: