1. C-4. Clinical trial updates: Low-molecular-weight heparin
Differing effects of anticoagulants on vWF
Content Points:
Increased circulating levels of vWF occur frequently in patients with ACS and have been shown to be predictive of an adverse outcome.1 In a follow-up study, Montalescot et al measured vWF release over the first 48 hours in 154 patients with non-ST-elevation ACS.2
Patients were randomly assigned to receive LMWH (enoxaparin or dalteparin), UFH, or PEG-hirudin.
Confirming the previous study, in each treatment group the mean vWF was always higher in patients with an event compared with those who remained free of events (data not shown).
As shown, the antithrombotic treatments varied in their effect on vWF levels. Enoxaparin and PEG-hirudin suppressed vWF release significantly more than UFH (P = and P < , respectively), while dalteparin, although lower, was not significantly better than UFH.2
1 Montalescot G, Philippe F, Ankri A, Vicaut E, Bearez E, Poulard JE, et al. Early increase of von Willebrand factor predicts adverse outcome in unstable coronary artery disease: Beneficial effects of enoxaparin. French Investigators of the ESSENCE Trial. Circulation. 1998;98:
2 Montalescot G, Collet JP, Lison L, Choussat R, Ankri A, Vicaut E, et al. Effects of various anticoagulant treatments on von Willebrand factor release in unstable angina. J Am Coll Cardiol. 2000;36:

2. LMWH inhibits factor VIIa generation and prothrombin activation in vivo
Content Points:
Factor VIIa (FVIIa) binds to tissue factor to form a complex with ~20,000-fold greater coagulant activity.
Gerotziafas et al administered enoxaparin 1 mg/kg subcutaneously (sc) twice daily to 14 patients with UA1; 20 healthy volunteers served as controls.
Compared with controls, the UA group had significantly elevated levels of FVIIa and prothrombin (as measured by the prothrombin fragments F1+2).
One hour after the first injection of enoxaparin, FVIIa and F1+2 levels decreased by 65% and 50%, respectively (P < 0.05 and P < 0.001, respectively). As shown, no significant fluctuations were observed during the 24-h period of observation in contrast to anti-Xa activity.
Thus, inhibition of FVIIa generation appears to be an important effect contributing to the anticoagulant mechanism of enoxaparin.
The similar effect of enoxaparin on the pharmacokinetics of FVIIa and F1+2 suggest that reduction in FVIIa generation and activity may result in reduced prothrombin activation.
1 Gerotziafas GT, Zafiropoulos A, Van Dreden P, Karavaggeli E, Goutzoumas N, Nikolaidis P, et al. Inhibition of factor VIIa generation and prothrombin activation by treatment with enoxaparin in patients with unstable angina. Br J Haematol :

3. LMWH in PCI: Patients meeting anticoagulant goal at time of procedure
Content Points:
The anticoagulant efficacy of LMWH in PCI has been established in a number of trials. Three of these trials reported the proportion of patients meeting anticoagulant goals at time of PCI who received LMWH as the sole anticoagulant.
PEPCI1 included 47 evaluable patients undergoing elective PCI. Enoxaparin 1 mg/kg sc was given 8-12 h prior to procedure, with an additional 0.3-mg/kg IV bolus immediately preprocedure. An adequate anticoagulation goal (anti-Xa activity 0.6 to 1.8 IU/mL maintained 1-C2 h) was achieved in 96% (45/47) of patients.
Collet et al measured anti-Xa activity in 451 consecutive patients with UA/NSTEMI who received enoxaparin 1 mg/kg sc.2 In all, 293 patients underwent PCI, with the average delay of h between drug's administration and catheterization. At catheterization, 97.6% in this cohort had anti-Xa activity greater than the lower limit of the therapeutic range (0.5 IU/mL). Anti-Xa activity was independent of renal function or age. The mean aPTT was 47+7 sec. Sheath removal was carried out >10 h after last dose of enoxaparin (ie, ~5-h postprocedure).
Choussat et al administered a single IV bolus of enoxaparin 0.5 mg/kg immediately preprocedure to 242 consecutive patients undergoing elective PCI3: 64 patients (26%) received eptifibatide. The proportion of patients with anti-Xa activity IU/mL was 94.6%. The proportion of patients with anti-Xa activity in this range was similar with or without eptifibatide. Sheath withdrawal was performed immediately postprocedure in patients who received enoxaparin alone and 4 h later in patients who received enoxaparin plus eptifibatide.
These studies demonstrate that reliable levels of anti-Xa activity consistently >0.5 IU/mL can be reliably achieved with either a low-dose or high-dose enoxaparin regimen. However, the low-dose regimen provides the further advantage of permitting sheath removal immediately following the procedure.
1 Martin JL, Fry ETA, Serano A, et al. Pharmacokinetic study of enoxaparin in patients undergoing coronary intervention [PEPCI] after treatment with subcutaneous enoxaparin in acute coronary syndromes. The PEPCI study. Eur Heart J. 2001;22(suppl 1):14. Abstract 143.
2 Collet JP, Montalescot G, Lison L, et al. Percutaneous coronary intervention after subcutaneous enoxaparin pretreatment in patients with unstable angina pectoris. Circulation. 2001;103:
3 Choussat R, Montalescot G, Collet JP, et al. A unique, low dose of intravenous enoxaparin in elective percutaneous coronary intervention. J Am Coll Cardiol. 2002;40:

4. Timecourse of anticoagulation with LMWH (enoxaparin) Content Points:
The slide shows anti-Xa activity in the 24 hours following administration of the low-dose enoxaparin regimen described in the previous slide.1
As shown, regardless of concomitant administration of GP IIb/IIIa inhibitor (eptifibatide), a high and constant degree of anticoagulation was maintained throughout the procedure.
1 Choussat R, Montalescot G, Collet JP, Vicaut E, Ankri A, Gallois V, et al. A unique, low dose of intravenous enoxaparin in elective percutaneous coronary intervention. J Am Coll Cardiol. 2002;40:

5. Evaluation of LMWH in high-risk UA/NSTEMI Content Points:
The Pitié-Salpétrière Registry on Ischemic Coronary Syndrome (PARIS) is a registry of UA/NSTEMI patients who are treated with aspirin, beta-blockers, IV nitrates, and enoxaparin.1 GP Iib/IIIa inhibitors are given only to patients with recurrent ischemia or elevated troponin (9%).
To evaluate the anticoagulant efficacy and safety of LMWH in high-risk patients, subjects were classified according to selected exclusion criteria used in the TIMI-11B and ESSENCE trials.2,3 These trials demonstrated that enoxaparin was superior to UFH in reducing clinical events without a significant increase in rate of major hemorrhage.
A total of 515 consecutive patients in the PARIS registry were enrolled.
Control cohort: 341 met the inclusion criteria for TIMI 11B/ESSENCE (26.1% underwent PCI)
High-risk cohort: 174 patients would not have been enrolled in the TIMI 11B/ESSENCE trials because of high-risk features (20.7% underwent PCI)
Enoxaparin 1 mg/kg sc was given every 12 h except in cases where creatinine clearance was <30 mL/min, when a reduced dose of 0.65 mg/kg was given.
1 Collet J-P, Montalescot G, Fine E, Golmard J-L, Dalby M, Choussat R, et al. Enoxaparin in unstable angina patients who would have been excluded from randomized pivotal trials. J Am Coll Cardiol. 2003;41:8-14.
2 Cohen M, Demers C, Gurfinkel EP, Turpie AGG, Fromell GJ, Goodman S, et al, for the Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-wave Coronary Events Study Group. A comparison of low-molecular weight heparin with unfractionated heparin for unstable coronary artery disease. N Engl J Med. 1997;337:
3 Antman EM, McCabe CH, Gurfinkel EP, Turpie AGG, Bernink PJ, Salein D, et al, for the TIMI 11B Investigators. 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. 1999;100:

6. Anticoagulant efficacy in high-risk patients receiving LMWH
Content Points:
As shown, both control and high-risk cohorts in the PARIS registry demonstrated virtually identical distribution of anti-Xa activity.1
Anti-Xa activity >0.5 IU/mL (lower limit of therapeutic range) was achieved in 94% of the overall study population.
This finding demonstrates that adequate downward adjustment of enoxaparin dosing was carried out in renal dysfunction patients, despite their predisposition to enoxaparin accumulation.
In addition, the PARIS registry data show that clinical trial results with LMWH in selected population are applicable to the unselected patients seen in routine practice.
1 Collet J-P, Montalescot G, Fine E, Golmard J-L, Dalby M, Choussat R, et al. Enoxaparin in unstable angina patients who would have been excluded from randomized pivotal trials. J Am Coll Cardiol. 2003;41:8-14.

7. Trials of LMWH plus GP Iib/IIIa inhibitors in PCI Content Points:
The NICE 3 and 4 trials evaluated enoxaparin plus concurrent therapies in patients with ACS. All patients received aspirin; none received additional anticoagulation after PCI. Primary outcome was incidence of major hemorrhage.
NICE 31: an observational study at 46 US and Canadian sites; 616 patients received enoxaparin 1 mg/kg sc bid with or without GP Iib/IIIa inhibitors (tirofiban, eptifibatide, or abciximab) at standard doses (enoxaparin alone n = 45). If the last enoxaparin dose was >8 h prior to PCI, 0.3-mg/kg IV bolus was also given. Primary outcome was incidence of non-CABG major bleeding compared with a rate of 2% estimated from prior studies. Outcome in patients undergoing PCI (n = 292): 0% (concurrent abciximab), 0.9% (concurrent tirofiban), 2.4% (concurrent eptifibatide).
NICE 42: Patients received reduced dose of enoxaparin IV (0.75 mg/kg) 5 min before abciximab IV (0.25-mg/kg bolus followed by mg/kg/min for 12 h). The 30-day rate of primary outcome was 0.2%.
Kereiakes et al3 conducted a dose-ranging study in 103 patients undergoing PCI with abciximab. Patients given dalteparin <8 h prior did not receive additional LMWH at PCI. Those given dalteparin 8-12 h prior received 40-IU/kg bolus. Patients given dalteparin >12 h prior were randomized to a 40- or 60-IU/kg bolus. Investigators concluded the 60-IU/kg dose appears to be safe and effective for PCI.
NRMI 34: 37,320 acute MI patients received LMWH or UFH in combination with GP Iib/IIIa inhibitors (tirofiban, eptifibatide, or abciximab); 53% and 81.2% of LMWH and UFH patients, respectively, had coronary angioplasty. (See slide 27.)
INTERACT5: a multicenter comparison of enoxaparin and UFH in 746 patients with high-risk UA/NSTEMI (all received aspirin and eptifibatide). PCI performed in 27.1% and 30.3% of enoxaparin and UFH groups. (See slides 28, 29.)
CRUISE6: a multicenter comparison of enoxaparin and UFH in 261 patients undergoing elective or urgent PCI. All patients also received eptifibatide and aspirin, and clopidogrel if a stent was inserted. (See slides 30, 31.)
1 Ferguson JJ, Antman EM, Bates ER, et al, the NICE 3 Investigators. The use of enoxaparin and IIb/IIIa antagonists in acute coronary syndromes, including PCI: Final results of the NICE 3 study. J Am Coll Cardiol. 2001;37(suppl A):365A. Abstract
2 Kereiakes DJ, Grines C, Fry E, , et al. National Investigators Collaborating on Enoxaparin. Enoxaparin and abciximab adjunctive pharmacotherapy during percutaneous coronary intervention. J Invasive Cardiol. 2001;13:
3 Kereiakes DJ, Kleiman NS, Fry E, et al. Dalteparin in combination with abciximab during percutaneous coronary intervention. Am Heart J. 2001;141: Kovar D, Canto JG, Rogers WJ, for the investigators in the National Registry of Myocardial Infarction 3. Safety and effectiveness of combined low molecular weight heparin and glycoprotein IIb/IIIa inhibitors. Am J Cardiol. 2002;90:
5 Goodman SG, Fichett D, Armstrong PW, Tan M, Langer A, for the Integrilin and Enoxaparin Randomized Assessment of Acute Coronary Syndrome Treatment (INTERACT) trial investigators. Randomized evaluation of the safety and efficacy of enoxaparin versus unfractionated heparin in high-risk patients with non-ST-segment elevation acute coronary syndromes receiving the glycoprotein IIb/IIIa inhibitor eptifibatide. Circulation. 2003;107:
6 Bhatt DL, Lee BI, Casterella PJ, et al. Safety of concomitant therapy with eptifibatide and enoxaparin in patients undergoing percutaneous coronary intervention. Results of the Coronary Revascularization Using Integrilin and Single bolus Enoxaparin Study. J Am Coll Cardiol. 2003;41:20-25.

8. NRMI 3: LMWH/UFH plus GP Iib/IIIa inhibitors Content Points:
Of 37,320 patients treated with GP Iib/IIIa inhibitors for acute MI in the National Registry of Myocardial Infarction 3 (NRMI 3) database, 2482 received concomitant LMWH and 34,838 received concomitant UFH.1
Coronary angioplasty was carried out in 52.3% of the LMWH group and 81.2% of the UFH group (P < 0.001).
As shown, there was no significant difference in the in-hospital rate of major bleeding between the two groups.
Trends in favor of LMWH were noted in recurrent MI, recurrent ischemia, in-hospital death, and all outcomes combined.
1 Kovar D, Canto JG, Rogers WJ, for the investigators in the National Registry of Myocardial Infarction 3. Safety and effectiveness of combined low molecular weight heparin and glycoprotein IIb/IIIa inhibitors. Am J Cardiol. 2002; 90:

9. INTERACT: LMWH/UFH plus GP Iib/IIIa inhibitor in UA/NSTEMI
Content Points:
The INTERACT (Integrilin and Enoxaparin Randomized Assessment of Acute Coronary Syndrome Treatment) trial randomized patients to UFH (titrated to an aPTT 1.5-2X control) or enoxaparin sc (1 mg/kg q12h) for 48 h.1 All patients also received aspirin and eptifibatide (180-mg/kg bolus followed by 2.0 mg/kg/min).
The decision to proceed to angiography and revascularization was left at the discretion of the investigator. PCI was carried out in 27.1% and 30.3% of the enoxaparin and UFH groups, respectively.
The primary safety outcome was the rate of 96-h non-CABG-related bleeding. The primary efficacy outcome was the rate of 96-h ischemia.
The slide summarizes the effects of the two treatments on the primary outcomes.
Ischemia, diagnosed by continuous electrocardiographic monitoring, occurred within the first 48 h in 14.3% and 25.4% of enoxaparin and UFH patients, respectively (P = ). In the next 48 h, ischemia occurred in 12.7% and 25.9%, respectively (P < ).
Within the first 96 h, minor non-CABG-related bleeding occurred in 30.3% and 20.8% of enoxaparin and UFH patients, respectively (P = 0.03). Major, non-CABG-related bleeding occurred in 1.8% and 4.6% of enoxaparin and UFH patients, respectively (P = ).
1 Goodman SG, Fichett D, Armstrong PW, Tan M, Langer A, for the Integrilin and Enoxaparin Randomized Assessment of Acute Coronary Syndrome Treatment (INTERACT) trial investigators. Randomized evaluation of the safety and efficacy of enoxaparin versus unfractionated heparin in high-risk patients with non-ST-segment elevation acute coronary syndromes receiving the glycoprotein IIb/IIIa inhibitor eptifibatide. Circulation. 2003;107:

10. INTERACT: LMWH/UFH plus GP Iib/IIIa inhibitor in non-ST-elevation ACS
Content Points:
This slide summarizes the cumulative secondary outcome of 30-day death or nonfatal MI in the INTERACT trial.1
This outcome occurred in 5% and 9% of the enoxaparin and UFH groups, respectively (P = 0.031).
The INTERACT investigators concluded that when compared with UFH in UA/NSTEMI patients who were also receiving aspirin and eptifibatide, enoxaparin improves outcomes.
1 Goodman SG, Fichett D, Armstrong PW, Tan M, Langer A, for the Integrilin and Enoxaparin Randomized Assessment of Acute Coronary Syndrome Treatment (INTERACT) trial investigators. Randomized evaluation of the safety and efficacy of enoxaparin versus unfractionated heparin in high-risk patients with non-ST-segment elevation acute coronary syndromes receiving the glycoprotein IIb/IIIa inhibitor eptifibatide. Circulation. 2003;107:

11. CRUISE: LMWH/UFH plus GP Iib/IIIa inhibitor in PCI Content Points:
The CRUISE (Coronary Revascularization Using Integrilin and Single Bolus Enoxaparin) trial randomized patients undergoing elective or urgent PCI at 12 medical centers to eptifibatide plus open-label enoxaparin (n = 129) or eptifibatide plus open-label UFH (n = 132).1
Eptifibatide was given as a 180-mg/kg bolus followed by a 2-mg/kg/min infusion, with a second 180-mg/kg bolus 10 min later. Enoxaparin 0.75 mg/kg was administered as a single IV bolus prior to PCI with no monitoring of anticoagulant efficacy. UFH was given as a 60-IU/kg bolus followed by additional boluses of 10 to 20 IU/kg to achieve an activated clotting time >200 sec.
All patients also received aspirin 325 mg daily. Patients treated with stents also received clopidogrel 75 mg daily for at least 30 days.
Median time to sheath removal was 4.4 h in both groups.
The primary outcome was the bleeding index, defined as a fall in hemoglobin over the first 24 h.
- The mean bleeding index was 0.8 g/dL for enoxaparin and 1.1 g/dL for UFH, a nonsignificant difference
Similar rates of other bleeding outcomes were also observed in both groups.
1 Bhatt DL, Lee BI, Casterella PJ, Pulsipher M, Rogers M, Cohen M, et al. Safety of concomitant therapy with eptifibatide and enoxaparin in patients undergoing percutaneous coronary intervention. Results of the Coronary Revascularization Using Integrilin and Single bolus Enoxaparin study. J Am Coll Cardiol. 2003;41:20-25.

12. ’ CRUISE: LMWH/UFH plus GP Iib/IIIa inhibitor in PCI (cont'd)
Content Points:
In the CRUISE trial, vascular complications were defined as hematoma, re-bleed after hemostasis, and pseudoaneurysm. These occurred in 9.3% and 9.8% of enoxaparin and UFH groups, respectively (P = 1.0). There were no occurrences of atrioventricular fistula in either group.
Angiographic complications were defined as major dissection, abrupt closure, thrombus formation, no reflow, and side-branch closure. These occurred in 6.3% and 6.2% of enoxaparin and UFH groups, respectively (P = 1.0).
MI occurred within 48 h in 8.5% and 7.6% of enoxaparin and UFH patients, respectively (P = 0.82).1
The CRUISE investigators concluded that compared with UFH plus eptifibatide, enoxaparin plus the same GP Iib/IIIa inhibitor is not associated with excess of bleeding or vascular, angiographic, or clinical complications.
1 Bhatt DL, Lee BI, Casterella PJ, Pulsipher M, Rogers M, Cohen M, et al. Safety of concomitant therapy with eptifibatide and enoxaparin in patients undergoing percutaneous coronary intervention. Results of the Coronary Revascularization Using Integrilin and Single bolus Enoxaparin study. J Am Coll Cardiol. 2003;41:20-25.

13. Consensus algorithm for use of LMWH in PCI Content Points:
A proposed algorithm for LMWH anticoagulation in patients undergoing PCI was reported by Kereiakes and colleagues.1
If catheterization is begun within 8 h of the last sc dose of enoxaparin, no additional anticoagulation is recommended. If catheterization is begun 8 to 12 h after the last sc dose, an additional single IV bolus of enoxaparin 0.3 mg/kg or multiple boluses of UFH (titrated to an activated clotting time of 200 to 250 sec) may be given.
1 Kereiakes DJ, Montalescot G, Antman EM, Cohen M, Darius H, Ferguson HH, et al. Low-molecular-weight heparin therapy for non-ST-elevation acute coronary syndromes and during percutaneous coronary intervention: An expert consensus. Am Heart J. 2002;144: