1. Section E: Clinical trial update: Heparins
Structure-activity relationships of heparins
Content Points:
UFH is a mixture of glycosaminoglycans with a wide range of molecular weights, ranging from approximately 3000 to 30,000 daltons.30
LMWHs are produced from UFH by cleavage to yield polymers with much narrower ranges of molecular weights. 31 Each depolymerization process is different, which results in variation between individual LMWHs, both in physical and pharmacologic properties:
– Enoxaparin, 3500 to 5500 daltons
– Nadroparin, 3600 to 5600 daltons
– Dalteparin, 5600 to 6400 daltons
Anti-factor IIa (thrombin) activity is dependent on a minimum glycosaminoglycan chain length of at least 18 saccharide units.32 Thus, LMWHs with greater amounts of longer-chain polymers have greater anti-factor IIa activity and, conversely, a lesser ratio of anti-Xa:anti-IIa activity.30
– Enoxaparin, anti-Xa:anti-IIa activity = 3.8:1
– Nadroparin, anti-Xa:anti-IIa activity = 3.6:1
– Dalteparin, anti-Xa:anti-IIa activity = 2.7:1
As discussed earlier in this slide kit, a higher level of anti-Xa activity is desirable, since that is associated with greater antithrombotic effect.
UFH also binds to platelet factor 4, a protein released from activated platelets. 30 This binding reduces the antithrombotic activity of UFH, since less is available to bind to thrombin. In contrast, LMWHs are much less sensitive to protein binding.32

2. Advantages of LMWH vs UFH
Content Points:
While they differ individually, LMWHs overall have several clinically relevant advantages over UFH.
They are easier to administer, since they can be given subcutaneously.30
They have a more predictable and rapidly effective anticoagulant effect, a consequence of lower binding to platelet factor 4, better bioavailability, and dose-independent clearance.30
There is no need for therapeutic monitoring with LMWHs.9
They have a longer half-life.32
They have lower incidence of thrombocytopenia.30

3. Pharmacokinetics of LMWH in patients at time of angiography
Content Points:
With LMWH, evaluation of anticoagulant activity by activated partial-thromboplastin time (aPTT) or activated clotting time (ACT) is not carried out. Consequently, interventional cardiologists have expressed concern about substitution of LMWH for UFH in patients scheduled for catheterization with possible PCI.
Collet et al measured anti-Xa activity in 45 consecutive patients with UA/NQMI.33
Study subjects received subcutaneous enoxaparin 1 mg/kg.
Of this unselected population, 293 patients underwent coronary angiography.
The average delay between administration of enoxaparin and catheterization was 5.3 ± 1.8 hours.
As shown on the slide, 97.6% of these patients had anti-Xa activity greater than the lower limit of the therapeutic range (0.5 U/mL) at time of catheterization. The mean level was 0.99 ± 0.22 U/mL.
Mean anti-Xa activity was independent of renal function or age:
– 0.99 ± 0.05 U/mL (creatinine clearance <40 mL/min) versus 0.97 ± 0.02 U/mL (normal renal function), P = 0.79
– 0.98 ± 0.02 U/mL (>80 years old) versus 1.02 ± 0.06 U/mL ( <80 years old), P = 0.51

4. Clinical implications of predictable anticoagulant effect
Content Points:
The study by Collet et al confirms the 12-hour dosing interval of enoxaparin will ensure continuous, effective anticoagulant activity, with minimal inter-patient variability.33
The study further showed that catheterization between 1 and 8 hours of a subcutaneous injection of enoxaparin can be safely carried out without additional anticoagulation in the cardiac catheterization laboratory.

5. ESSENCE: Evaluation of LMWH and UFH in UA/NQMI
Content Points:
Enoxaparin is the most widely studied LMWH in the setting of ACS.
The ESSENCE trial (Efficacy and Safety of Subcutaneous Enoxaparin in Non–Q-wave Coronary Events) was a comparison of UFH and the LMWH enoxaparin in 3171 patients with UA or NQMI.34
Enoxaparin was given subcutaneously, 1 mg/kg q12h.
UFH was given as an initial IV bolus (usually 5000 U) followed by a continuous infusion at a dose adjusted according to the aPTT.
The primary outcome was combined death, MI, and recurrent angina at 14 days.

6. ESSENCE: Primary outcome
Content Points:
At 14 days, the primary outcome occurred in 16.6% of the enoxaparin group and 19.8% of the UFH group (odds ratio, 0.80; 95% CI, 0.67 to 0.96; P = 0.019).34
At 30 days, the primary outcome occurred in 19.8% of the enoxaparin group and 23.3% of the UFH group (odds ratio, 0.81; 95% CI, 0.68 to 0.96; P = 0.016).

7. ESSENCE: Cumulative 30-day costs for all patients
Content Points:
Mark et al conducted an economic analysis of the ESSENCE findings, using US medical-cost data collected prospectively during the course of the study.35
Hospital costs were calculated from records of participating hospitals. Physician fees were calculated from the 1995 Medicare Fee Schedule.
The mean cost of a course of anticoagulant therapy was $155 (enoxaparin) and $80 (UFH). However, enoxaparin was associated with less resource use, which resulted in low hospital and physician costs.
As shown, switching from UFH to enoxaparin saves a mean of $1,172 per patient (P = 0.04).

8. TIMI 11B: Evaluation of LMWH and UFH in UA/NQMI
Content Points:
The TIMI 11B trial was conducted in 3910 patients with UA or NQMI.36
During the hospitalization phase, study subjects were randomized to receive either:
– Enoxaparin (given as an initial 30-mg IV bolus, followed by 1 mg/kg subcutaneously q12h)
– IV UFH (administered as an initial bolus of 70 U/kg followed by continuous infusion to a target aPTT of 1.5 to 2.5 times control)
After discharge, the enoxaparin treatment was continued for up to 43 days; those in the placebo group received placebo injections.
The primary outcome was combined death, recurrent MI, or urgent revascularization.

9. TIMI 11B: Primary outcome at 72 hours
Content Points:
The curves in TIMI 11B began to separate by 8 hours.36
At 48 hours, the primary outcome rate was 7.3% in the UFH group and 5.5% in the enoxaparin group (odds ratio, 0.75; 95% CI, 0.58 to 0.97; P = 0.026).
Note that the curves continue to diverge beyond 48 hours.

10. TIMI 11B: Primary outcome at 43 days
Content Points:
At 8 days, the primary outcome rate was 14.5% in the UFH group and 12.4% in the enoxaparin group (odds ratio, 0.83; 95% CI, 0.69 to 1.00; P = 0.048).36
At 14 days, the primary outcome rate was 16.7% in the UFH group and 14.2% in the enoxaparin group (odds ratio, 0.82; 95% CI, 0.69 to 0.98; P = 0.029).
At study end, the primary outcome rate was 19.7% in the UFH group and 17.3% in the enoxaparin group (odds ratio, 0.85; 95% CI, 0.72 to 1.00; P = 0.048).
The investigators concluded that enoxaparin is superior to UFH in reducing the combined outcome of death, MI, and revascularization during acute management of patients with UA or NQMI. No further relative decrease in events occurred with subsequent enoxaparin treatment.

11. TIMI 11B–ESSENCE meta-analysis: Treatment effect on death, MI
Content Points:
TIMI 11B and ESSENCE were not powered to detect statistically significant differences in outcomes other than composite ones. Since the two trials have similar designs and patient populations, a meta-analysis was conducted to further evaluate treatment effects.37
As shown, the composite outcome of death and nonfatal MI was consistently lower at all time points up to 43 days in the group that received enoxaparin, with statistical significance attained at day 8.
A subsequent meta-analysis (summarized on the next slide) demonstrated that these differences in treatment effects were maintained for up to 1 year.

12. TIMI 11B–ESSENCE meta-analysis: Treatment effect maintained long-term
Content Points:
In the TIMI 11B and ESSENCE trials, meta-analysis showed that the rate of the primary composite outcome was significantly lower in patients treated with enoxaparin compared with UFH after 1 year of follow-up.38
Point estimates of the individual components of the primary outcome also favored enoxaparin over UFH.

13. TIMI 11B–ESSENCE meta-analysis: Treatment effects in patients with/without PCI
Content Points:
Fox et al analyzed a cohort of 6098 of the original 7081 pooled TIMI 11B–ESSENCE population.39
The slide summarizes data obtained from all patients who underwent PCI during hospitalization compared to those who were treated medically.
Patients who underwent PCI were a higher-risk population than those who were treated medically. Consistent with this, the PCI group sustained more events (death, MI) before and after PCI.
Enoxaparin compared with UFH was associated with a lower rate of events in patients who underwent PCI and in patients treated medically.
– In patients who underwent PCI, the relative risk for post-PCI events was 0.60 (95% CI, 0.34 to 1.05) and the relative risk for events before and after PCI was 0.87 (95% CI, 0.60 to 1.27)
– In patients treated medically, the relative risk for events was 0.83 (95% CI, 0.67 to 1.04)
These data demonstrate the efficacy of enoxaparin as anticoagulant therapy in patients scheduled for PCI.

14. TIMI 11B–ESSENCE meta-analysis: Hemorrhagic events (acute phase)
Content Points:
During the acute phase (up to day 8) of the ESSENCE and TIMI 11B trials, there was no significant differences in the rates of major hemorrhage between enoxaparin and UFH in either trial or in the pooled data.37
– The odds ratios were 0.91 (95% CI, 0.47 to 1.47), 1.52 (95% CI, 0.86 to 2.69), and 1.23 (95% CI, 0.80 to 1.89; P = 0.25) for ESSENCE, TIMI 11B, and the meta-analysis, respectively
There was an increased rate of minor hemorrhage with enoxaparin during the acute phase of these trials.
– The odds ratios were 1.82 (95% CI, 1.39 to 2.38), 2.97 (95% CI, 2.3 to 3.81), and 2.38 (95% CI, 1.98 to 2.85; P < ) for ESSENCE, TIMI 11B, and the meta-analysis, respectively

15. Trials of LMWH vs UFH in patients with UA/NSTEMI
Content Points:
Four large randomized trials have compared LMWH with UFH in patients with UA/NSTEMI.
Two trials, ESSENCE and TIMI 11B are discussed in previous slides.34,36
The FRIC study (FRagmin In unstable Coronary artery disease) compared the LMWH dalteparin and UFH in 1482 patients.40 The primary outcome was combined death, MI, and refractory angina.
– In an initial open phase, patients received subcutaneous dalteparin 120 U/kg q12h or UFH (initial IV bolus of 5000 U, followed by an infusion of 1000 U/h to a target aPTT of 1.5 times control) for 6 days; this was followed by a double-blind phase (days 6 to 45), during which patients received dalteparin 7500 U once daily or placebo
– At 6 days, the primary outcome occurred in 7.6% of the UFH group and 9.3% of the dalteparin group (relative risk, 1.18; 95% CI, 0.84 to 1.66)
The FRAX.I.S. trial (FRAXiparine in Ischaemic Syndrome) compared the LMWH nadroparin administered for 6 or 14 days with UFH in 3468 patients.41 The primary outcome was the same as for FRIC.
– Nadroparin patients received an initial IV bolus of 86 U/kg followed by subcutaneous injections of 86 U/kg q12h
– UFH patients received an initial IV bolus of 5000 U, followed by an infusion of 1250 U/h titrated to target aPTT
– At 14 days, the primary outcome occurred in 18.1% of the UFH group, in 17.8% of patients treated with nadroparin for 6 days, and 20.0% of patients treated with nadroparin for 14 days. Between-group differences were nonsignificant
– The relative risk for all nadroparin patients was (95% CI, to 1.410)
The heterogeneity in results with different LMWHs suggests that these agents are not interchangeable.
The remaining slides in this section discuss trials of LMWH in patients with STEMI.

16. HART-II: Evaluation of combined fibrinolytic and UFH/LMWH
Content Points:
The HART-II trial (Second Trial of Heparin and Aspirin Reperfusion Therapy) included 400 patients with STEMI who received aspirin and an accelerated infusion of alteplase (15-mg IV bolus, then a 0.75-mg/kg IV infusion for 30 minutes to a maximum of 30 mg, followed by an 0.5-mg IV infusion over 60 minutes to a maximum of 35 mg).42
The primary objective of the trial was to demonstrate the noninferiority of enoxaparin versus UFH.
Following administration of aspirin and fibrinolytic therapy, patients were randomized to enoxaparin (initial 30-mg IV bolus, followed by 1 mg/kg subcutaneously q12h) or UFH (initial bolus of 4000 U [<67 kg bodyweight] or 5000 U [≥67 kg bodyweight], followed by an infusion of 15 U/kg/h to a target aPTT of 2 to 2.5 times control).
The primary outcome was patency of the infarct-related artery at 90 minutes

17. HART-II: Infarct artery patency at 90 min
Content Points:
At 90 minutes after combined fibrinolytic/heparin therapy, TIMI grade 2 or 3 flow rate was achieved in 80.1% and 75.1% of enoxaparin and UFH patients, respectively.42
The difference between the two heparins was mainly due to higher proportion of patients with TIMI 3 flow in the enoxaparin group (52.9% vs 47.6%).
These findings confirmed the noninferiority of enoxaparin and trended towards demonstrating superiority for the LMWH.

18. Evaluation of combined fibrinolytic and UFH/LMWH in STEMI
Content Points:
Three trials evaluate effects of LMWH on clinical outcomes in patients with STEMI: Baird et al,43 ASSENT-3,44 and ENTIRE–TIMI 23.45
Baird et al randomized 300 patients receiving fibrinolytic therapy for STEMI to either enoxaparin (initial 40-mg IV bolus, followed by 40 mg subcutaneously q8h) or UFH (initial IV bolus of 5000 U, followed by infusion of 30,000 U/24h adjusted to an aPTT of 2 to 2.5 times normal).43
Patients were recruited consecutively as they presented to a mobile coronary care unit or to the emergency department of the study center.
– Those presenting to the mobile unit received either anistreplase 30 U or streptokinase 1.5 MU
– Those presenting to the emergency room received streptokinase
– Those previously treated with fibrinolytic therapy received 100-mg alteplase by an accelerated regimen
The primary outcome was combined death, MI, and readmission for UA.

19. Treatment effects of fibrinolytic plus UFH/LMWH
Content Points:
At 90 days, the primary outcome occurred in 36.4% and 25.5% of UFH and enoxaparin patients, respectively (odds ratio, 0.7; 95% CI, 0.49 to 0.99; P = 0.04).43
Each component of the primary outcome was also reduced by enoxaparin relative to UFH, although the differences did not reach statistical significance.
There was no difference in major hemorrhage between those receiving enoxaparin and UFH (3% vs 4%, data not shown on slide).
The investigators concluded that enoxaparin resulted in fewer recurrent cardiac events than UFH at 90 days.

20. ASSENT-3: Evaluation of combined fibrinolytic, GP IIb/IIIa inhibition, and UFH/LMWH
Content Points:
The ASSENT-3 trial (Assessment of the Safety and Efficacy of a New Thrombolytic Regimen) included 6095 patients with STEMI of less than 6-hours duration.44
Study subjects were randomized to one of three regimens.
– Enoxaparin group: Full-dose tenecteplase (30 mg if bodyweight <60 kg; 35 mg if bodyweight 60 to 69 kg; 40 mg if bodyweight 70 to 79 kg; 45 mg if bodyweight 80 to 89 kg) plus enoxaparin (initial IV bolus of 30 mg, followed by 1 mg/kg subcutaneously q12h)
- Enoxaparin was administered up to hospital discharge, revascularization, or a maximum of 7 days
– Abciximab group: Half-dose tenecteplase (also weight-adjusted), plus UFH (initial IV bolus of 60 U/kg, followed by 12 U/kg infusion adjusted to an aPTT of 50 to 70 s), plus abciximab (initial IV bolus of 0.25 mg/kg, followed by a m/kg/min infusion for 12 hours)
– UFH group: Full-dose tenecteplase plus UFH
The primary efficacy outcome was combined death, MI, and revascularization.
The primary safety outcome was the primary outcome plus intracranial hemorrhage or noncerebral major bleeding.

21. ASSENT-3: Primary efficacy outcome
Content Points:
At 30 days, the primary efficacy outcome occurred in 15.4% of the UFH group, 11.4% of the enoxaparin group, and 11.1% of the abciximab group.44
The relative risk for enoxaparin versus UFH was 0.74 (95% CI, 0.63 to 0.87; P = ).
The relative risk for abciximab versus UFH was 0.72 (95% CI, 0.61 to 0.84; P < ).
The ASSENT-3 investigators concluded that, compared with UFH, abciximab or enoxaparin as adjunctive therapy to fibrinolysis with tenecteplase reduces ischemic complications of STEMI.

22. ASSENT-3: Primary efficacy plus safety outcome
Content Points:
At 30 days, the primary efficacy plus safety outcome occurred in 17.0% of the UFH group, 13.7% of the enoxaparin group, and 14.2% of the abciximab group.44
The relative risk for enoxaparin versus UFH was 0.81 (95% CI, 0.70 to 0.93; P = 0.037).
The relative risk for abciximab versus UFH was 0.84 (95% CI, 0.72 to 0.96; P = ).
Further details on stroke and hemorrhagic complications are provided on the next slide.

23. ASSENT-3: Stroke and noncerebral hemorrhagic complications
Content Points:
Rates of total stroke, intracranial hemorrhage, and ischemic stroke did not vary significantly among the treatment groups.44
The rates of thrombocytopenia and total bleeding episodes were significantly higher in the abciximab group compared with the UFH group (P ≤ and P = , respectively).
More bleeding complications were also seen in the enoxaparin group compared with the UFH group, although the differences were not significant.
The ASSENT-3 investigators concluded that their data support consideration of tenecteplase plus enoxaparin as an alternative reperfusion regimen to tenecteplase plus abciximab.

24. ENTIRE–TIMI 23: Evaluation of combined fibrinolytic, GP IIb/IIIa inhibition, and UFH/LMWH
Content Points:
ENTIRE–TIMI 23 was a dose-ranging study of LMWH and included 483 patients with STEMI of less than 6-hours duration.45
All patients received aspirin (initial dose of ≥160 mg po or 250- to 500-mg IV, followed by 100 to 325 mg po daily), and then randomized to the following groups:
– Full-dose tenecteplase group: Tenecteplase 0.53 mg/kg, followed by further randomization to UFH (initial IV bolus of 60 U/kg, followed by 12-U/kg continuous infusion to maintain an aPTT of 1.5 to 2.5 times normal) or one of two different enoxaparin regimens:
- 30-mg bolus mg q12h for up to 8 days
- 1.0 mg q12h, no bolus
– Half-dose tenecteplase plus abciximab group: Tenecteplase 0.27 mg/kg plus abciximab (0.25-mg/kg bolus, followed by infusion of mg/kg/min), followed by randomization to UFH (initial bolus of 40 U/kg, followed by continuous infusion of 7 U/kg) or to one of three enoxaparin regimens:
- 30-mg bolus mg q12h for one day mg q12h for up to 8 days
- 2 x 0.3 mg q12h mg q12h, no bolus
- 2 x 0.75 mg q12h mg q12h, no bolus
The primary efficacy outcome was TIMI 3 flow at 90 minutes.
The primary safety outcome was TIMI major hemorrhage at 30 days.

25. ENTIRE–TIMI 23: Treatment effects on primary efficacy outcome
Content Points:
Enoxaparin was associated with similar TIMI 3 flow rates as UFH.45
In the full-dose tenecteplase group, the rate of TIMI 3 flow at 90 minutes was 52% in the UFH group and 48% to 51% in enoxaparin groups.
In the half-dose tenecteplase plus abciximab group, the rate of TIMI 3 flow was 48% in the UFH group and 52% to 58% in enoxaparin groups.

26. ENTIRE–TIMI 23: Treatment effects on primary safety outcome
Content Points:
No important differences were noted among enoxaparin groups with regard to major hemorrhage, so the data for these groups were combined.45
The rate of major hemorrhage in the full-dose tenecteplase group was 2.4% in the UFH group and 1.9% in all enoxaparin groups combined.
In the half-dose tenecteplase plus abciximab group, the rate of major hemorrhage was 5.2% in the UFH group and 8.5% in all enoxaparin groups combined.
The study investigators concluded that there was a similar risk for major hemorrhage in patients treated with UFH and enoxaparin.

27. ENTIRE–TIMI 23: Treatment effects on death/MI
Content Points:
Through 30 days, the rate for the combined outcome of death/MI in the full-dose tenecteplase group was 15.9% in UFH patients and 4.4% in enoxaparin patients (P = 0.005).45
In the half-dose tenecteplase plus abciximab group, the combined outcome occurred in 6.5% of UFH patients and 5.5% of enoxaparin patients.
The pooled rate was 11.3% among all UFH patients and 4.9% among all enoxaparin patients (P = 0.01, data not shown on slide).
The investigators concluded that enoxaparin was associated with similar TIMI 3 flow rates as UFH while exhibiting advantages with respect to reduction in ischemic events through 30 days.
Based on the results of ASSENT-3 and ENTIRE–TIMI 23, it is also recommended that a phase 3 trial be conducted to evaluate enoxaparin as replacement for UFH in reperfusion regimens and as part of combination regimens with IV GP IIb/IIIa inhibitors.45