1. Enoxaparin in Acute Coronary Syndromes
Hossam Kandil, MD
Professor of Cardiology
Cairo University

2. Story of Heparin Discovery
In the 1930s, several researchers were investigating heparin
Erik Jorpes at Karolinska Institutet published his research on the structure of heparin in 1935
This made it possible for the Swedish company Vitrum AB to launch the first heparin product for intravenous use in 1936
Between 1933 and 1936, Connaught Medical Research Laboratories, then a part of the University of Toronto, perfected a technique for producing safe, non-toxic heparin that could be administered to patients in a salt solution

3. Heparin Structure
Native heparin is a polymer with a molecular weight ranging from 3 kDa to 50 kDa
Average molecular weight of most commercial heparin preparations is in the range of 12 kDa to 15 kDa
Heparin is a member of the glycosamineglycan family of carbohydrates (which includes the closely-related molecule heparin sulfate) and consists of a variably- sulfated repeating disaccharide units

4. Heparin Structure
Up 85% of heparins are made from beef lung and from porcine intestinal mucosa
Heparin, a highly-sulfated glycosamineglycan, has the highest negative charge density of any known biological molecule
One unit of heparin (the "Howell Unit") is an amount approximately equivalent to 0.002 mg of pure heparin, which is the quantity required to keep 1 mL of cat's blood fluid for 24 hours at 0°C

5. How to Make UFH Combine Cook at 90° F for 17 hours Add
5,000 lbs cow intestines
200 gallons of water
10 gallons of chloroform
5 gallons toluene
Cook at 90° F for 17 hours
Add
30 gallons acetic acid
35 gallons ammonia, sodium hydroxide to adjust pH
Bring to a boil, skim off the fat
Filter solids for UFH

6. Heparins are complex mixtures of heterogeneous sugar chains
UFH
15,000 Da
Anti-Xa/IIa = 1.0
LMWH
~6,000 Da
Anti-Xa/IIa = 2–8
Ultra-LMWH
~1,500 Da
Anti-Xa/IIa = 10–50
Pentasaccharide
< 2,000 Da
Pure anti-Xa
UFH-
derived
Synthetic
heparin
mimetic
All LMWHs come from unfractionated heparin source material (UFH).
UFH is a highly complex mixture of linear polysaccharide (glycosaminoglycan) chains of varying chemical structure.
To manufacture LMWHs, the larger UFH chains are broken into smaller chains through varying processes of chemical or enzymatic depolymerization.
Is the depolymerization step only related to reduction in the chain-length size?
Pentasaccharide (5 saccharides) is the smallest sequence that has affinity for ATIII.
Does the depolymerization process only affect the average molecular weight and the anti-Xa activity?
Fareed J, et al. Semin Thromb Hemost. 2004;30:

7. Low Molecular Weight Heparin
LMWH inactivates factor Xa, like UFH, but has a lesser effect on thrombin
As a result, LMW heparins do not prolong the aPTT in a predictable fashion
Advantages over UFH:
More predictable anticoagulant effect
Reduced likelihood of inducing immune-mediated thrombocytopenia

8. Low Molecular Weight Heparin
A number of trials have evaluated the effects of LMWH in patients with unstable angina or NSTEMI
Main conclusion from these trials is that Enoxaparin provides comparable or superior benefit to UFH

9. Low Molecular Weight Heparin
Other LMWHs are effective compared to placebo
Less effective than Enoxaparin
Not more effective than UFH
May be associated with an increased bleeding risk

10. Enoxaparin in UA/NSTEMI
ESSENCE TIMI 11B TESSMA
INTERACT A TO Z
STEEPLE
SYNERGY
UA/NSTEMI with Enoxaparin
Enoxaparin  GP IIb/IIIa inhibitors
Intervention: Enoxaparin  PCI
Intervention: Enoxaparin  PCI  GP IIb/IIIa inhibitors

11. ESSENCE Trial
Compared effectiveness of aspirin plus LMWH (Enoxaparin, 1 mg/kg every 12 hours) to aspirin plus IV-UFH
3171 patients with unstable angina (angina at rest) or acute NSTEMI
Therapy was given for a minimum of 48 hours to a maximum of eight days

12. ESSENCE Trial
At 30 days, Enoxaparin therapy was associated with significant reductions in the incidence of a combined end point of:
Death, MI, and recurrent angina (19.8 vs 23.3 % with UFH) or a revascularization procedure (27.0 vs 32.2 %)

13. ESSENCE trial
No difference between the two groups in the rates of major bleeding (6.5 vs 7.0 %) or severe thrombocytopenia (0.4 vs 0.6 %)
These benefits were maintained at one year for both the combined end point (32 vs 36 %) and the need for repeat revascularization (36 vs 41 %)

14. ESSENCE trial
Enoxaparin therapy was also associated with a significantly lower rate of recurrent ischemic events on 48 hour ST segment monitoring after drug discontinuation (26 vs 45 % with UFH)
Duration of ischemic episodes was shorter with Enoxaparin (4.6 vs 18.0 minutes per 24 hours)

15. TIMI 11B trial 
Benefits of Enoxaparin (1 mg/kg every 12 hours for eight days, then 40 to 60 mg every 12 hours through day 43) compared to UFH (continuous intravenous infusion for at least three days) in UA or NSTEMI were confirmed in the TIMI 11B trial of 3910 patients
Incidence of the primary end point (death, MI, or urgent revascularization) was significantly lower with Enoxaparin at eight days (12.4 vs 14.5 for heparin)

16. SYNERGY trial of use in PCI
 There has been concern about the use of Enoxaparin in patients with UA or NSTEMI scheduled for an early invasive strategy due to:
Inability to easily monitor or fully reverse the anticoagulant effects of LMWH
Higher rate of bleeding with equivalent efficacy end points using Enoxaparin compared to UFH in patients with an intended early invasive strategy in Phase A of the A to Z trial

17. SYNERGY trial 10,027 patients with a non-ST elevation ACS
Early invasive management strategy was planned
Patients were randomly assigned to receive open label Enoxaparin (1 mg/kg subcutaneously every 12 hours) or UFH (60 U/kg initial bolus followed by an infusion of 12 U/kg per hour, adjusted to a goal activated partial thromboplastin time [aPTT] of 1.5 to times the upper limit of normal or 50 to 70 seconds

18. SYNERGY trial
Concomitant medications in SYNERGY included aspirin (95 %), clopidogrel or ticlopidine (66 %), and a GP IIb/IIIa inhibitor (57 %). Coronary angiography was performed in 92 % of the SYNERGY patients; 47 % underwent PCI and 19 % underwent surgical revascularization

19. SYNERGY trial
No significant reduction in the primary end point of death or nonfatal MI at 30 days or at six months with Enoxaparin (14.0 vs 14.5 % and 17.6 vs 17.8%, respectively, with UFH)
There was also no difference in death or nonfatal MI or in all-cause mortality at one year (7.4 vs 7.8 %)
There was a significant increase in in-hospital major bleeding by TIMI criteria (at least a 5 g/dL decrease in hemoglobin, at least a 15 % decrease in hematocrit, or intracranial bleeding) with Enoxaparin (9.1 vs 7.6 % for UFH).

20. SYNERGY trial
There was no significant difference in the need for transfusion (17 vs 16 %)
These findings are consistent with those found in Phase A of the A to Z trial
Both cardiovascular and bleeding outcomes were worse in patients initially treated with either Enoxaparin or UFH and then switched over compared to patients who did not switch

21. SYNERGY trial
Results from SYNERGY suggest that, in patients with a non-ST elevation ACS who receive a GP IIb/IIIa inhibitor and undergo PCI, Enoxaparin is as effective as UFH, but is associated with a small but statistically significant increase in major bleeding

22. Enoxaparin in STEMI

23. Enoxaparin in ST-elevation MI
Trial n
Year published
Blinding
Randomization arms
Enoxaparin UFH
Endpoint description
ASSENT
4075
2001
Open-label
30 mg bolus; 1 mg/kg bid for ≤7 days
60 U/kg bolus, 12 U/kg/h for 48 h to aPTT s
Death 30 days; MI in-hospital; major bleeding (requiring transfusion or intervention due to haemodynamic compromise or ICH) in-hospital
HART II
400
30 mg bolus, 1 mg/kg bid for ≥3 days
U bolus, 15 U/kg/h for ≥3 days to aPTT x control
Death 30 days; MI 30 days; TIMI major bleeding in-hospitala
Baird et al.
300
2002
40 mg bolus, 40 mg tid for 4 days
5000 U bolus, 30,000 U infusion over 24 h for 4 days to aPTT x control
Death 90 days; MI 90 days; major bleeding (clinically significant haemorrhage or ICH) on study drug
ENTIRE-TIMI 23
242
0 or 30 mg bolus; 1 mg/kg bid for ≤8 days
60 U/kg bolus, 12 U/kg/h for ≤3 days to aPTT x control
Death 30 days; MI 30 days; TIMI major bleeding 30 daysa
ASSENT 3 Plus
1635
2003
Death 30 days; MI in-hospital; major bleeding (requiring transfusion or intervention because of haemodynamic compromise or ICH) in-hospital
ExTRACT-TIMI 25
20,479
2006
Double-blind
30 mg bolus (if age <75); 1 mg/kg bid (if age <75) or 0.75 mg/kg bid (if age ≥75) for ≤8 days
60 U/kg bolus (omitted if open-label UFH received within 3 h), 12 U/kg/h for ≥3 days to aPTT x control

24. Acute Coronary Syndromes*
1.57 Million Hospital Admissions - ACS
UA/NSTEMI†
STEMI
1.24 million Admissions per year
.33 million Admissions per year
10 Years Clinical Evidence for Enoxaparin in ACS
1997
Nearly than 22,000 UA/NSTEMI patients studied
2004
ESSENCE
ACUTE II
A-to-Z
TIMI 11B
INTERACT
SYNERGY
More than 30,000 STEMI patients studied
2007
2001
ExTRACT-TIMI 25
HART-II
ENTIRE-TIMI 23
ASSENT-3
ASSENT-3 PLUS
Baird et al
AMI-SK
TETAMI
Heart Disease and Stroke Statistics – 2007 Update. Circulation 2007; 115: *Primary and secondary diagnoses. †About 0.57 million NSTEMI and 0.67 million UA.

25. Enoxaparin Vs. UFH For The Comparison Of Myocardial Infarction

26. Enoxaparin Vs. UFH For The Comparison Of Death Or Non-Fatal MI

27. Enoxaparin Vs. UFH For The Comparison of Major Bleed

28. Enoxaparin Vs. UFH For the Comparison of Death

29. Enoxaparin Vs. UFH For The Comparison Of Death, Non-fatal Myocardial Infarction, Or Non-fatal Major Bleed

30. Guidelines On Heparin Use
Enoxaparin and UFH appear to be of equal efficacy when patients with UA and NSTEMI are evaluated in the aggregate
Patients who are managed by a conservative strategy appear to have fewer adverse cardiovascular events when treated with Enoxaparin compared to UFH

31. Guidelines on Heparin Use
For patients undergoing an early invasive strategy, UFH may be preferable due to the increased risk of bleeding with Enoxaparin seen in the SYNERGY trial
Among patients in whom a conservative strategy is selected, either Enoxaparin or UFH is recommended, but it is considered reasonable (a weaker recommendation) to prefer Enoxaparin (or Fondaparinux)
The recommended duration of therapy is duration of hospitalization (maximum eight days) for Enoxaparin or UFH for 48 hours

32. Guidelines on Heparin Use
Among patients at increased risk for bleeding, Fondaparinux is preferred
Among patients in whom coronary artery bypass graft surgery (CABG) is planned within the next 24 hours, UFH is preferred because its anticoagulant effect can be more rapidly reversed than that of Enoxaparin

33. Guidelines on Heparin Use
In patients already being treated with Enoxaparin before PCI, Enoxaparin should be continued and the patient should be not be switched to UFH at a dose consistent with institutional practice
Among patients in whom medical therapy is selected after coronary angiography and a heparin has been given prior to angiography, Enoxaparin should be continued for the duration of hospitalization (maximum eight days) and UFH should be continued for at least 48 hours or until discharge

34. Guidelines On Heparin Use
Other LMWHs - dalteparin, nadroparin, and tinzaparin - are not recommended in patients with a non-ST elevation ACS
Although these drugs are effective compared to placebo, they may be less effective than Enoxaparin, are not more effective than UFH, and may be associated with an increased bleeding risk

35. Thank You

36. Meta-analyses of Enoxaparin vs UFH
 A 2004 meta-analysis included data on 21,946 patients from six randomized trials including ESSENCE, TIMI 11B, Phase A of the A to Z, and SYNERGY trials
Enoxaparin was associated with a significant reduction in the incidence of death or nonfatal MI at 30 days (10.1 vs 11.0 % with UFH, odds ratio 0.91, 95% CI )
A similar significant reduction in the rate of death or nonfatal MI at 30 days was noted in a 2007 meta-analysis (9.8 vs 11.4 % with UFH, odds ratio 0.84)

37. Meta-analyses of Enoxaparin vs UFH
The two meta-analyses differed as to whether Enoxaparin was or was not associated with a small but significant increase in major bleeding
In analyses from TIMI 11B and ESSENCE, the benefit of Enoxaparin was primarily seen in high-risk patients with TIMI risk scores ≥ 4 (TIMI 11B) or ≥ 5 (ESSENCE)
Such a subset analysis was not included in the meta-analyses

38. Meta-analyses of Enoxaparin vs UFH
The utility of the meta-analyses is limited by the heterogeneity of the studies evaluated
GP IIb/IIIa inhibitors were not used in ESSENCE and TIMI 11B, were given to all patients in Phase A of A to Z, and to approximately one-half of patients in SYNERGY

39. Meta-analyses of Enoxaparin vs UFH
In addition, diagnostic catheterization was performed in 92 % of patients in SYNERGY but in only 45 to 65 % of patients in the other trials
Specific role of Enoxaparin in patients treated with GP IIb/IIIa inhibitors and in patients undergoing invasive management cannot be determined from the meta-analyses