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

Enoxaparin in Acute Coronary Enoxaparin in Acute Coronary SyndromesSyndromes

Hossam Kandil, MDHossam Kandil, MDProfessor of CardiologyProfessor of Cardiology

Cairo UniversityCairo University

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

• 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

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

Heparin Structure

How to Make UFHHow to Make UFH

CombineCombine– 5,000 lbs cow intestines5,000 lbs cow intestines– 200 gallons of water200 gallons of water– 10 gallons of chloroform10 gallons of chloroform– 5 gallons toluene5 gallons toluene

Cook at 90° F for 17 hoursCook at 90° F for 17 hours AddAdd

– 30 gallons acetic acid30 gallons acetic acid– 35 gallons ammonia, sodium hydroxide to adjust pH35 gallons ammonia, sodium hydroxide to adjust pH

Bring to a boil, skim off the fatBring to a boil, skim off the fat Filter solids for UFHFilter solids for UFH

Heparins are complex mixtures Heparins are complex mixtures of heterogeneous sugar chainsof heterogeneous sugar chains

UFH15,000 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 DaPure anti-Xa

UFH-derived

Synthetic heparinmimetic

Does the depolymerization process only affect the

average molecular weight and the anti-Xa activity?

Fareed J, et al. Semin Thromb Hemost. 2004;30:703-13.

Low Molecular Weight HeparinLow Molecular Weight Heparin

• LMWH inactivates factor Xa, like UFH, but LMWH inactivates factor Xa, like UFH, but has a lesser effect on thrombinhas a lesser effect on thrombin

• As a result, LMW heparins do not prolong the As a result, LMW heparins do not prolong the aPTT in a predictable fashionaPTT in a predictable fashion

• Advantages over UFH:Advantages over UFH:

• More predictable anticoagulant effectMore predictable anticoagulant effect

• Reduced likelihood of inducing immune-mediated Reduced likelihood of inducing immune-mediated thrombocytopeniathrombocytopenia

• A number of trials have evaluated the effects A number of trials have evaluated the effects of LMWH in patients with unstable angina or of LMWH in patients with unstable angina or NSTEMINSTEMI

• Main conclusion from these trials is that Main conclusion from these trials is that Enoxaparin provides comparable or superior Enoxaparin provides comparable or superior benefit to UFHbenefit to UFH


• Other LMWHs are effective compared to Other LMWHs are effective compared to placeboplacebo

• Less effective than EnoxaparinLess effective than Enoxaparin

• Not more effective than UFHNot more effective than UFH

• May be associated with an increased May be associated with an increased bleeding riskbleeding risk


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

Enoxaparin in UA/NSTEMIEnoxaparin in UA/NSTEMI

ESSENCE TrialESSENCE Trial

• Compared effectiveness of aspirin plus Compared effectiveness of aspirin plus LMWH (Enoxaparin, 1 mg/kg every 12 hours) LMWH (Enoxaparin, 1 mg/kg every 12 hours) to aspirin plus IV-UFHto aspirin plus IV-UFH

• 3171 patients with unstable angina (angina at 3171 patients with unstable angina (angina at rest) or acute NSTEMIrest) or acute NSTEMI

• Therapy was given for a minimum of 48 hours Therapy was given for a minimum of 48 hours to a maximum of eight daysto a maximum of eight days

ESSENCE TrialESSENCE Trial

• At 30 days, Enoxaparin therapy was associated At 30 days, Enoxaparin therapy was associated with significant reductions in the incidence of a with significant reductions in the incidence of a combined end point of:combined end point of:

• Death, MI, and recurrent angina (19.8 vs 23.3 % Death, MI, and recurrent angina (19.8 vs 23.3 % with UFH) or a revascularization procedure with UFH) or a revascularization procedure (27.0 vs 32.2 %)(27.0 vs 32.2 %)

ESSENCE trialESSENCE trial

• No difference between the two groups in the No difference between the two groups in the rates of major bleeding (6.5 vs 7.0 %) or rates of major bleeding (6.5 vs 7.0 %) or severe thrombocytopenia (0.4 vs 0.6 %)severe thrombocytopenia (0.4 vs 0.6 %)

• These benefits were maintained at one year These benefits were maintained at one year for both the combined end point (32 vs 36 %) for both the combined end point (32 vs 36 %) and the need for repeat revascularization (36 and the need for repeat revascularization (36 vs 41 %) vs 41 %)

ESSENCE trialESSENCE trial• Enoxaparin therapy was also associated with Enoxaparin therapy was also associated with

a significantly lower rate of recurrent ischemic a significantly lower rate of recurrent ischemic events on 48 hour ST segment monitoring events on 48 hour ST segment monitoring after drug discontinuation (26 vs 45 % with after drug discontinuation (26 vs 45 % with UFH)UFH)

• Duration of ischemic episodes was shorter Duration of ischemic episodes was shorter with Enoxaparin (4.6 vs 18.0 minutes per 24 with Enoxaparin (4.6 vs 18.0 minutes per 24 hours)hours)

TIMI 11B trial TIMI 11B trial • Benefits of Enoxaparin (1 mg/kg every 12 hours Benefits of Enoxaparin (1 mg/kg every 12 hours

for eight days, then 40 to 60 mg every 12 hours for eight days, then 40 to 60 mg every 12 hours through day 43) compared to UFH (continuous through day 43) compared to UFH (continuous intravenous infusion for at least three days) in UA intravenous infusion for at least three days) in UA or NSTEMI were confirmed in the TIMI 11B trial or NSTEMI were confirmed in the TIMI 11B trial of 3910 patientsof 3910 patients

• Incidence of the primary end point (death, MI, or Incidence of the primary end point (death, MI, or urgent revascularization) was significantly lower urgent revascularization) was significantly lower with Enoxaparin at eight days (12.4 vs 14.5 for with Enoxaparin at eight days (12.4 vs 14.5 for heparin)heparin)

SYNERGY trial of use in PCISYNERGY trial of use in PCI• There has been concern about the use of There has been concern about the use of

Enoxaparin in patients with UA or NSTEMI Enoxaparin in patients with UA or NSTEMI scheduled for an early invasive strategy due scheduled for an early invasive strategy due to: to:

• Inability to easily monitor or fully reverse the Inability to easily monitor or fully reverse the anticoagulant effects of LMWHanticoagulant effects of LMWH

• Higher rate of bleeding with equivalent efficacy Higher rate of bleeding with equivalent efficacy end points using Enoxaparin compared to UFH in end points using Enoxaparin compared to UFH in patients with an intended early invasive strategy in patients with an intended early invasive strategy in Phase A of the A to Z trial Phase A of the A to Z trial

SYNERGY trialSYNERGY trial

• 10,027 patients with a non-ST elevation ACS10,027 patients with a non-ST elevation ACS

• Early invasive management strategy was Early invasive management strategy was plannedplanned

• Patients were randomly assigned to receive Patients were randomly assigned to receive open label Enoxaparin (1 mg/kg open label Enoxaparin (1 mg/kg subcutaneously every 12 hours) or UFH (60 subcutaneously every 12 hours) or UFH (60 U/kg initial bolus followed by an infusion of 12 U/kg initial bolus followed by an infusion of 12 U/kg per hour, adjusted to a goal activated U/kg per hour, adjusted to a goal activated partial thromboplastin time [aPTT] of 1.5 to partial thromboplastin time [aPTT] of 1.5 to 2.0 times the upper limit of normal or 50 to 70 2.0 times the upper limit of normal or 50 to 70 secondsseconds


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

SYNERGY trialSYNERGY trial• No significant reduction in the primary end point of No significant reduction in the primary end point of

death or nonfatal MI at 30 days or at six months with death or nonfatal MI at 30 days or at six months with Enoxaparin (14.0 vs 14.5 % and 17.6 vs 17.8%, Enoxaparin (14.0 vs 14.5 % and 17.6 vs 17.8%, respectively, with UFH)respectively, with UFH)

• There was also no difference in death or nonfatal MI or There was also no difference in death or nonfatal MI or in all-cause mortality at one year (7.4 vs 7.8 %)in all-cause mortality at one year (7.4 vs 7.8 %)

• There was a significant increase in in-hospital major There was a significant increase in in-hospital major bleeding by TIMI criteria (at least a 5 g/dL decrease in bleeding by TIMI criteria (at least a 5 g/dL decrease in hemoglobin, at least a 15 % decrease in hematocrit, or hemoglobin, at least a 15 % decrease in hematocrit, or intracranial bleeding) with Enoxaparin (9.1 vs 7.6 % for intracranial bleeding) with Enoxaparin (9.1 vs 7.6 % for UFH).UFH).


• There was no significant difference in the There was no significant difference in the need for transfusion (17 vs 16 %)need for transfusion (17 vs 16 %)

• These findings are consistent with those These findings are consistent with those found in Phase A of the A to Z trialfound in Phase A of the A to Z trial

• Both cardiovascular and bleeding outcomes Both cardiovascular and bleeding outcomes were worse in patients initially treated with were worse in patients initially treated with either Enoxaparin or UFH and then switched either Enoxaparin or UFH and then switched over compared to patients who did not switchover compared to patients who did not switch


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

Enoxaparin in STEMIEnoxaparin in STEMI

Enoxaparin in ST-elevation MIEnoxaparin 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 50-70 s

Death 30 days; MI in-hospital; major bleeding (requiring transfusion or intervention due to haemodynamic compromise or ICH) in-hospital

HART II 400 2001 Open-label 30 mg bolus, 1 mg/kg bid for ≥3 days

4000-5000 U bolus, 15 U/kg/h for ≥3 days to aPTT 2.0-2.5 x control

Death 30 days; MI 30 days; TIMI major bleeding in-hospitala

Baird et al. 300 2002 Open-label 40 mg bolus, 40 mg tid for 4 days

5000 U bolus, 30,000 U infusion over 24 h for 4 days to aPTT 2.0-2.5 x control

Death 90 days; MI 90 days; major bleeding (clinically significant haemorrhage or ICH) on study drug

ENTIRE-TIMI 23 242 2002 Open-label 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 1.5-2.5 x control

Death 30 days; MI 30 days; TIMI major bleeding 30 daysa

ASSENT 3 Plus 1635 2003 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 50-70 s

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 1.5-2.0 x control

Death 30 days; MI 30 days; TIMI major bleeding 30 daysa

Heart Disease and Stroke Statistics – 2007 Update. Circulation 2007; 115:69-171. *Primary and secondary diagnoses. †About 0.57 million NSTEMI and 0.67 million UA.

Acute Coronary Syndromes*Acute Coronary Syndromes*

1.57 Million Hospital Admissions - ACS

UA/NSTEMI† STEMI

1.24 million Admissions per year

.33 million Admissions per year

2007 More than 30,000 STEMI patients studied

1997 Nearly than 22,000 UA/NSTEMI patients studied

2001

2004

ASSENT-3

ESSENCE

AMI-SKBaird et alENTIRE-TIMI 23 ASSENT-3 PLUS

TETAMI

ExTRACT-TIMI 25HART-II

TIMI 11BACUTE II

INTERACTA-to-Z

SYNERGY

10 Years Clinical Evidence for Enoxaparin in ACS10 Years Clinical Evidence for Enoxaparin in ACS

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

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

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

Enoxaparin Vs. UFH For the Comparison Enoxaparin Vs. UFH For the Comparison of Deathof Death

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

BleedBleed

Guidelines On Heparin Use Guidelines On Heparin Use

• Enoxaparin and UFH appear to be of equal Enoxaparin and UFH appear to be of equal efficacy when patients with UA and NSTEMI efficacy when patients with UA and NSTEMI are evaluated in the aggregateare evaluated in the aggregate

• Patients who are managed by a conservative Patients who are managed by a conservative strategy appear to have fewer adverse strategy appear to have fewer adverse cardiovascular events when treated with cardiovascular events when treated with Enoxaparin compared to UFHEnoxaparin compared to UFH

Guidelines on Heparin Use Guidelines on Heparin Use • For patients undergoing an early invasive For patients undergoing an early invasive

strategy, UFH may be preferable due to the strategy, UFH may be preferable due to the increased risk of bleeding with Enoxaparin seen increased risk of bleeding with Enoxaparin seen in the SYNERGY trialin the SYNERGY trial

• Among patients in whom a conservative strategy Among patients in whom a conservative strategy is selected, either Enoxaparin or UFH is is selected, either Enoxaparin or UFH is recommended, but it is considered reasonable (a recommended, but it is considered reasonable (a weaker recommendation) to prefer Enoxaparin weaker recommendation) to prefer Enoxaparin (or Fondaparinux)(or Fondaparinux)

• The recommended duration of therapy is The recommended duration of therapy is duration of hospitalization (maximum eight days) duration of hospitalization (maximum eight days) for Enoxaparin or UFH for 48 hoursfor Enoxaparin or UFH for 48 hours

Guidelines on Heparin Use Guidelines on Heparin Use

• Among patients at increased risk for bleeding, Among patients at increased risk for bleeding, Fondaparinux is preferredFondaparinux is preferred

• Among patients in whom coronary artery Among patients in whom coronary artery bypass graft surgery (CABG) is planned bypass graft surgery (CABG) is planned within the next 24 hours, UFH is preferred within the next 24 hours, UFH is preferred because its anticoagulant effect can be more because its anticoagulant effect can be more rapidly reversed than that of Enoxaparinrapidly reversed than that of Enoxaparin

Guidelines on Heparin Use Guidelines on Heparin Use • In patients already being treated with In patients already being treated with

Enoxaparin before PCI, Enoxaparin should be Enoxaparin before PCI, Enoxaparin should be continued and the patient should be not be continued and the patient should be not be switched to UFH at a dose consistent with switched to UFH at a dose consistent with institutional practiceinstitutional practice

• Among patients in whom medical therapy is Among patients in whom medical therapy is selected after coronary angiography and a selected after coronary angiography and a heparin has been given prior to angiography, heparin has been given prior to angiography, Enoxaparin should be continued for the Enoxaparin should be continued for the duration of hospitalization (maximum eight duration of hospitalization (maximum eight days) and UFH should be continued for at days) and UFH should be continued for at least 48 hours or until dischargeleast 48 hours or until discharge

Guidelines On Heparin Use Guidelines On Heparin Use

• Other LMWHs - dalteparin, nadroparin, and Other LMWHs - dalteparin, nadroparin, and tinzaparin - are not recommended in patients tinzaparin - are not recommended in patients with a non-ST elevation ACSwith a non-ST elevation ACS

• Although these drugs are effective compared Although these drugs are effective compared to placebo, they may be less effective than to placebo, they may be less effective than Enoxaparin, are not more effective than UFH, Enoxaparin, are not more effective than UFH, and may be associated with an increased and may be associated with an increased bleeding riskbleeding risk

Thank You

Meta-analyses of Enoxaparin vs UFHMeta-analyses of Enoxaparin vs UFH

• A 2004 meta-analysis included data on 21,946 patients A 2004 meta-analysis included data on 21,946 patients from six randomized trials including ESSENCE, TIMI from six randomized trials including ESSENCE, TIMI 11B, Phase A of the A to Z, and SYNERGY trials11B, Phase A of the A to Z, and SYNERGY trials

• Enoxaparin was associated with a significant reduction Enoxaparin was associated with a significant reduction in the incidence of death or nonfatal MI at 30 days in the incidence of death or nonfatal MI at 30 days (10.1 vs 11.0 % with UFH, odds ratio 0.91, 95% CI (10.1 vs 11.0 % with UFH, odds ratio 0.91, 95% CI 0.83-0.99)0.83-0.99)

• A similar significant reduction in the rate of death or A similar significant reduction in the rate of death or nonfatal MI at 30 days was noted in a 2007 meta-nonfatal MI at 30 days was noted in a 2007 meta-analysis (9.8 vs 11.4 % with UFH, odds ratio 0.84)analysis (9.8 vs 11.4 % with UFH, odds ratio 0.84)


• The two meta-analyses differed as to whether The two meta-analyses differed as to whether Enoxaparin was or was not associated with a Enoxaparin was or was not associated with a small but significant increase in major small but significant increase in major bleedingbleeding

• In analyses from TIMI 11B and ESSENCE, In analyses from TIMI 11B and ESSENCE, the benefit of Enoxaparin was primarily seen the benefit of Enoxaparin was primarily seen in high-risk patients with TIMI risk scores ≥ 4 in high-risk patients with TIMI risk scores ≥ 4 (TIMI 11B) or ≥ 5 (ESSENCE)(TIMI 11B) or ≥ 5 (ESSENCE)

• Such a subset analysis was not included in Such a subset analysis was not included in the meta-analysesthe meta-analyses


• The utility of the meta-analyses is limited by The utility of the meta-analyses is limited by the heterogeneity of the studies evaluatedthe heterogeneity of the studies evaluated

• GP IIb/IIIa inhibitors were not used in GP IIb/IIIa inhibitors were not used in ESSENCE and TIMI 11B, were given to all ESSENCE and TIMI 11B, were given to all patients in Phase A of A to Z, and to patients in Phase A of A to Z, and to approximately one-half of patients in approximately one-half of patients in SYNERGYSYNERGY


• In addition, diagnostic catheterization was In addition, diagnostic catheterization was performed in 92 % of patients in SYNERGY performed in 92 % of patients in SYNERGY but in only 45 to 65 % of patients in the other but in only 45 to 65 % of patients in the other trialstrials

• Specific role of Enoxaparin in patients treated Specific role of Enoxaparin in patients treated with GP IIb/IIIa inhibitors and in patients with GP IIb/IIIa inhibitors and in patients undergoing invasive management cannot be undergoing invasive management cannot be determined from the meta-analysesdetermined from the meta-analyses

Documents

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