New anticoagulant strategies in ST elevation myocardial infarction: Trials and clinical implications

Figures & data

Figure 1 Interaction of anti-thrombotic agents with coagulation cascade. UFH-antithrombin III complex has approximately equal inhibitory effects on factor Xa and IIa. LMWH-antithrombin III complex has greater relative specificity for factor Xa. Pentasaccharide-antithrombin III complex acts only on factor Xa.

Abbreviations: UFH, unfractionated heparin; LMWH, low molecular weight heparin; DTI, direct thrombin inhibitors.

Table 1 Important randomized controlled trials comparing LMWH with UFH in patients treated with fibrinolytic therapy for STEMI

Trial	Patients	LMWH regimen	UFH regimen	Outcomes
Baird et ala	300	Enoxaparin 40 mg IV bolus then 40 mg SC 8 hourly for 4 days	IV bolus, then infusion to maintain aPTT 2–2.5 × normal for 4 days	Significant reduction in death, non-fatal reinfarction or readmission with unstable angina at 90 days in favor of enoxaparin. No significant difference in major hemorrhage.
HART IIb	400	Enoxaparin 30 mg IV bolus then 1 mg/kg SC 12 hourly for ≥72 hours	IV bolus, then infusion to maintain aPTT 2–2.5 × normal for ≥77 hours	Enoxaparin non-inferior to UFH. No significant difference in adverse events.
ENTIRE-TIMI 23c	483	Enoxaparin 30 mg IV bolus then 1 mg/kg SC 12 hourly for 8 days or discharge	IV bolus, then infusion to maintain aPTT 1.5–2.5 × normal for ≥36 hours	No significant difference in TIMI 3 flow at 1 hour. Significant reduction in death/reinfarction at 30 days for enoxaparin compared with UFH. No significant difference in major bleeding.
ASSENT-3d,e	6095	Enoxaparin 30 mg IV bolus then 1 mg/kg SC 12 hourly for 7 days or discharge (2040 patients)	IV bolus, then infusion to maintain aPTT 50–70s for ≥48 hours(2038 patients)	Significant reductions in 30-day mortality, in-hospital reinfarction and in-hospital recurrent ischemia for enoxaparin compared with UFH. No significant increase in overall bleeding.
ASSENT-3 PLUSf	1639 (pre-hospital)	Enoxaparin 30 mg IV bolus then 1 mg/kg SC 12 hourly for 7 days or discharge	IV bolus, then infusion to maintain aPTT 50–70s for ≥48 hours	Reduction in early ischemic events with enoxaparin. Excess intracranial hemorrhage in patients >75 years.
ExTRACTg	20475	Enoxaparin 30 mg IV bolus then 1 mg/kg SC 12 hourly for 8 days or dischargeh	IV bolus, then infusion to maintain aPTT 1.5–2 × normal for ≥48 hours	Significant reduction in death or re-infarction. Significant increase in major bleeding. No significant difference in intracranial hemorrhage.

a Baird et al 2002.

b Ross et al 2001.

c Antman et al 2002.

d Assessment of the Safety and Efficacy of a New Thrombolytic Regimen (ASSENT)-3 Investigators 2001.

e Third arm in this trial was half-dose tenecteplase with weight-adjusted low-dose UFH and a 12-hour abciximab infusion.

f Wallentin et al 2003.

g Antman et al 2006.

h Regimen included a reduced dose in patients ≥75 years (no initial IV bolus, SC dose reduced to 0.75 mg/kg) and a reduced frequency (once a day) in patients with impaired renal function.

Abbreviations: LMWH, low molecular weight heparin; UFH, unfractionated heparin; IV, intravenous; SC, subcutaneous.

Table 2 Clinical endpoint trials for the use of fondaparinux in STEMI patients

Trial	Patients regimen	Fondaparinux regimen	UFH	Outcomes
PENTALYSEa	326 patients receiving fibrinolytic therapy	4 mg, 8 mg, or 12 mg, initial dose IV then SC once daily for 5–7 days	IV bolus, then infusion to maintain aPTT 50–75s for 48–72 hours	Fondaparinux as safe and effective as UFH in restoring coronary flow and preventing reocclusion.
OASIS-6b	Stratum 1: 5658 patients	2.5 mg SC once daily for up to 8 days	Placebo	Fondaparinux associated with a significant reduction in death or reinfarction compared with placebo. Fondaparinux associated with fewer major bleeds than placebo(non-significant).
	Stratum 2: 6434 patients	2.5 mg IV bolus then 2.5 mg SC once daily for up to 8 days	IV bolus, then infusion to maintain aPTT 1.5–2 × normal for up to 48 hours	No significant difference in death or reinfarction between fondaparinux and UFH arms. No significant difference in bleeding.

a Coussement et al 2001.

b Yusuf et al 2006.

Abbreviations: UFH, unfractionated heparin; IV, intravenous; SC, subcutaneous.

Table 3 Evidence for direct thrombin inhibitors as adjuvant anticoagulation for patients with STEMI receiving fibrinolytic therapy

Trial	Patients	DTI regimen	UFH regimen	Outcomes
GUSTO IIb triala	2274 patients treated with fibrinolytic therapy	Hirudin IV infusion to maintain aPTT 60–85s for 3–5 days	IV bolus, then infusion to maintain aPTT 60–85s for 3–5 days	In patients receiving streptokinase, hirudin compared with UFH was associated with a reduction death or reinfarction. No significant difference in death or reinfarction for patients treated with tissue-type plasminogen activator.
HIT 4b	1208 patients treated with streptokinase	Hirudin IV bolus followed by SC twice daily for 5–7 days	12500 U twice daily by SC injection	No significant difference in death or reinfarction. No significant difference in bleeding.
HEROc	412 patients treated with streptokinase	Bivalirudin IV bolus then infusion for 60 hours	IV bolus, then infusion for 60 hours	No significant difference in death or reinfarction. Significant reduction in major bleeding with bivalirudin.
HERO-2d	17073 patients treated with streptokinase	Bivalirudin IV bolus then infusion for 48 hours	IV bolus, then infusion to maintain aPTT 50–75s for 48 hours	No significant difference in 30 day mortality. Bivalirudin significantly reduced the rate of early (4 days) reinfarction.

a Metz et al 1998.

b Neuhaus et al 1999.

c White et al 1997.

d White et al 2001.

Abbreviations: UFH, unfractionated heparin; DTI, direct thrombin inhibitor; IV. intravenous; SC, subcutaneous.

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