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Figure.
Cumulative meta-analysis of randomized trials comparing LMWH with UFH showing reinfarction and death at 30 days (A) and major bleeding during hospitalization or at 7 days (B). ASSENT indicates Assessment of the Safety and Efficacy of a New Thrombolytic Regimen; CI, confidence interval; ENTIRE-TIMI 23, Enoxaparin and TNK-tPA with or without GP IIb/IIIa Inhibitor as Reperfusion strategy–Thrombolysis in Myocardial Infarction 23; ExTRACT-TIMI 25, Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial Infarction Treatment–Thrombolysis in Myocardial Infarction; HART II, Second Trial of Heparin and Aspirin Reperfusion Therapy; LMWH, low-molecular-weight heparin; OR, odds ratio; and UFH, unfractionated heparin.

Cumulative meta-analysis of randomized trials comparing LMWH with UFH showing reinfarction and death at 30 days (A) and major bleeding during hospitalization or at 7 days (B). ASSENT indicates Assessment of the Safety and Efficacy of a New Thrombolytic Regimen; CI, confidence interval; ENTIRE-TIMI 23, Enoxaparin and TNK-tPA with or without GP IIb/IIIa Inhibitor as Reperfusion strategy–Thrombolysis in Myocardial Infarction 23; ExTRACT-TIMI 25, Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial Infarction Treatment–Thrombolysis in Myocardial Infarction; HART II, Second Trial of Heparin and Aspirin Reperfusion Therapy; LMWH, low-molecular-weight heparin; OR, odds ratio; and UFH, unfractionated heparin.

Table. 
Patient Outcomes for Patients Comparing LMWH With UFH
Patient Outcomes for Patients Comparing LMWH With UFH
1.
Antman  EMMorrow  DA McCabe  CH  et al. ExTRACT-TIMI 25 Investigators, Enoxaparin versus unfractionated heparin with fibrinolysis for ST-elevation myocardial infarction. N Engl J Med 2006;354 (14) 1477- 1488
PubMedArticle
2.
Eikelboom  JWQuinlan  DJMehta  SRTurpie  AGMenown  IBYusuf  S Unfractionated and low-molecular-weight heparin as adjuncts to thrombolysis in aspirin-treated patients with ST-elevation acute myocardial infarction: a meta-analysis of the randomized trials. Circulation 2005;112 (25) 3855- 3867
PubMedArticle
3.
Wang  XKZhang  YYang  CMWang  YLiu  GY Use of unfractionated heparin and a low-molecular-weight heparin following thrombolytic therapy for acute ST-segment elevation myocardial infarction. Clin Drug Investig 2006;26 (6) 341- 349
PubMedArticle
4.
Assessment of the Safety and Efficacy of a New Thrombolytic Regimen (ASSENT)-3 Investigators, Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT-3 randomised trial in acute myocardial infarction. Lancet 2001;358 (9282) 605- 613
PubMedArticle
5.
Ross  AMMolhoek  PLundergan  C  et al. HART II Investigators, Randomized comparison of enoxaparin, a low-molecular-weight heparin, with unfractionated heparin adjunctive to recombinant tissue plasminogen activator thrombolysis and aspirin: Second Trial of Heparin and Aspirin Reperfusion Therapy (HART II). Circulation 2001;104 (6) 648- 652
PubMedArticle
6.
Baird  SHMenown  IBA McBride  SJTrouton  TGWilson  C Randomized comparison of enoxaparin with unfractionated heparin following fibrinolytic therapy for acute myocardial infarction. Eur Heart J 2002;23 (8) 627- 632
PubMedArticle
7.
Antman  EMLouwerenburg  HWBaars  HF  et al.  Enoxaparin as adjunctive antithrombin therapy for ST-elevation myocardial infarction: results of the ENTIRE–Thrombolysis in Myocardial Infarction (TIMI) 23 trial. Circulation 2002;105 (14) 1642- 1649
PubMedArticle
8.
Wallentin  LBergstrand  LDellborg  M  et al. ASSENT PLUS Investigators, Low molecular weight heparin (dalteparin) compared to unfractionated heparin as an adjunct to rt-PA (alteplase) for improvement of coronary artery patency in acute myocardial infarction: the ASSENT Plus study. Eur Heart J 2003;24897- 908
PubMedArticle
9.
Wallentin  LGoldstein  PArmstrong  PW  et al.  Efficacy and safety of tenecteplase in combination with the low-molecular-weight heparin enoxaparin or unfractionated heparin in the prehospital setting: the Assessment of the Safety and Efficacy of a New Thrombolytic Regimen (ASSENT)-3 PLUS randomized trial in acute myocardial infarction. Circulation 2003;108 (2) 135- 142
PubMedArticle
Research Letters
June 22, 2009

Low-Molecular-Weight Heparin as an Adjunct to Thrombolysis in ST Elevation Myocardial Infarction

Arch Intern Med. 2009;169(12):1163-1164. doi:10.1001/archinternmed.2009.126

The Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial Infarction Treatment (ExTRACT)–Thrombolysis in Myocardial Infarction (TIMI)-25 study1 demonstrated that the administration of enoxaparin sodium, 30 mg intravenously, followed by subcutaneous injections of 1 mg/kg twice daily (dose modified in patients 75 years or older), compared with intravenous unfractionated heparin (UFH), 60 U/kg bolus (maximum 4000 U), followed by 12 U/kg/h (initial maximum, 1000 U/h, and subsequently adjusted to maintain an activated partial thromboplastin time of 1.5-2.0 times the control value), reduced the risk of nonfatal reinfarction in patients with ST elevation myocardial infarction (STEMI) treated with thrombolysis. Because the ExTRACT-TIMI 25 study seems likely to be the last large trial evaluating the efficacy and safety of low-molecular-weight heparin (LMWH) in patients with STEMI, we added the results of this pivotal 20 000 patient trial to our meta-analysis published in 2005.2 Our updated literature search identified 1 additional study by Wang and colleagues3 published in 2006 involving 186 patients with STEMI who were randomized to receive parnaparin sodium or UFH; this study was also added to our meta-analysis.

Including the ExTRACT-TIMI 25 study and the study by Wang and colleagues,3 8 trials involving a combined total of 27 758 patients have compared LMWH with UFH in patients with STEMI. During hospitalization or at 7 days, LMWH compared with UFH reduced reinfarction by almost one-half (2.1% vs 3.9%) (odds ratio [OR] 0.53; 95% confidence interval [CI], 0.46-0.61) (number needed to treat [NNT], 56) (Table). The rates of death were not significantly different in the 2 treatment groups (5.3% vs 5.8%) (OR, 0.92; 95% CI, 0.83-1.02), but LMWH compared with UFH significantly increased major bleeding events (2.2% vs 1.6%) (OR, 1.39; 95% CI, 1.17-1.66) (number needed to harm [NNH], 167) and minor bleeding events (7.2% vs 5.8%) (OR, 1.31; 95% CI, 1.18-1.45) (NNH, 71). The benefit of LMWH in reducing reinfarction remained evident at 30 days, and estimates for other outcomes were similar at 7 and 30 days. Stroke rates were identical in the 2 randomized treatment groups at 30 days.

The inclusion of data from the ExTRACT-TIMI 25 study1 and the study by Wang et al3 in our meta-analysis substantially increased the number of outcome events (number of reinfarctions increased from 253 events to 1043 events; death, from 412 events to 1911 events; and major bleeding events, from 206 events to 520 events), thereby greatly improving the precision of the estimates of effect size. A reduced risk of reinfarction became evident after the first trial in 2001, when 4078 patients had been randomized and 144 reinfarctions had occurred (Figure). Cumulative data from subsequent trials resulted in a narrowing of the 95% CI, but the point estimates remained similar. A statistically significant increase in the risk of major bleeding with LMWH compared with UFH was not evident until after the publication of the results of the ExTRACT-TIMI 25 study in 2006. There was a nonsignificant 8% lower risk of death observed with LMWH compared with UFH during hospitalization or at days 7 (P = .10) and 30 (P = .08) (Table).

All of the estimates obtained from our updated analysis are similar to our original meta-analysis, approximating a one-half reduction in reinfarction during hospitalization or at day 7 and a one-third reduction in reinfarction through day 30. There was no significant heterogeneity among the trials for any of the outcomes examined, and the data from this meta-analysis represent the best estimates of the efficacy and safety of LMWH compared with UFH in patients with STEMI treated with thrombolysis.

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Article Information

Correspondence: Dr Quinlan, Department of Radiology, King's College Hospital, Denmark Hill, London SE5 9RS, England (dan.quinlan@consultoberon.com).

Author Contributions:Study concept and design: Quinlan and Eikelboom. Acquisition of data: Quinlan and Eikelboom. Analysis and interpretation of data: Quinlan and Eikelboom. Drafting of the manuscript: Quinlan and Eikelboom. Critical revision of the manuscript for important intellectual content: Quinlan and Eikelboom. Statistical analysis: Quinlan and Eikelboom. Administrative, technical, and material support: Quinlan and Eikelboom. Study supervision: Quinlan and Eikelboom.

Financial Disclosure: None reported.

Additional Contributions: Leah Teoh, MA, from Sanofi-Aventis provided missing data from the EXTRACT-TIMI 25 study.

References
1.
Antman  EMMorrow  DA McCabe  CH  et al. ExTRACT-TIMI 25 Investigators, Enoxaparin versus unfractionated heparin with fibrinolysis for ST-elevation myocardial infarction. N Engl J Med 2006;354 (14) 1477- 1488
PubMedArticle
2.
Eikelboom  JWQuinlan  DJMehta  SRTurpie  AGMenown  IBYusuf  S Unfractionated and low-molecular-weight heparin as adjuncts to thrombolysis in aspirin-treated patients with ST-elevation acute myocardial infarction: a meta-analysis of the randomized trials. Circulation 2005;112 (25) 3855- 3867
PubMedArticle
3.
Wang  XKZhang  YYang  CMWang  YLiu  GY Use of unfractionated heparin and a low-molecular-weight heparin following thrombolytic therapy for acute ST-segment elevation myocardial infarction. Clin Drug Investig 2006;26 (6) 341- 349
PubMedArticle
4.
Assessment of the Safety and Efficacy of a New Thrombolytic Regimen (ASSENT)-3 Investigators, Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT-3 randomised trial in acute myocardial infarction. Lancet 2001;358 (9282) 605- 613
PubMedArticle
5.
Ross  AMMolhoek  PLundergan  C  et al. HART II Investigators, Randomized comparison of enoxaparin, a low-molecular-weight heparin, with unfractionated heparin adjunctive to recombinant tissue plasminogen activator thrombolysis and aspirin: Second Trial of Heparin and Aspirin Reperfusion Therapy (HART II). Circulation 2001;104 (6) 648- 652
PubMedArticle
6.
Baird  SHMenown  IBA McBride  SJTrouton  TGWilson  C Randomized comparison of enoxaparin with unfractionated heparin following fibrinolytic therapy for acute myocardial infarction. Eur Heart J 2002;23 (8) 627- 632
PubMedArticle
7.
Antman  EMLouwerenburg  HWBaars  HF  et al.  Enoxaparin as adjunctive antithrombin therapy for ST-elevation myocardial infarction: results of the ENTIRE–Thrombolysis in Myocardial Infarction (TIMI) 23 trial. Circulation 2002;105 (14) 1642- 1649
PubMedArticle
8.
Wallentin  LBergstrand  LDellborg  M  et al. ASSENT PLUS Investigators, Low molecular weight heparin (dalteparin) compared to unfractionated heparin as an adjunct to rt-PA (alteplase) for improvement of coronary artery patency in acute myocardial infarction: the ASSENT Plus study. Eur Heart J 2003;24897- 908
PubMedArticle
9.
Wallentin  LGoldstein  PArmstrong  PW  et al.  Efficacy and safety of tenecteplase in combination with the low-molecular-weight heparin enoxaparin or unfractionated heparin in the prehospital setting: the Assessment of the Safety and Efficacy of a New Thrombolytic Regimen (ASSENT)-3 PLUS randomized trial in acute myocardial infarction. Circulation 2003;108 (2) 135- 142
PubMedArticle
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