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).
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.
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.
Correspondence: Dr Quinlan, Department of Radiology, King's College Hospital, Denmark Hill, London SE5 9RS, England (firstname.lastname@example.org).
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.
Thank you for submitting a comment on this article. It will be reviewed by JAMA Internal Medicine editors. You will be notified when your comment has been published. Comments should not exceed 500 words of text and 10 references.
Do not submit personal medical questions or information that could identify a specific patient, questions about a particular case, or general inquiries to an author. Only content that has not been published, posted, or submitted elsewhere should be submitted. By submitting this Comment, you and any coauthors transfer copyright to the journal if your Comment is posted.
* = Required Field
Disclosure of Any Conflicts of Interest*
Indicate all relevant conflicts of interest of each author below, including all relevant financial interests, activities, and relationships within the past 3 years including, but not limited to, employment, affiliation, grants or funding, consultancies, honoraria or payment, speakers’ bureaus, stock ownership or options, expert testimony, royalties, donation of medical equipment, or patents planned, pending, or issued. If all authors have none, check "No potential conflicts or relevant financial interests" in the box below. Please also indicate any funding received in support of this work. The information will be posted with your response.
Some tools below are only available to our subscribers or users with an online account.
Download citation file:
Web of Science® Times Cited: 2
Customize your page view by dragging & repositioning the boxes below.
The Rational Clinical Examination: Evidence-Based Clinical Diagnosis
Evidence To Support The Update
The Rational Clinical Examination: Evidence-Based Clinical Diagnosis
All results at
Enter your username and email address. We'll send you a link to reset your password.
Enter your username and email address. We'll send instructions on how to reset your password to the email address we have on record.
Athens and Shibboleth are access management services that provide single sign-on to protected resources. They replace the multiple user names and passwords necessary to access subscription-based content with a single user name and password that can be entered once per session. It operates independently of a user's location or IP address. If your institution uses Athens or Shibboleth authentication, please contact your site administrator to receive your user name and password.