The Cochrane Library – Feedback

Low molecular weight heparins versus unfractionated heparin for acute coronary syndromes

Kirk Magee, William W Sevcik, David Moher, Brian H Rowe

DOI:10.1002/14651858.CD002132

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David Cundiff, MD
Date received: July 22, 2008
Cite this comment as: http://www.cochranefeedback.com/cf/cda/citation.do?id=9851#9851

I thank Dr. Magee for the reply.

The ‘Plain language summary’ states: “The review of trials found that UFH and LMWH were equally effective in preventing death…… Consider changing this statement to “…….equally ineffective in preventing death…..” As you noted in your reply to my first feedback letter, “We found no evidence for difference in overall mortality between the groups treated with heparins compared to placebo (RR = 1.01; 95% CI: 0.43, 2.38)”.

The appropriateness of this review is predicated on the efficacy of heparins when compared with placebo where all subjects are also treated with aspirin. The authors maintain that their recently published Cochrane Review of this topic establishes the benefit of a heparin plus aspirin versus aspirin alone. I dispute that contention (See my feedback letter for Magee K, Moher D, Rowe B. Heparin versus placebo for acute coronary syndromes. Cochrane Database of Systematic Reviews. 2008 (Issue 2):Art. No.: CD003462. DOI: 003410.001002/14651858.CD14003462.) This heparin versus placebo review did not account for events (MIs and reactivation of angina) related to rebound hypercoagulability after discontinuing heparin.

Neither LMWHs or UFH are evidence-based to be beneficial for people with acute coronary syndrome, so comparing them is inappropriate. With additional antiplatelet agents and invasive procedures in recent years, heparins are significantly more hazardous that when the trials in this review were done. These drugs should not be used for acute coronary syndrome outside of a placebo-controlled RCT.

David K. Cundiff, MD
Date received: July 28, 2007
Cite this comment as: http://www.cochranefeedback.com/cf/cda/citation.do?id=9697#9697

The two RCTs cited as “weak” justification for heparin in treating ACSs both indicate that, compared with ASA alone, heparin + ASA is evidence-based to increase major bleeding but not to reduce deaths or heart attacks.1, 2 Since heparin is not evidence-based to improve clinical outcomes compared with ASA or placebo for ACSs, there is no need to do this review of unfractionated heparin versus LMWHs. The authors’ conclusion, “This systematic review of randomized controlled trials supports the use of subcutaneous LMWH in the early treatment of acute coronary syndrome…..” is not warranted and should be revised. Both heparin and LMWHs are evidence-based to cause significant iatrogenic morbidity and mortality in ACS. Neither is evidence-based to reduce morbidity or mortality.

The discrepant incidences of thrombocytopenia in the two largest studies (ESSENCE 3% [95/3171]3 and FRAXIS [0.1% 3/ 2817]4 requires an explanation. This is more strange since the median duration of heparin or LMWH in the ESSENCE trial was 2.6 days versus between 6-14 days in the FRAXIS trial. The clinical outcomes of the patients who developed thrombocytopenia should be documented and discussed.

In the “Implications for research,” the authors do not recommend RCTs with a platelet inhibitor together with a LMWH versus a platelet inhibitor alone. Given the lack of evidence supporting either UFH or LMWH, this would be the only trial that would be appropriate to consider.

1. Theroux P, Ouimet H, McCans J, et al. Aspirin, heparin, or both to treat acute unstable angina. New England Journal of Medicine. 1988;319:1105-1111.
2. Risk of myocardial infarction and death during treatment with low-dose aspirin and intravenous heparin in men with unstable coronary artery disease. The RISC Group. Lancet. 1990;336:830-837.
3. Cohen M, Demers C, Gurfinkel EP, et al. A comparison of low-molecular-weight heparin with unfractionated heparin for unstable coronary artery disease. Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-Wave Coronary Events Study Group (ESSENCE). New England Journal of Medicine. 1997;337(7):447-452.
4. The FRAX.I.S. Study Group. Comparison of two treatment durations (6 days and 14 days) of a low molecular weight heparin with a 6-day treatment of infractionated heparin in the inital management of unstable angina or non-Q wave myocardial infarction: FRAX.I.S. (FRAXiparine in Ischaemic Syndrome). European Heart Journal. 1999;20(21):1553-1562.


David K. Cundiff, MD
Date received: July 13, 2007
Cite this comment as: http://www.cochranefeedback.com/cf/cda/citation.do?id=9679#9679

The two RCTs cited as “weak” justification for heparin in treating ACSs both indicate that, compared with ASA alone, heparin + ASA is evidence-based to increase major bleeding but not to reduce deaths or heart attacks.1, 2 Since heparin is not evidence-based to improve clinical outcomes compared with ASA or placebo for ACSs, there is no need to do this review of unfractionated heparin versus LMWHs. The authors’ conclusion, “This systematic review of randomized controlled trials supports the use of subcutaneous LMWH in the early treatment of acute coronary syndrome…..” is not warranted and should be revised. Both heparin and LMWHs are evidence-based to cause significant iatrogenic morbidity and mortality in ACS. Neither is evidence-based to reduce morbidity or mortality.

In the “Implications for research,” the authors do not recommend RCTs with a platelet inhibitor together with a LMWH versus a platelet inhibitor alone. Given the lack of evidence supporting either UFH or LMWH, this would be the only trial that would be appropriate to consider.

1. Theroux P, Ouimet H, McCans J, et al. Aspirin, heparin, or both to treat acute unstable angina. New England Journal of Medicine. 1988;319:1105-1111.
2. Risk of myocardial infarction and death during treatment with low-dose aspirin and intravenous heparin in men with unstable coronary artery disease. The RISC Group. Lancet. 1990;336:830-837.


John Eikelboom
Date received: March 3, 2003
Cite this comment as: http://www.cochranefeedback.com/cf/cda/citation.do?id=9030#9030

Congratulations. Nice review

Two comments:

1. Our review (Eikelboom et al. Lancet 2000) did include the study by Gurfinkel et al 1995. It is incorrectly suggested in the discussion that we did not do so.

2. Suvarno et al was not properly randomised (alternate treatment allocation). I understand that Cochrane includes quasi-randomised studies but wonder whether this practice should continue...

Sincerely

John Eikelboom

I have received honoraria from companies that manufacture low molecular weight heparins