KD Magee,
DOI:10.1002/14651858.CD002132
Add feedback to this review/protocol
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.
Dr.
Cundiff raises legitimate concerns in his letter. If there is no evidence
supporting the benefit of UFH in the treatment of ACS then why compare LMWH to
UFH? At the time the review was initially conducted, UFH was the standard
practice for the treatment of ACS as recommended by the AHA/ACC. We wanted to
compare the newer treatment modality, LMWH, against the current standard of
care. Having completed this review, we then asked the same question asked by
Dr. Cundiff: What is the evidence for the use of any heparin in the treatment
of ACS? To answer this question, we submitted the protocol for the systematic
review that Dr. Cundiff cites in his letter: K Magee, D Moher, B Rowe. Heparin versus placebo for acute
coronary syndromes. Cochrane Database of Systematic Reviews 2002, Issue
1. Art. No.: CD003462. DOI: 10.1002/14651858.CD003462. Protocol.
(Heart)
It
is anticipated this review will be published by the end of 2007. In the
meantime, I would refer to the conclusions reached by this unpublished review:
We
identified 59 potentially relevant studies, 8 of which (3110 participants) were
included in this review. 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). Heparins reduced the occurrence of MI (RR = 0.45;
95% CI: 0.30, 0.67). We found no evidence for difference in occurrence of
recurrent angina (RR = 0.81; 95% CI: 0.60, 1.09), revascularization procedures
(RR = 0.93; 95% CI: 0.76, 1.15), major bleeds (RR = 2.05; 95% CI: 0.91, 4.60),
or thrombocytopenia (RR = 0.20; 95% CI: 0.01, 4.24). More patients treated with
heparins experienced minor bleeds (RR = 6.80; 95% CI: 1.23, 37.49). From these
results, 37 patients need to be treated with heparin to prevent 1 additional
MI. As a sub-group, patients treated with LMWH experienced a lower incidence of
MI, recurrent angina and required fewer revascularization procedures.
In
essence, all heparins reduced the occurrence of MI and were associated with more
minor bleeds compared to placebo. As a subgroup, the positive effects were more
pronounced with LMWHs. This supports the results and conclusions of the
systematic review comparing LMWH to UFH for the treatment of ACS.
David
Cundiff
Kirk Magee
My Rebuttal
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.