We read with interest the meta-analytic overview by Silvain et al. which shows enoxaparin to be superior to unfractionated eparin (UFH) in reducing mortality of patients undergoing percutaneous coronary intervention (PCI), including those with ST-elevation myocardial infarction (STEMI); indeed, the randomised controlled trial (RCT) ATOLL, conducted in 910 primary PCI patients, found enoxaparin, compared with UFH, to significantly reduce the incidence of a composite endpoint, but not to improve survival as a single endpoint [2].
- Conversely, in a meta-analysis of 16286 patients, we report a significant reduction of all-cause mortality with low-molecular weight heparins (mostly enoxaparin) vs UFH [3].
- The lack of significant survival benefit in ATOLL may be explained by the relatively low number of enrolled patients: indeed, sample size calculation according to the study findings for all-cause mortality yields over 1000 patients per group to reach 80% power.
- ATOLL investigated high-risk patients, more closely reflecting real world practice. Such a strategy in a RCT, however, may lead to biased conclusions, given the large number of clinical factors potentially influencing outcome[4-5]; in fact, although a risk factor may not be significantly umbalanced between groups, it may still exert a strong influence on the results[4-5]; a pertinent recommendation would be to perform both unadjusted and adjusted analyses and compare the obtained information.
- In ATOLL, no adjustment procedure was performed, whereas separate adjusted and unadjusted analyses in our meta-analysis showed consistent survival benefits with enoxaparin [3].
- By risk profile meta-regression, we observed that patients at greatest risk derived the maximum benefit from enoxaparin [3], while such analysis was not possible in ATOLL.
- For these reasons, we share the comments by the authors regarding the consistent mortality benefits with enoxaparin in PCI and we therefore believe enoxaparin, compared with UFH, improves survival also in the setting of primary PCI, despite the non significant results for mortality as single endpoint observed in ATOLL.

References

1. Silvain J, Beygui F, Barthélémy O, Pollack C Jr, Cohen M, Zeymer U, Huber K, Goldstein P, Cayla G, Collet JP, Vicaut E, Montalescot G. Efficacy and safety of enoxaparin versus unfractionated heparin during percutaneous coronary intervention: systematic review and meta-analysis. BMJ 2012 [ahead of print].
2. Montalescot G, Zeymer U, Silvain J, Boulanger B, Cohen M, Goldstein P, Ecollan P, Combes X, Huber K, Pollack C Jr, Bénezet JF, Stibbe O, Filippi E, Teiger E, Cayla G, Elhadad S, Adnet F, Chouihed T, Gallula S, Greffet A, Aout M, Collet JP, Vicaut E; ATOLL Investigators. Intravenous enoxaparin or unfractionated heparin in primary percutaneous coronary intervention for ST-elevation myocardial infarction: the international randomised open-label ATOLL trial. Lancet 2011;378:693-703.
3. Navarese EP, De Luca G, Castriota F, Kozinski M, Gurbel P, Gibson CM, Andreotti F, Buffon A, Siller-Matula JM, Sukiennik A, De Servi S, Kubica J. Low-Molecular-Weight Heparins vs Unfractionated Heparin in the Setting of Percutaneous Coronary Intervention for ST-elevation Myocardial Infarction: a Meta-analysis. J Thromb Haemost 2011; July [Epub ahead of print].
4. Altman DG. Comparability of randomized groups. Statistician 1985;34:125–36.
5. Senn SJ. Covariate imbalance and random allocation in clinical trials. Stat Med 1989; 8:467-75.

Competing interests: None declared