Bangalore S, Toklu B, Kotwal A et al 

BMJ 2014 (Nov 11);349:g6419 doi: http://dx.doi.org/10.1136/bmj.g6419

In patients with ST segment elevation myocardial infarction undergoing primary percutaneous coronary intervention (PCI), anticoagulant treatment options include unfractionated heparin, low molecular weight heparin (LMWH), fondaparinux and bivalirudin. 

The 2013 American College of Cardiology Foundation and American Heart Association guideline for management of patients with ST segment elevation myocardial infarction recommends unfractionated heparin with or without planned glycoprotein IIb/IIIa inhibitors (GpIIb/IIIa inhibitor) or bivalirudin as class I indications for patients undergoing primary PCI, with a preference for bivalirudin over unfractionated heparin plus GpIIb/IIIa inhibitor in patients at high risk of bleeding (class IIa). 

The 2012 European Society of Cardiology guidelines, however, recommend bivalirudin over unfractionated heparin plus GpIIb/IIIa inhibitor (class I) but also recommend LMWH (with or without GpIIb/IIIa inhibitor) over unfractionated heparin (class IIb). The wide range of treatment options recommended in these guidelines stems from the broad comparative evidence base investigating the relative merits (both related to anti-ischemic efficacy and safety) of these respective therapies.

In this US based study the objective was to evaluate systematically (using data from randomised trials) the ischaemic and bleeding outcomes with various anticoagulant therapies in order to provide a hierarchy of treatment efficacy and safety in patients undergoing primary PCI for ST segment elevation myocardial infarction. In addition, to be relevant to contemporary practice, only randomised trials performed in the era of stents and P2Y12 (ADP) receptor inhibitors were included.

The study is a mixed treatment comparison and direct comparison meta-analysis of randomised trials in the era of stents and P2Y12 inhibitors. A search was undertaken of Medline, Embase, Cochrane Central Register of Controlled Trials (CENTRAL) for randomised trials comparing unfractionated heparin plus glycoprotein IIb/IIIa inhibitor(GpIIb/IIIa inhibitor), unfractionated heparin, bivalirudin, fondaparinux, or LMWH plus GpIIb/IIIa inhibitor for patients undergoing primary PCI.

The primary efficacy outcome was short term (in hospital or within 30 days) major adverse cardiovascular event; the primary safety outcome was short term major bleeding.

The authors identified 22 randomised trials that enrolled 22,434 patients. In the mixed treatment comparison models, when compared with unfractionated heparin plus GpIIb/IIIa inhibitor, unfractionated heparin was associated with a higher risk of major adverse cardiovascular events (relative risk 1.49 [95% confidence interval 1.21 to 1.84], as were bivalirudin (relative risk 1.34 [1.01 to 1.78]) and fondaparinux (1.78 [1.01 to 3.14]). LMWH plus GpIIb/IIIa inhibitor showed highest treatment efficacy, followed (in order) by unfractionated heparin plus GpIIb/IIIa inhibitor, bivalirudin, unfractionated heparin, and fondaparinux. Bivalirudin was associated with lower major bleeding risk compared with unfractionated heparin plus GpIIb/IIIa inhibitor (relative risk 0.47 [0.30 to 0.74]) or unfractionated heparin (0.58 [0.37 to 0.90]). Bivalirudin, followed by unfractionated heparin, LMWH plus GpIIb/IIIa inhibitor, unfractionated heparin plus GpIIb/IIIa inhibitor, and fondaparinux were the hierarchy for treatment safety. 

Results were similar in direct comparison meta-analyses: bivalirudin was associated with a 39%, 44% and 65% higher risk of myocardial infarction, urgent revascularisation and stent thrombosis respectively, when compared with unfractionated heparin with or without GpIIb/IIIa inhibitor. 

However, bivalirudin was associated with a 48% lower risk of major bleeding compared with unfractionated heparin plus GpIIb/IIIa inhibitor and 32% lower compared with unfractionated heparin alone.

The conclusion is that in patients undergoing primary PCI, unfractionated heparin plus GpIIb/IIIa inhibitor and LMWH plus GpIIb/IIIa inhibitor were most efficacious, with the lowest rate of major adverse cardiovascular events, whereas bivalirudin was safest, with the lowest bleeding. These relationships should be considered in selecting anticoagulant therapies in patients undergoing primary PCI.