Factor Xa inhibitors for acute coronary syndromes: Cochrane systematic review

Abstract

Background

The activation of coagulation mechanisms plays a central role in the pathogenesis of acute coronary syndromes (ACS). Administration of unfractionated heparin (UFH) and low molecular weight heparins (LMWH), agents preventing the progression of thrombus formation, is a crucial therapeutic strategy. However, some limitations related to their use have recently stimulated the development of new synthetic agents.

Objectives

To evaluate the clinical efficacy and safety of factor Xa inhibitors for treatment of ACS compared to UFH or LMWH.

Search methods

We searched the Cochrane Central Register of Controlled Trials (CENTRAL) of the Cochrane Library (Issue 1, 2008), PubMed, EMBASE and LILACS as well as the publications from International Congresses and the reference lists of the selected studies in December 2008.

Selection criteria

We used randomized controlled trials (RCTs) comparing factor Xa inhibitors to UFH or LMWH during the course of ACS. Outcome measures included all-cause mortality, myocardial infarction, re-infarction, ischemia recurrence, and adverse events.

Data collection and analysis

The selection, quality assessment and data extraction of the included trials were done independently by two authors and disagreements were resolved by consensus. Data were analysed by the use of risk ratio (RR) with 95% confidence interval (CI), and the numbers needed to treat (NNT) were reported as needed.

Main results

A total of four RCTs involving 27,976 subjects were included. Fondaparinux was the only factor Xa inhibitor identified in our included RCTs. Fondaparinux appeared to be related to a lower risk in all-cause mortality at 90 to 180 days (RR 0.89; 95% CI 0.81 to 0.97), especially in the group where enoxaparin (a LMWH) was the control drug. Fondaparinux was also associated with a lower risk in major and minor bleeding at 30 days compared to enoxaparin (RR 0.63, 95% CI 0.55 to 0.73; RR 0.34, 95% CI 0.28 to 0.43, respectively), but not when compared to UFHs (RR 1.41; 95% CI 0.49 to 4.10; RR 0.70, 95% CI 0.14 to 3.39 respectively).

Authors' conclusions

The therapeutic efficacy of factor Xa inhibitors in ACS seemed to be related to a reduced risk in all-cause mortality at 90 to 180 days, with a better safety profile than enoxaparin in terms of reduce incidence of major and minor bleeding.

Author(s)

Brito Viviana, Ciapponi Agustín, Kwong Joey

Summary

Factor Xa inhibitors for acute coronary syndromes

The use of unfractionated heparin and low molecular weight heparins greatly reduces the risk of mortality and morbidity in acute coronary syndromes. However, their use has been associated with a risk of adverse events such as major bleeding, which has prompted researchers to seek safer alternative anticoagulants such as the synthetic inhibitors of the Xa factor - a crucial enzyme in the coagulation cascade. We systematically reviewed efficacy and safety of factor Xa inhibitors in treating acute coronary syndromes when compared to unfractionated heparins or low molecular weight heparins. A total of four trials involving 27,976 subjects was included. Xa inhibitors reduced all-cause mortality at 30 days, with the effect becoming more significant at 180 days. However, no significant differences were observed in the incidence of myocardial infarction or reinfarction at 30 days. Factor Xa inhibitors were found to be safer than enoxaparin, a low molecular weight heparin, due to reduced incidences of major and minor bleeding at 30 patients in patients receiving conservative treatment.

Reviewer's Conclusions

Implications for practice

The findings of this systematic review suggest that administration of fondaparinux appeared to be at least as effective as UFH and enoxaparin in ACS, with the added benefit of a reduced risk of long-term mortality at six months and reduced rates of adverse effects (major and minor bleeding). However, we need to emphasize that more evidence, specifically about their clinical and safety profile in populations with a higher risk of thrombotic or bleeding complications (e.g. those receiving concomitant treatment with drugs affecting the coagulation process, those undergoing revascularization and the elderly), are required (Alexander 2007a; Alexander 2007b; Maan 2009).

Implications for research

New clinical trials, some of them on development, evaluating the following items should be considered:

  • The efficacy and safety of the use of the factor Xa inhibitors associated with glycoprotein (GP) IIa/IIIb inhibitors, in order to explore their safety profile when they are combined with drugs which could also affect platelet aggregation and so interfere with the coagulation process
  • Fatal and non-fatal outcomes related to the use of factor Xa inhibitors in patients undergoing to revascularization therapy, especially PCI, and in subgroups with increased risk of bleeding such as the elderly
  • Head-to-head studies on the efficacy and safety of the different types of factor Xa inhibitors (direct and indirect), in order to investigate potential relationship between their clinical efficacy and safety profiles and drug types.

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