The Impact of Haemorrhagic Complications on Mortality in Acute Coronary Syndromes - Implications for Anticoagulant Selection

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Non-ST-segment elevation (NSTE) acute coronary syndromes (ACS) include unstable angina (UA) and NSTE myocardial infarction (NSTEMI), and account for one and a half million hospitalisations in the US annually. Patients with ACS are typically managed by initial medical stabilisation followed by an early invasive approach, whereby cardiac catheterisation is performed, usually within 24 hours of admission. Based upon the results of cardiac catheterisation and other clinical factors, the majority of patients subsequently undergo revascularisation, either with percutaneous coronary intervention (PCI) or, less commonly, with coronary artery bypass surgery (CABG). Because of the critical role of thrombus formation and platelet aggregation in the pathophysiology of ACS, therapy targeted at inhibition of the coagulation cascade and platelets is important, both in the initial medical stabilisation and subsequent revascularisation. Although anticoagulants reduce rates of ischaemic events, they increase the risk of haemorrhagic complications. Recently, haemorrhagic complications have been associated with an increase in short- and long-term adverse outcomes, including mortality. Future advances in anticoagulants will need to focus on:

  • reducing ischaemic event rates;
  • minimising haemorrhagic complication rates; and
  • achieving compatibility with the early invasive approach with subsequent PCI that is commonly employed in patients with ACS.
Anticoagulant Therapy

Intravenous anticoagulant therapy is a key component of the pharmacologic management of nearly all patients with ACS. An agent initiated in the initial medical stabilisation phase and consistently maintained through cardiac catheterisation and revascularisation appears desirable, as it may further reduce ischaemic events and perhaps favourably influence the incidence of haemorrhagic complications.

The pathophysiology of ACS typically involves a disrupted atherosclerotic plaque with activation of the coagulation cascade and platelets, leading to thrombus formation and compromise of myocardial blood supply. Thrombin (Factor IIa), a serine protease generated at sites of vascular injury, is central in this process and converts fibrinogen (Factor I) to fibrin (Ia) and activates Factors V, VIII, XI, and XIII.15 In part, these result in the generation of more thrombin by a positive feedback mechanism. Thrombin is also a highly potent platelet activator.

Beyond its effects on clotting and platelets, thrombin elicits a host of responses in the vascular endothelium including shape and permeability changes, mobilisation of adhesive molecules to the endothelial surface and stimulation of autocoid and cytokine production. Thrombin is chemotactic for monocytes and mitogenic for lymphocytes and mesenchymal cells. Patients with ACS are further classified, based upon the presence or absence of myocardial injury as detected by the release of cardiac markers. In both NSTEMI and UA, the resultant thrombus is usually non-occlusive. The broader classification of ACS (beyond the scope of this paper) includes STEMI, which most commonly results from an occlusive thrombus and is frequently associated with transmural myocardial injury.

Unfractionated heparin (UFH) is an indirect antithrombin that inactivates thrombin, Factor Xa and other clotting factors. Several limitations of UFH prevent it from being an ideal anti-thrombin. These unfavourable characteristics have incited the development of superior agents.

Enoxaparin, a low-molecular-weight heparin (LMWH), is also an indirect antithrombin that inhibits thrombin, Factor Xa and other clotting factors. However, enoxaparin has a reduced anti-thrombin activity relative to anti-Factor Xa activity, compared with UFH. In the Efficacy and Safety of Subcutaneous Enoxaparin in Unstable Angina and Non-Q-Wave MI (ESSENCE) trial of 3,171 patients with unstable coronary artery disease (CAD), enoxaparin was associated with a significant reduction in the composite end-point of death, MI or recurrent angina at 14 days when compared with UFH. However, overall bleeding was significantly higher in the enoxaparin group compared with UFH. Although LMWH has fewer limitations than UFH, it retains some of the shortcomings of UFH, and may have s ome of its own.

Fondaparinux is a synthetic pentasaccharide that is a selective inhibitor of Factor Xa and has a half-life of 15 hours. Fondaparinux (like UFH and LMWH) is an indirect inhibitor that also requires anti-thrombin III (ATIII) to exert its effect. In the Pentasaccharide in Unstable Angina (PENTUA) (dose-finding) study, patients with ACS treated with four incremental doses of fondaparinux had similar ischaemic event rates at nine days compared with those treated with enoxaparin. No significant differences in major or minor bleeding were observed between the four fondaparinux groups and enoxaparin.

Bivalirudin, a direct thrombin inhibitor with a half-life of 25 minutes, does not have the unique limitations of indirect antithrombins such as UFH, LMWH and fondaparinux. Bivalirudin is not dependent upon ATIII, is not associated with heparin-induced thrombocyloptaenia (HIT), and is approved for use in patients with, or at risk of, HIT undergoing PCI, in addition to its other indications in PCI. In the Bivalirudin Angioplasty Trial, Bittl et al. reported that bivalirudin significantly reduced the combination of death, MI or revascularisation by 22% at seven days when compared with UFH in 4,312 patients with unstable angina undergoing coronary angioplasty. Importantly, bivalirudin also significantly reduced clinically significant bleeding by 66% compared with UFH. This ability to achieve lower rates of ischaemic and haemorrhagic events with bivalirudin was somewhat unique compared with other studies, which appeared to suggest an inverse relationship between ischaemic event reduction (efficacy) and the risk of haemorrhagic complications (safety).

Eptifibatide is a platelet glycoprotein IIb/IIIa inhibitor (GPI), and is effective in reducing ischaemic event rates when used in combination with UFH (compared with UFH monotherapy); however, this combination is associated with increased rates of haemorrhagic complications. In the 10,948 patients with ACS in the Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) trial, combination therapy with eptifibatide plus UFH resulted in a significant 1.5% absolute reduction in a composite end-point of death and non-fatal MI at 30 days compared with UFH monotherapy; however, this reduction was offset by a significant 1.5% absolute increase in rates of Thrombolysis in Myocardial Infarction (TIMI) major bleeding.

Haemorrhagic Complications

The benefit of an anticoagulant in reducing ischaemic events in patients with ACS must be balanced by its risk of increasing haemorrhagic complications. As ischaemic event rates decline, the relative importance of the haemorrhagic risk of therapy becomes more important. In addition to direct patient risks, haemorrhagic complications also increase the length and cost of hospitalisation.

Recent registry and retrospective analyses have reported the frequency and independent predictors of haemorrhagic complications in ACS. In the Global Registry of Acute Coronary Events (GRACE) registry of 24,045 patients with ACS, the overall rate of major bleeding was 3.9%. Factors independently associated with a higher risk of major bleeding included: advanced age, female gender, lower blood pressure, history of bleeding, history of renal insufficiency and use of a GPI. A recent review by Eikelboom et al. found patients with major bleeding were more likely to be older, have diabetes, a history of stroke, lower blood pressure, higher serum creatinine and ST-segment changes on presenting electrocardiogram (ECG).

Comparisons between ACS trials with regard to haemorrhagic predictors, rates and the impact of haemorrhage on outcomes including mortality is difficult, as many definitions are used. In addition, these differences may impact whether the severity of bleeding impacts outcomes. Most definitions of haemorrhage include occult declines in haemoglobin, overt bleeding, bleeding requiring surgical intervention and blood product transfusion. Transfusion rates in ACS trials vary widely, and carry intrinsic risks. Sites of bleeding are numerous, and in the GRACE registry were most commonly gastrointestinal or at the vascular access site, and less commonly retroperitoneal or genitourinary.

There is an increasing body of data supporting the association between haemorrhagic complications and short- and long-term mortality. In the GRACE registry, patients with major bleeding had significantly higher rates of in-hospital death than those without major bleeding. After adjusting for confounding variables, major bleeding remained associated with an increased risk of in-hospital death. In the analysis of Eikelboom et al., major bleeding was independently associated with an increased hazard of death during the first 30 days (hazard ratio (HR), 5.37; 95% CI, 3.97-7.26; p<0.0001) as well as after 30 days (HR, 1.54; 95% CI, 1.01-2.36; p=0.047). In addition, there was an increasing risk of death with increasing severity of bleeding from minor to major to life-threatening bleeding (p for trend=0.0009).

Recent Trials

Three recent, large trials have prospectively assessed ischaemic and haemorrhagic outcomes in patients with ACS. Two of these trials also reported ischaemic and haemorrhagic event rates as a combined efficacy and safety end-point described as 'net clinical outcome' or 'balance of benefit and risk'.

In the Superior Yield of the New strategy of Enoxaparin, Revascularization and GlYcoprotein IIb/IIIa inhibitors (SYNERGY) trial, indicate that, when compared with UFH in ACS:

  • enoxaparin was not more effective at reducing composite ischaemic events; and
  • enoxaparin resulted in significantly higher rates of TIMI major bleeding.

In the OASIS-5 trial, the overall results indicate that, compared with enoxaparin, fondaparinux was not more effective at reducing composite ischaemic events, but did result in lower rates of major bleeding and lower rates of mortality at 30 and 180 days.

The Acute Catheterization and Urgent Intervention Triage strategY (ACUITY) trial compared 13,819 moderate or high-risk patients with ACS who were treated with one of three anticoagulant regimens.

The results, which are currently pending publication, were presented by Gregg W Stone at the Annual Scientific Session of the American College of Cardiology in Atlanta in March 2006. The authors' unpublished analyses from ACUITY indicate that major bleeding and transfusion are independent predictors of early mortality, underscoring the importance of these issues in optimising outcomes. These encouraging results from ACUITY indicate that bivalirudin monotherapy results in similar ischaemic event rates as combination therapy with heparin (UFH or enoxaparin) plus GPI and results in significantly lower rates of haemorrhagic complications including transfusion.



A growing body of data supports an association between haemorrhagic complications and an increased risk of adverse outcomes, including mortality. In addition, there is a direct relationship between the severity of bleeding (from minor to life-threatening) and the risk of mortality. Recent data also suggest that a reduction in rates of haemorrhagic events may be associated with a lower risk of mortality. Bleeding complications are associated with an increased risk of blood product transfusion (with its inherent risks, including an increase in mortality), as well as an increased cost and length of hospitalisation. The extensive list of the predictors of bleeding, including: age, female gender, anaemia, renal insufficiency, history of bleeding, diabetes, and the use of a GPI, implies that a large proportion of patients with ACS are at an increased risk of haemorrhagic complications.

Although a reduction in the rate of ischaemic events with anticoagulant therapy has traditionally been associated with an increase in haemorrhagic complications, recent data with newer agents such as bivalirudin and fondaparinux indicate that this is no longer the case, and that efficacy and safety can be achieved simultaneously. Given these findings, it is prudent to select an anticoagulant that fulfills the following criteria:

  • comparable efficacy to 'gold-standard' regimens in reducing ischaemic events;
  • superiority in minimising haemorrhagic complications; and
  • the ability to seamlessly integrate into the early invasive approach, in which PCI is most commonly employed.

Until comparative data are available, the authors conclude that although the ACUITY and OASIS- 5 trials suggest that bivalirudin or fondaparinux may be highly attractive for patients with ACS, the data favour bivalirudin, because of its comparable efficacy to heparin plus GPI, low haemorrhagic risk and extensive experience in PCI - as demonstrated in the Randomized Evaluation in Coronary Intervention Linking Angiomax to Reduced Clinical Events (REPLACE)-2 trial, which reported similar findings in over 6,000 patients undergoing elective or urgent PCI.

A version of this article containing references and figures can be found in the Reference Section on the website supporting this briefing (