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 1.5 million hospitalizations in the US annually.1 Patients with ACS are typically managed by initial medical stabilization followed by an early invasive approach, whereby cardiac catheterization is performed, usually within 24 hours of admission. Based upon the results of cardiac catheterization and other clinical factors, the majority of patients subsequently undergo revascularization, either with percutaneous coronary intervention (PCI) or, less commonly, with coronary artery bypass surgery (CABG). Due to 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 stabilization and subsequent revascularization. Although anticoagulants reduce rates of ischemic events, they increase the risk of hemorrhagic complications.2-7 Recently, hemorrhagic complications have been associated with an increase in short- and long-term adverse outcomes, including mortality.5,8-11 Future advances in anticoagulants will need to focus on:

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

Management Strat egy

The American College of Cardiology (ACC)/ American Heart Association (AHA) 2002 Guideline Update for the Management of Patients With Unstable Angina and Non-ST-Segment Elevation Myocardial Infarction supports a strategy of standard medical therapy and either an early invasive approach (early, routine cardiac catheterization) or an early conservative approach (deferred, selective cardiac catheterization).12 Clinical factors, including a risk assessment, help determine which strategy should be employed and, after incorporating the results of cardiac catheterization, revascularization (either with PCI or CABG) or on-going medical therapy is recommended. The recent Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes with Early Implementation of the ACC/AHA Guidelines (CRUSADE) Registry analysis of 56,352 patients with ACS confirmed that patients are commonly managed by an early invasive approach followed by PCI.13 Among patients who presented on a weekday, 73% underwent cardiac catheterization, with a median time from presentation to cardiac catheterization of 23.4 hours. Of these patients, 17.3% underwent cardiac catheterization within six hours, 22.5% within 12 hours, 39.3% within 24 hours, and 54.8% within 48 hours.

In addition, the majority of these patients underwent revascularization, with PCI in 42% (median time 22.6 hours) and CABG in 13.4% (median time 69.9 hours). Interestingly, although patients who presented on a weekend had a significantly longer median time to cardiac catheterization than patients who presented on a weekday (46.3 versus 23.4 hours, p<0.0001), the overall frequencies of cardiac catheterization, revascularization, and in-hospital adverse events were similar.

Anticoagulant Therapy

Intravenous anticoagulant therapy is a key component of the pharmacologic management of nearly all patients with ACS, regardless of whether the early management strategy is invasive or conservative, the subsequent management strategy involves revascularization or medical therapy, and the revascularization technique utilised is PCI or CABG. This therapy is typically initiated upon presentation in the pre-procedural medical stabilization phase and continued or modified during the peri-procedural phase of PCI and CABG. An agent initiated in the initial medical stabilization phase and consistently maintained through cardiac catheterization and revascularization appears desirable, as it may further reduce ischemic events and perhaps favorably influence the incidence of hemorrhagic complications.14

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, mobilization 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 (see Figure 1). Patients with ACS are further classified, based upon the presence (NSTEMI) or absence (UA) 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. In a study from nearly 20 years ago,Theroux et al. reported that heparin was associated with a significant decrease in the risk of MI and refractory angina compared with placebo in 479 patients with acute unstable angina.16 Several limitations of UFH prevent it from being an ideal antithrombin, from both the efficacy and safety standpoint, such as dependence on circulating anti-thrombin III (ATIII), unpredictable pharmacokinetic and pharmacodynamic properties, binding to plasma proteins, a reduced ability to inhibit fibrin-bound thrombin, platelet activation, and heparin-induced thrombocytopenia (HIT).17-19 These unfavorable characteristics have incited the development of superior agents.20

Enoxaparin, a low-molecular-weight heparin (LMWH), is also an indirect anti-thrombin 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 (16.6% versus 19.8%; p=0.019). However, overall bleeding was significantly higher in the enoxaparin group compared with UFH (18.4% versus 14.2%; p=0.001).21 Although LMWH has fewer limitations than UFH, it retains some of the shortcomings of UFH (such as HIT), and may have some of its own.22

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 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 (2.5-12mg subcutaneously once-daily) had similar ischemic 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.23

Bivalirudin, a direct thrombin inhibitor with a half-life of 25 minutes, does not have the unique limitations of indirect anti-thrombins, such as UFH, LMWH and fondaparinux.24 Bivalirudin is not dependent upon ATIII, is not associated with 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 revascularization by 22% at seven days (p=0.039) 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 (p<0.001).25 This ability to achieve lower rates of ischemic and hemorrhagic events with bivalirudin (compared with UFH) was somewhat unique compared with other studies, which appeared to suggest an inverse relationship between ischemic event reduction (efficacy) and the risk of hemorrhagic complications (safety).

Eptifibatide is a platelet glycoprotein IIb/IIIa inhibitor (GPI), and is effective in reducing ischemic event rates when used in combination with UFH (compared with UFH monotherapy); however, this combination is associated with increased rates of hemorrhagic 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 (14.2% versus 15.7%; p=0.04); however, this reduction was offset by a significant 1.5% absolute increase in rates of Thrombolysis in Myocardial Infarction (TIMI) major bleeding (10.6% versus 9.1%, p=0.02).26

Hemorrhagic Complications

The benefit of an anticoagulant in reducing ischemic events in patients with ACS must be balanced by its risk of increasing hemorrhagic complications. As ischemic event rates decline (in part due to lower complication rates with contemporary PCI), the relative importance of the hemorrhagic risk of therapy becomes more important. In addition to direct patient risks, hemorrhagic complications also increase the length and cost of hospitalization.27

Recent registry and retrospective analyses have reported the frequency and independent predictors of hemorrhagic complications in ACS. In the Global Registry of Acute Coronary Events (GRACE) registry of 24,045 patients with ACS, including patients with STEMI, the overall rate of major bleeding was 3.9% (see Figure 2).11 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. evaluated 34,146 patients with ACS from the Organization to Assess Ischemic Syndromes (OASIS) registry,OASIS-2, and Clopidogrel in Unstable Angina (CURE) trials and found an overall rate of major bleeding of 2.3%. 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).9

Comparisons between ACS trials with regard to hemorrhagic predictors, rates and the impact of hemorrhage on outcomes including mortality is difficult, as many definitions (TIMI, GUSTO, trialspecific, etc.) are used. In addition, these differences may impact whether the severity (minor, major, life-threatening, etc.) of bleeding impacts outcomes. Most definitions of hemorrhage include occult declines in hemoglobin, overt bleeding, bleeding requiring surgical intervention, and blood product transfusion. Transfusion rates in ACS trials vary widely, and carry intrinsic risks.8 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 hemorrhagic 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 (18.6% versus 5.1%, p<0.001) (see Figure 3). After adjusting for confounding variables, major bleeding remained associated with an increased risk of in-hospital death (adjusted odds ratio (OR) 1.64, 95% confidence interval (CI) 1.18-2.28). 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 ischemic and hemorrhagic outcomes in patients with ACS. Two of these trials also reported ischemic and hemorrhagic event rates as a combined efficacy and safety end-point described as 'net clinical outcomeÔÇÖ or 'balance of benefit and riskÔÇÖ.

In the Superior Yield of the New strategy of Enoxaparin, Revascularization and GlYcoprotein IIb/IIIa inhibitors (SYNERGY) trial, 10,027 patients with high-risk ACS were randomly assigned to enoxaparin or UFH.28 The primary composite ischemic end-point of all-cause death or non-fatal MI during the first 30 days was similar in patients treated with enoxaparin and UFH (14.0% versus 14.5%; OR, 0.96; 95% CI, 0.86-1.06). Although enoxaparin was not associated with a reduction in ischemic event rates, it was associated with significantly higher rates of TIMI major bleeding (9.1% versus 7.6, p=0.008), and higher trends in GUSTO severe bleeding (2.7% versus 2.2%, p=0.08) and transfusions (17.0% versus 16.0%, p=0.16) compared with patients treated with UFH. The overall results of the SYNERGY trial indicate that, when compared with UFH in ACS:

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

In the OASIS-5 trial, 20,078 patients with ACS were randomized to fondaparinux (2.5mg subcutaneously once daily) or enoxaparin.29 The primary composite ischemic end-point of death, MI or refractory ischemia at nine days was similar in patients treated with fondaparinux and enoxaparin (5.8% versus 5.7%; HR, 1.01; 95% CI, 0.90-1.13). However, rates of major bleeding at nine days were significantly lower for fondaparinux than for enoxaparin (2.2% versus 4.1%; HR, 0.52; p<0.001). When the primary composite ischemic end-point and major bleeding were combined (balance of benefit and risk), event rates significantly favored fondaparinux over enoxaparin (7.3% versus 9.0%; HR, 0.81; p<0.001). Mortality was also significantly lower in patients treated with fondaparinux at 30 days (2.9% versus 3.5%, p=0.02) and at 180 days (5.8% versus 6.5%, p=0.05). Major bleeding was associated with significantly higher rates of death (13.2% versus 2.8%), reinfarction (11.9% versus 3.6%), and stroke (3.5% versus 0.7%, p<0.001 for all), compared with patients without bleeding.The overall results of OASIS-5 indicate that, compared with enoxaparin, fondaparinux was not more effective at reducing composite ischemic events, but did result in lower rates of major bleeding and lower rates of mortality at 30 and 180 days.

These results suggest the possibility that a reduction in hemorrhagic complications may be associated with a reduction in mortality. These favourable bleeding and mortality results with fondaparinux in OASIS-5 should be interpreted with the understanding that the comparison was with enoxaparin, which in the SYNERGY trial did not have greater efficacy than UFH and resulted in higher rates of major bleeding. Data comparing fondaparinux to bivalirudin monotherapy or combination heparin and GPI therapy will help clarify its relative efficacy and safety compared with these other regimens. In addition, fondaparinux is not currently approved for use in PCI.

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:

  • heparin (either UFH or enoxaparin) plus GPI;
  • bivalirudin plus GPI; or
  • bivalirudin monotherapy.30

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. Patients treated with bivalirudin monotherapy had similar composite ischemic event rates at 30 days (7.8% versus 7.3%, p=not significant), and significantly lower rates of non-CABG major bleeding (3.0 % versus 5.7%, p<0.0001) and minor bleeding (12.8% versus 21.6%, p<0.001) as patients treated with heparin plus GPI. When the ischemic composite and major bleeding were combined (net clinical outcome), event rates were significantly lower with bivalirudin monotherapy (10.1% versus 11.7%, p=0.015) compared with combination therapy with heparin plus GPI. The authorsÔÇÖ unpublished analyses from ACUITY indicate that major bleeding and transfusion are independent predictors of early (30-day) mortality, underscoring the importance of these issues in optimizing outcomes. These encouraging results from ACUITY indicate that bivalirudin monotherapy results in similar ischemic event rates as combination therapy with heparin (UFH or enoxaparin) plus GPI, and results in significantly lower rates of hemorrhagic complications including transfusion.

Conclusion

A growing body of data supports an association between hemorrhagic 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 hemorrhagic 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 hospitalization. The extensive list of the predictors of bleeding, including: age, female gender, anemia, 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 hemorrhagic complications.31

Although a reduction in the rate of ischemic events with anticoagulant therapy has traditionally been associated with an increase in hemorrhagic 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 fulfils the following criteria:

  • comparable efficacy to 'gold-standardÔÇÖ regimens in reducing ischemic events;
  • superiority in minimizing hemorrhagic 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 hemorrhagic risk and extensive experience in PCIÔÇöas 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.6 

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