Immediate Pharmacology in the Current Era of Reperfusion Therapy

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Acknowledgements:The authors would like to thank Barbara Semb for expert secretarial assistance.

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Effective translation of reperfusion therapy to mortality reductions in ST-segment elevation myocardial infarction (STEMI) remains both time-critical in its implementation and dependent on optimal antithrombotic therapy. Innumerable clinical studies have explored several antithrombin and antiplatelet therapies in the immediate management of STEMI. With the wide array of the therapies now available, the choice of agents initiated before reperfusion in the context of both catheter-based and pharmacologic reperfusion needs to be rational and evidence-based. Furthermore, with an apparent ceiling in mortality benefit observed in clinical trials, benefits in terms of reduced recurrent myocardial infarction (MI) and reduced bleeding events become increasingly important considerations.

Before considering the evidence supporting the various pharmacotherapies, it is useful to review the goals of reperfusion therapy for STEMI. Emergent restoration of epicardial, and therefore myocardial, blood flow is aimed at preservation of cardiac muscle integrity and electrical stability, hopefully leading to reductions in death. In achieving this goal, both catheter-based and pharmacologic reperfusion have recognised limitations. These include: an apparent ceiling in efficacy in terms of mortality reduction; attenuated benefit due to re-infarction; bleeding complications including catastrophic events such as intracerebral hemorrhage; and often, inability to achieve timely access for all patients, particularly when considering primary percutaneous coronary intervention (PCI). Hence, innovations in adjunctive pharmacology in this context need to address at least one of these limitations, and ideally all of them.

Beginning in the era of fibrinolysis, adjunctive antiplatelet therapy with aspirin has been established as a cornerstone of effective reperfusion.This evidence has led to the exploration of more robust approaches to antiplatelet therapy as an adjunct to both catheter-based and pharmacologic reperfusion. Initial studies with abciximab, an intravenous (IV) glycoprotein IIb/IIIa inhibitor, demonstrate robust reductions in the composite of death and MI by 30 days and six months, with modest increases in bleeding events among patients undergoing PCI.1 While the data with abciximab has been mixed, especially within trials of relatively low-risk STEMI patients, meta-analysis of the entire clinical trial experience of 27,115 patients suggests that a 1% absolute reduction in mortality is achieved compared with placebo (abciximab: 2.4% versus 3.4%, p=0.047) by 30 days in the context of catheter-based reperfusion with benefits sustained in late follow-up.2,3 Appropriately controlled comparative data with the small molecule intravenous glycoprotein IIb/IIIa inhibitors eptifibatide and tirofiban are currently lacking, though improvements in perfusion are reported.4

In contrast, the evidence for combining abciximab and eptifibatide with either full-dose or half-dose fibrinolysis suggests improved rates and initial restoration of epicardial blood flow, but no reductions in mortality and an increased risk of bleeding events.5,6 Hence, these combined approaches to pharmacologic reperfusion cannot be recommended.

More recent evidence with clopidogrel, a thienopyridine adenosine diphosphate (ADP) antagonist, has rekindled interest in the dual antiplatelet approach as adjunctive pharmacology for fibrinolysis. In the Clopidogrel as Adjunctive Reperfusion Therapy (CLARITY) trial, a 300 mg loading dose of clopidogrel followed by a 75 mg daily dose was associated with an improvement in coronary artery patency at 3.5 days (and death or MI before angiography) (0.64, 95% confidence interval (CI) 0.53-0.76, p<0.001), with reductions in recurrent MI and recurrent ischemia without an overall reduction in death.7 Supporting these data is the large-scale clinical experience among 45,852 STEMI patients in China. Despite the fact that only ~54% of patients received fibrinolytic therapy, clopidogrel in addition to aspirin was associated with a 7% reduction in all-cause mortality (odds ratio 0.93, 95% CI 0.87-0.99, p=0.03).8 In contradistinction to the intravenous glycoprotein IIb/IIIa inhibitor experience, adequately designed and powered studies of administration of clopidogrel prior to primary PCI have not been conducted. While the use of dual antiplatelet therapy following stent placement has become routine, whether upfront or even pre-hospital administration of large clopidogrel loading doses among patients destined for primary PCI leads to incremental reductions in death or MI is unknown and may not be expected given the relatively delayed onset of action (> 2-3 hours).

Innovations in antithrombin therapies in the management of STEMI have demonstrated reductions in MI, but reductions in short-term mortality remains elusive and bleeding has increased. Extending the experience of enoxaparin, an indirect inhibitor of thrombin and factor X through its interaction with antithrombin, in non-ST-segment acute coronary syndrome (ACS) to the management of STEMI patients undergoing fibrinolysis in the Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial Infarction Treatment (EXTRACT) trial demonstrates a 17% reduction in the 30-day rate of death or nonfatal MI (odds ratio 0.87, CI 0.77-0.90, p<0.001), with this difference largely driven by reductions in non-fatal MI.9 These benefits were achieved with a modest increase in bleeding (heparin 1.4% versus enoxaparin 2.1%, p<0.001). In the EXTRACT study the dose of enoxaparin was adjusted in the elderly with elimination of the 30 mg intravenous bolus of enoxaparin and reduction of the twice-daily regimen of 1 mg/kg enoxaparin given subcutaneously (SC) to 0.75 mg/kg twice daily.

The relative reduction in death and MI with enoxaparin in the elderly was reduced to attenuated (6%), but because of the substantially higher risk in elderly patients, the absolute risk reduction was similar to that seen in younger patients. Importantly, bleeding rates, including intracranial hemorrhage rates, were similar in patients randomized to unfractionated heparin or to enoxaparin. In EXTRACT a once-daily regimen was also used in patients with a creatinine clearance of <30 ml/minute. Interestingly, no benefit with enoxaparin was seen among patients not undergoing reperfusion therapy in a well-powered randomised trial.10 Evidence of a benefit of enoxaparin among patients receiving catheter-based reperfusion is currently limited to uncontrolled studies though these appear to suggest that the practice is feasible and provides reasonable anti-Xa levels.11

Data with fondaparinux, a long-acting factor Xa inhibitor, also demonstrate advantages among patients presenting with STEMI. This agent was studied in the Organization for the Assessment of Strategies for Ischemic Syndromes (OASIS)-6 study in patients with STEMI. In a complex study including a stratified randomisation based on the intent to use unfractionated heparin, fondaparinux was associated with an overall 14% relative risk reduction or 1.5% absolute risk reduction (11.6% versus 9.7%, p<0.008) in death or non-fatal MI at 30 days.12 A significant early 0.9% absolute mortality benefit was also observed with this benefit persisting throughout the six-month follow-up. While bleeding rates were lower in the fondaparinux group, this benefit did not reach statistical significance, in contrast to the OASIS-5 study in patients with non-ST elevation MI.13 Furthermore, significant heterogeneity was seen in the results depending on the form of reperfusion therapy undertaken. Among patients receiving no reperfusion and those receiving fibrinolysis, fondaparinux was associated with significant and comparable benefit with hazard ratios for death or MI of 0.8 (95% CI 0.65-0.98, p=0.003) and 0.759 (95% CI 0.68-0.92, p=0.003), respectively. However, among those undergoing primary PCI, a non-significant excess risk was observed (4.9% unfractionated heparin versus 6% fondaparinux; HR 1.24, 95% CI 0.95-1.63, p=0.12; p for heterogeneity = 0.04). The mechanism of this difference is unclear, but may be related to the lower risk of this subpopulation and an increased risk of catheter thrombosis. Hence, while the data for this agent among patients undergoing pharmacologic reperfusion is strong, there appears to be little role for fondaparinux in catheter-based reperfusion.

Recent years have seen a resurgence in interest in the use of direct thrombin inhibition for the management of patients with ACS undergoing PCI. Early studies focused on the adjunctive role of recombinant hirudin and bivalirudin among patients undergoing fibrinolysis with no benefits in terms of mortality observed.14,15 While not evident with recombinant hirudin, bivalirudin, in the context of adjunctive therapy with streptokinase, was associated with a reduction in recurrent MI (HR 0.7, 95% CI 0.56-0.87, p=0.001) and modest increases in bleeding when compared with unfractionated heparin in the 17,073 patient study: Hirulog and Early Reperfusion or Occlusion (HERO)-2 Trial.14 Randomized trial evidence with primary PCI is currently confined to the Global Use of Strategies to Open Occluded Arteries (GUSTO) IIb angioplasty sub-study where patients undergoing primary PCI in the era before stenting are allocated to either hirudin or unfractionated heparin. Among the 503 patients in this study, a non-significant 23% reduction (p=0.37) in the 30-day incidence of death, recurrent MI or stroke, with no excess in bleeding, was observed.16 In the current era of coronary stenting, a randomized clinical trial with bivalirudin in primary PCI (HORIZONS) is on-going and contemporary evidence is limited to single-center registries suggesting the use of this agent is feasible.17

The key challenge to the clinician undertaking reperfusion is the integration of these data into effective clinical practice. Clearly impacting the choices is the form of reperfusion most commonly undertaken.

Within the context of fibrinolysis, intensifying antiplatelet therapy with clopidogrel in addition to aspirin provides incremental benefits in terms of recurrent MI and probably mortality and does not compromise safety if rescue PCI is required. Furthermore, more novel antithrombin approaches with enoxaparin, fondaparinux or bivalirudin are associated with some ischemic advantages, largely in recurrent MI, with less bleeding seen with fondaparinux. Whether enoxaparin and bivalirudin are more efficacious or safer options if rescue PCI is required may be postulated based on the observations seen in patients with non-ST-elevation ACS18-20 though direct supportive evidence for the concept is currently lacking. Among patients undergoing primary PCI, current evidence supports the use of abciximab started as early as possible, with the role of initial clopidogrel loading before PCI currently being undefined.

However, such practice seems reasonable, given the limited disadvantages of such an approach in terms of bleeding, and the infrequent requirement for urgent coronary artery bypass grafting (CABG) in the context of reperfusion therapy. No definitive advantages with the novel antithrombin approaches in primary PCI have yet been clarified. Such benefits should not be inferred from the trials with fibrinolysis, due to the greater impact of these agents on recurrent MI and the lower rates of this event following primary PCI compared with fibrinolysis. Whether the early initiation of these antithrombin therapies will extend the window of benefit and therefore allow improved access to primary PCI needs further exploration. Nevertheless, the over-arching consideration is the effective incorporation of these agents, whichever choices are made, into effective and timely systems of care in order to realize the clinical benefits promised by the randomized trial data.


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