Despite a solid conceptual basis for pharmaco-mechanical perfusion of patients with ST-elevation myocardial infarction (STEMI), the role of fibrinolytic therapy in combination with percutaneous coronary intervention (PCI) appears highly questionable.

Most recently, the ASSENT-4 trial comparing primary PCI with PCI facilitated by tenecteplase (TNK) was terminated early as a result of excess mortality and adverse events in the facilitated arm at 30 days.¹ However, in the recent CAPITAL AMI study, 170 patients randomized to receive thrombolysis with TNK or TNK-facilitated PCI showed a significant reduction in the composite primary end point of death, reinfarction, recurrent ischemia, or stroke at 6 months.²

Current guidelines recommend that patients with non-ST-elevation acute coronary syndromes (NSTE-ACS) be managed with an invasive strategy. A recent meta-analysis of 7 randomized trials involving more than 9000 patients by Mehta et al showed a significant 18% reduction in death or MI and a 34% reduction in rehospitalization for acute cardiac ischemia when a routine versus a selective invasive strategy was employed in NSTE-ACS patients.³ Fox et al showed a comparable reduction in death or MI (26%) with a routine invasive strategy, again consistent with current guidelines.⁴ Nevertheless, ICTUS, the most recently reported trial, showed no benefit for the routine invasive strategy, suggesting that a rethinking of treatment strategy may be required.⁵

Anticoagulant therapy is essential in the management of patients with NSTE-ACS. Agents such as unfractionated heparin (UFH) and low-molecular-weight heparins (LMWHs) inactivate thrombin via anti-IIa and anti-Xa activity, whereas newer direct thrombin inhibitors have anti-Xa activity alone. The Michelangelo OASIS-5 trial compared the LMWH enoxaparin with the synthetic factor Xa inhibitor fondaparinux in more than 20,000 patients with NSTE-ACS.⁶ At day 9, the incidence of the primary composite efficacy end point (death, MI, and refractory ischemia) was the same in both groups. However, patients in the fondaparinux group had a significant 48% reduction in major bleeding, as well as an 11% reduction in mortality at 6 months. In addition, there appeared to have been issues with the doses of enoxaparin used in the study, and the full paper is needed to establish the validity of these data.

References
1. van de Werf F et al. ASSENT-4 PCI – the assessment of safety and efficacy of a new treatment strategy for acute myocardial infarction. European Society of Cardiology 2005 Hotline session.
2. Le May MR, Wells GA, Labinaz M, et al. Combined angioplasty and pharmacological intervention versus thrombolysis alone in acute myocardial infarction (CAPITAL AMI Study). J Am Coll Cardiol. 2005;46:417–424.
3. Mehta SR, Cannon CP, Fox KA, et al. Routine vs selective invasive strategies in patients with acute coronary syndromes: a collaborative meta-analysis of randomized trials. JAMA. 2005;293:2908–2917.
4. Fox KA, Poole-Wilson P, Clayton TC, et al. 5-year outcome of an interventional strategy in non-ST-elevation acute coronary syndrome: the British Heart Foundation RITA 3 randomised trial. Lancet. 2005;366:914–920.
5. de Winter RJ, Windhausen F, Cornel JH, et al, for the Invasive versus Conservative Treatment in Unstable Coronary Syndromes (ICTUS) Investigators. Early invasive versus selectively invasive management for acute coronary syndromes. N Engl J Med. 2005;353:1095–1104.
6. Mehta SR, Yusuf S. Efficacy and safety of fondaparinux compared to enoxaparin in 20,000 high-risk patients with ACS without ST elevation: the OASIS 5 Michelangelo programme. European Society of Cardiology 2005 Podium presentation.

The clinical utility of an agent generally evolves over a series of trials. Six randomized trials have compared enoxaparin and UFH in patients with NSTE-ACS. A recent systematic overview of nearly 22,000 patients by Petersen et al found that 30-day mortality in the intent-to-treat populations was not different in patients treated with enoxaparin compared with UFH (OR 0.996; 95% CI, 0.846–1.173).¹ However, patients treated with enoxaparin had a significant reduction in the incidence of the composite end point of death or MI at 30 days (OR 0.905; 95% CI, 0.826–0.993). Treatment effect was consistent across trials of varying design, with no observed heterogeneity. The analysis found no significant difference either in in-hospital blood transfusion or major bleeding.

The recent OASIS-5 study appeared to show the superiority of fondaparinux over enoxaparin in the treatment of ACS. However, the enoxaparin regimen used in the study may have led to increased bleeding. In the recent SYNERGY study in this setting, UFH and enoxaparin were dosed for 34 and 46 hours, respectively.² In OASIS-5, the average duration of treatment was more than 5 days, which would have exacerbated any accumulation due to reduced renal function. There may have also been issues with adding UFH therapy to patients undergoing PCI. In addition, patients stayed in the hospital for 9 days, which does not reflect contemporary management practices. Dr Pollack concluded that the full OASIS-5 paper is needed to allow further interpretation of the data.

RESCUE-ACS is a prospective, open-label, randomized, parallel-group study involving initiation of antithrombin therapy in the emergency department, which intends to provide a comparison between enoxaparin and UFH in NSTE-ACS patients with TIMI risk score >= 4, employing a contemporary management strategy of aggressive antiplatelet therapy and early intervention. In the trial, 560 patients received enoxaparin and 571 received UFH. Of the 1131 patients enrolled, 60% underwent diagnostic angiography within a mean of 2.5 ± 14.7 days following randomization. Mean time to PCI was 69 hours from randomization. Full results will be available for this study soon.

References
1. Petersen JL, Mahaffey KW, Hasselblad V, et al. Efficacy and bleeding complications among patients randomized to enoxaparin or unfractionated heparin for antithrombin therapy in non-ST-segment elevation acute coronary syndromes: a systematic overview. JAMA. 2004;292:89–96.
2. Ferguson JJ, Mahaffey KW, Huang Y, et al, for the SYNERGY Investigators. Enoxaparin versus unfractionated heparin: consequences of treatment duration on efficacy and safety in SYNERGY [abstract]. J Am Coll Cardiol. 2005;45(3, suppl A):231A.

STEEPLE is the first large-scale, prospective, open-label, randomized, controlled clinical trial comparing intravenous enoxaparin with UFH in the catheterization laboratory.¹ In this multicenter study, 3528 patients undergoing nonemergent PCI were randomized to receive IV enoxaparin (0.5 mg/kg or 0.75 mg/kg) or a UFH regimen adjusted to activated clotting time (ACT), stratified by physician selection of glycoprotein (GP) IIb/IIIa inhibition. The primary end point was the incidence of major and minor bleeding not related to coronary-artery bypass grafting (CABG) up to 48 hours following index PCI.

The primary end point of non-CABG-related bleeding was significantly lower with enoxaparin 0.5 mg/kg (P = 0.014), with rates of 6.0%, 6.6%, and 8.7% for enoxaparin 0.5, enoxaparin 0.75, and UFH, respectively. The main secondary end point was the percentage of patients who had target anticoagulation levels at the beginning and end of the procedure. This was significantly better with both enoxaparin groups than with UFH, with 78.8%, 91.7%, and 19.7% of patients achieving target anticoagulation levels at both time points with enoxaparin 0.5, enoxaparin 0.75, and UFH, respectively (P < 0.0001 for both comparisons). A secondary efficacy end point was the composite of non-CABG major bleeding at 48 hours and all-cause mortality, non-fatal MI, or urgent target vessel revascularization at 30 days. The rate of this end point was 7.2%, 7.9%, and 8.4% with enoxaparin 0.5, enoxaparin 0.75, and UFH, respectively (P = NS for both comparisons).

Dr Montalescot concluded that management with IV enoxaparin in patients scheduled to undergo elective PCI is associated with significantly less bleeding and comparable efficacy compared with UFH.

Reference
1. Borentain M, Montalescot G, Bouzamondo A, Choussat R, Hulot JS, Lechat P. Low-molecular-weight heparin vs. unfractionated heparin in percutaneous coronary intervention: a combined analysis. Catheter Cardiovasc Interv. 2005;65:212–221.

Despite a conceptual basis for use of antithrombin therapy in STEMI patients undergoing fibrinolysis, available evidence suggests that the rate of early recanalization of infarct-related arteries is not enhanced by administration of LMWH. However, accumulated evidence appears consistent with a lower rate of reocclusion of the infarct-related artery, of reinfarction, or of recurrent ischemic events in patients who receive LMWH. The CREATE trial found that reviparin was associated with a reduction in the incidence of mortality and recurrent MI in STEMI patients compared with placebo.¹ The OASIS-6 trial will evaluate the benefits of fondaparinux in STEMI patients.

The ENTIRE-TIMI 23 study evaluated the use of enoxaparin with TNK versus UFH in STEMI patients. This study showed that enoxaparin resulted in equivalent TIMI 3 flow rates, with no difference in the rate of TIMI major bleeding. However, the rate of death and MI at 30 days was significantly lower in the enoxaparin-treated group (4.4% versus 15.9%, P = 005).²

In a subgroup analysis of the CLARITY-TIMI 28 study, which showed the efficacy of clopidogrel versus placebo in reducing ischemic events in 3491 STEMI patients, treatment with LMWH was associated with significantly lower rates of a closed infarct-related artery (13.5% versus 22.5%; OR 0.76 [95% CI, 0.60-0.97]; P < 0.03) and of cardiovascular death or MI at 30 days (6.9% versus 11.5%; OR 0.69 [95% CI, 0.49-0.99]; P < 0.047).³

ExTRACT-TIMI 25 is a randomized, double-blind, double-dummy, parallel-group trial designed to provide definitive data on the safety and efficacy of using enoxaparin throughout the index hospitalization versus standard treatment with UFH as adjunctive antithrombin therapy in STEMI patients who are eligible for fibrinolysis. If dose reduction of enoxaparin in the elderly (to 75% of the standard maintenance dose) and more conservative use of UFH (in contrast to prior fibrinolysis trials) are associated with lower rates of bleeding compared with historical data, then a means for improving the safety of pharmacologic reperfusion will be established.

References
1. Yusuf S, Mehta SR, Xie C, et al; CREATE Trial Group Investigators. Effects of reviparin, a low-molecular-weight heparin, on mortality, reinfarction, and strokes in patients with acute myocardial infarction presenting with ST-segment elevation. JAMA. 2005;293:427–435.
2. Antman EM, Louwerenburg HW, Baars HF, et al. Enoxaparin as adjunctive antithrombin therapy for ST-elevation myocardial infarction: results of the ENTIRE-Thrombolysis in Myocardial Infarction (TIMI) 23 Trial. Circulation. 2002;105:1642–1649.
3. Sabatine MS, Cannon CP, Morrow DA, et al. Low-molecular-weight heparin is associated with superior outcomes compared with unfractionated heparin in patients with ST-elevation myocardial infarction: a CLARITY-TIMI 28 substudy. Circulation. 2005;112(17, suppl):1602.

The global annual burden of cardiovascular disease is estimated to increase to 6 million deaths in the developed world and 19 million in the developing world. Cardiovascular diseases are responsible for 30% of deaths in the developing world. A 2% improvement in mortality would avert 36 million deaths in 2015 and would save an incredible 500 million life-years between 2006 and 2015.

Recent initiatives in the United States to improve quality of care have focused on measuring hospital compliance to guidelines. Examples of this are the CRUSADE and ADHERE registries. In the CRUSADE registry, which was started to improve compliance to the 2002 unstable angina/non-ST-elevation MI guidelines,¹ compliance improved from 68.1% in 2002 to 79.3% in 2004. In addition, payment-for-performance initiatives have recently shown that compliance to guidelines can increase appropriate patient care. This suggests that doctors, practices, hospitals, and healthcare systems will change their behavior to match the way they are paid.

Dr Califf concluded that a cycle of quality assessment and feedback produces measurable reduction in death and disability of a greater magnitude than will be seen with any new treatment. He stated that doctors have a professional responsibility to apply proven therapies with the kind of reliability that consumers expect from other industries.

Reference
1. Braunwald E, Antman EM, Beasley JW, et al. ACC/AHA 2002 guideline update for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction — summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Unstable Angina). J Am Coll Cardiol. 2002;40:1366–1374.