Pharmacoinvasive Management of Acute Coronary Syndrome in the Setting of Percutaneous Coronary Intervention: Evidence-Based, Sit


1Dean J. Kereiakes, MD, 2James Tcheng, MD, 3Edward T.A. Fry, MD, 4Deepak L. Bhatt, MD, 5Gideon Bosker, MD,
6Jose G. Diez, MD, 7James J. Ferguson, III, MD, 8Glenn N. Levine, MD, 9Gary L. Schaer, MD, 10James Zidar, MD

The CATH (Cardiac Catheterization and Antithrombotic Therapy in the Hospital) Clinical Consensus Panel Report

A total of 5,225 patients were enrolled in the PARAGON B trial. Among these patients, the type of heparin used was known in 5,200 (99.5%). The median duration of therapy was 72.8 hours for UFH and 79.7 hours for LMWH. LMWH was used in about one-fifth of the study cohort. Of the 389 sites that participated, approximately 61% of the sites used UFH only, 10% used LMWH only, and 28% used either UFH or LMWH (at the discretion of the attending physician). Enoxaparin was used in 91% of the patients treated with LMWH.36 In the PARAGON B trial, use of the LMWH enoxaparin in conjunction with a GP IIb/IIIa inhibitor was safe and associated with a lower revascularization rate. The lower event rate for patients managed with LMWH in the lamifiban group was sustained at 6 months, with a lower revascularization rate (51.5% versus 42.8%) and a lower composite rate of death/MI (13.8% versus 11.9%). Bleeding was comparable in the 2 groups (1.4% with UFH versus 0.9% with LMWH). The propensity adjusted OR for 30-day revascularization was significantly lower with LMWH (OR, 0.67; 95% CI, 0.57–0.79; p < 0.001). There were no significant differences in death/MI/SRI at 30 days (p < 0.465), death/MI at 30 days (p < 0.264) and stroke at 30 days with the type of heparin used (p < 0.201) after propensity risk adjustment. These findings support the rationale for combining GP IIb/IIIa blockers and enoxaparin for interventional management of ACS.36
Pharmacoeconomic implications of the use of enoxaparin in ACS. A number of studies support the observation that enoxaparin reduces the incidence of adverse cardiovascular endpoints, including recurrent MI and the need for revascularization, without increasing major bleeding in patients with ACS, including unstable angina and acute STEMI.2,37–39 These clinical benefits are associated with economic benefits in terms of reduced expenditure on urgent revascularization procedures, the requirement for additional drug therapies, and drug administration. Accordingly, several pharmacoeconomic analyses have been conducted on the use of enoxaparin in ACS.40–43
Enoxaparin has been shown to be associated with cost-saving compared with UFH in the management of unstable angina and NSTEMI in health economic studies from Canada, the United States, the United Kingdom, South America and France.40–43 These cost savings accrue from a reduction in the cost of drug administration (primarily associated with subcutaneous dosing of enoxaparin compared with intravenous UFH), the amount of nursing time required (which increases the availability of nurses for other duties), elimination of monitoring, the need for revascularization procedures (and any complications arising from these procedures) and the duration of hospitalization.42
Glycoprotein (GP) IIb/IIIa receptor antagonists Currently, therapy with a GP IIb/IIIa antagonist for ACS patients without high-risk triggers is not supported by evidence-based trials.44 Particularly, the use of abciximab in patients being managed without revascularization may be associated with inferior outcomes.44 These observations are from the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO-IV) acute coronary syndrome trial44 and a detailed evaluation of medical therapy in previously reported GP IIb/IIIa agent trials.
The GUSTO-IV acute coronary syndrome trial45 enrolled 7,800 patients with unstable angina/NSTEMI who presented with at least 5 minutes of ACS-consistent chest pain and either ST-segment depression or increased troponin levels. All patients received aspirin and a heparin compound and were randomized to 1 of 3 arms (placebo, an abciximab bolus and 24-hour infusion, or an abciximab bolus and 48-hour infusion), as part of medical (no revascularization) management. At 30 days, the composite of death or MI ranged from 8.0–9.1%, with no differences among the 3 treatment groups. At 48 hours, death occurred more commonly in the 48-hour abciximab group than in the placebo group (0.3% versus 0.9%; p = 0.008). The lack of benefit of abciximab was observed in most subgroups, including high-risk patients as defined by an increased concentration of troponin. Based on these data, there appears to be no role for abciximab as a component of the pharmacological regimen for the ACS patient who is not anticipated to undergo catheterization or PCI.
Among 1,069 patients in the PRISM-PLUS trial who did not undergo early PCI, tirofiban was beneficial in a high-risk subgroup (retrospectively applied TIMI risk score > 4), whether they underwent PCI (OR, 0.60; 95% CI, 0.35–1.01) or not (OR, 0.69; 95% CI, 0.49–0.99).1,46 However, no apparent benefit was observed in patients who were at lower risk.46
Based on this and other studies, patients with high-risk ACS should receive a small molecule GP IIb/IIIa inhibitor. Although the data supporting the use of GP IIb/IIIa antagonists are clearly stronger in patients undergoing early revascularization, NSTEMI patients with high-risk features who are being managed medically also benefit from the addition of a GP IIb/IIIa antagonist, although the degree of benefit is less marked.47 Emergency physicians and non-interventional cardiologists should initiate therapy with a small molecule GP IIb/IIIa antagonist such as eptifibatide when the NSTE-ACS patient manifests high-risk features, even when the timing of intervention is uncertain.
Support for early administration of eptifibatide in high-risk ACS patients managed with either an interventional strategy or because cardiac catheterization facilities were not available and/or transfer was not feasible (an alternative medical approach) is derived primarily from the PURSUIT-United States (US) study.48 PURSUIT (Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy) was a multinational, randomized, placebo-controlled trial which demonstrated that eptifibatide reduced the incidence of death or MI among patients with acute ischemic syndromes without ST-segment elevation. Because of differences in practice patterns among participating countries, a prospectively planned analysis of outcomes by regions of the world was performed. The PURSUIT-US subset analysis provides a detailed assessment of eptifibatide among the subgroup of patients enrolled within the United States. Of the 10,948 patients randomized worldwide, a total of 4,035 were enrolled within the US. Patients were allocated to placebo or eptifibatide infusion for 72–96 hours. Other medical therapies and revascularization strategies were employed at the discretion of the treating physician.
Eptifibatide reduced the primary endpoint of death or MI to 30 days from 15.4% to 11.9% (p = 0.003) among patients in the US. The treatment effect was achieved early and maintained over a period of 6 months (18.9% versus 15.2%; p = 0.004). Bleeding events were more common in patients receiving eptifibatide, but were predominantly associated with invasive procedures. The magnitude of clinical benefit from eptifibatide was greater among patients in the US than elsewhere in the world.
Baseline patient demographic and management features differed between the US and other countries. The median hospital length of stay was shorter in the US (5 days, interquartile range, 3–8 days) than outside of the US (10 days, 7–15 days). Patients enrolled in the US were more likely to have had the study drug administered for < 72 hours due to early hospital discharge (28% of US patients compared with 2% of non-US patients) and more likely to undergo coronary artery bypass surgery (15% of US patients versus 7% of non-US patients). Patients in the US more commonly received a heparin infusion and more frequently underwent cardiac catheterization and coronary revascularization. In particular, invasive diagnostic and revascularization procedures were carried out earlier in the US. The median time from randomization to cardiac catheterization was 24 hours (range, 13–55 hours) in the US and 117 hours (range, 64–210 hours) outside of the US; corresponding times for percutaneous intervention were 38 hours (range, 16–75 hours) and 139 hours (range, 69–282 hours) and for coronary bypass surgery were 93 hours (range, 48–142 hours) and 256 hours (range, 140–407 hours).
The primary composite endpoint of death or MI at 30 days was reduced from 15.4% to 11.9% for the placebo and eptifibatide groups, respectively (3.5% absolute risk reduction, 23% relative risk reduction; p = 0.0025). This difference was predominantly due to a decrease in the incidence of MI (23% relative risk reduction), with a less pronounced effect of eptifibatide on mortality (14% relative risk reduction).
The clinical benefit of eptifibatide was observed early (within the first 96 hours) and was maintained without attenuation after discontinuation of study drug. The absolute number of events (death or MI) prevented per 100 patients treated was 3.2 at 96 hours, 3.0 at 7 days, 3.5 at 30 days and 3.7 at 6 months. Eptifibatide benefit was gender-independent, with both men and women in the United States having comparable clinical benefit.
Perhaps due to more frequent and timely interventional strategies in the US, the reduction in ischemic events by eptifibatide was greater (p = 0.024) at every time point among the PURSUIT patients enrolled in the United States as compared to those enrolled in non-US sites. At 30 days, the composite endpoint of death or MI was reduced by 33% (p = 0.017) in patients undergoing PCI within the first 72 hours and by 19% (p = 0.036) in patients who did not undergo early PCI. Patients treated with early PCI had somewhat enhanced benefit from eptifibatide therapy, with an absolute 5.5 events prevented per 100 patients treated as compared with 2.8 events per 100 patients who did not receive early PCI. The interaction between eptifibatide therapy and early PCI was not statistically significant (p = 0.32). A stabilization effect prior to PCI was also noted, with a 31% relative reduction in the incidence of preprocedural MI from 9.8% to 6.8% (p = 0.052).48 Some caution in interpretation of this subset analysis is appropriate, as neither the decision to perform PCI nor the timing of revascularization were randomly assigned in this study.
One investigative group43 performed a meta-analysis of the effect of medical therapy with GP IIb/IIIa agents from all 6 large, randomized, placebo-controlled trials (including the GUSTO-IV acute coronary syndrome trial), involving 31,402 patients with ACS not routinely scheduled to undergo coronary revascularization. A significant reduction in the likelihood of the composite endpoint of death or MI was demonstrated in the GP IIb/IIIa treatment arm (11.8% versus 10.8%; OR, 0.91; 95% CI, 0.84–0.98; p = 0.015). Although not scheduled for coronary revascularization procedures, a total of 11,965 of the 31,402 patients (38%) actually underwent PCI or CABG within 30 days; in this late interventional subgroup, the OR for death or MI in the treated patients was 0.89 (95% CI, 0.80–0.98). In the 19,416 patients in this analysis who did not undergo PCI or CABG, the OR for death or MI in the GP IIb/IIIa group was 0.95 (95% CI, 0.86–1.05; p = not significant). Major bleeding complications were significantly more common in the GP IIb/IIIa group compared with those in the placebo group (2.4% versus 1.4%; p < 0.0001). The conclusion of this analysis was that in patients with unstable angina/NSTEMI and high-risk features who are not scheduled for early revascularization, treatment with GP IIb/IIIa inhibitor should be considered.49

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