Pexelizumab fails to inhibit assembly of the terminal complement complex in patients with ST-elevation myocardial infarction undergoing primary percutaneous coronary intervention. Insight from a substudy of the Assessment of Pexelizumab in Acute Myocardial Infarction (APEX-AMI) trial.

BACKGROUND: Reasons for pexelizumab lack of benefit in ST-elevation myocardial infarction patients undergoing primary percutaneous coronary intervention remain unclear. In a substudy of the APEX-AMI trial, we explored the hypothesis that early complement activation preceding drug administration explained the failure. METHODS: A panel of terminal complement complex proteins and fragments and biomarkers of inflammation, apoptosis, and high-risk features were assessed in serum obtained before and 24 hours after administration of placebo or pexelizumab and primary percutaneous coronary intervention (n = 356) and in human umbilical vein endothelial cell cultures coincubated with serum (n = 45). RESULTS: In the placebo group, C5a and sC5b-9 levels increased by 37% (7.9-14.2 ηg/mL, P = .007) and 96% (442-845 ηg/mL, P < .0001), respectively, during the first 24 hours. Pexelizumab prevented the increase in C5a (P = .01 vs placebo), but not that of sC5b-9 (502-1,157 ηg/mL, not significant vs placebo). Levels of C-reactive protein, interleukin (IL) 6, IL-1ß, Regulated on Activation, Normal T Cell Expressed and Secreted (RANTES) or Chemokine C-C motif ligand 5 (CCL5), and N-terminal probrain natriuretic peptide increased significantly in both groups; those of IL-10, IL-12, IL-1ra, and Interferon gamma-induced protein 10 (IP-10) or C-X-C motif chemokine 10 (CXCL10) decreased. Pexelizumab halved the increase in IL-6 (+92% vs 156%, P = .01) without effects on other markers, including C-reactive protein and N-terminal probrain natriuretic peptide. In cell culture, pexelizumab inhibited C5a, sC5b-9, and membrane-bound C5b-9 by 92%, 75%, and 78%, respectively (all P < .0001), without influencing cytokine levels and cell apoptosis. CONCLUSIONS: The blockage of both C5a and terminal complement in cell culture, but of C5a only in vivo with minimal effects on inflammation and risk biomarkers, supports the hypothesis that late administration of pexelizumab after the ischemia/reperfusion insult precluded adequate myocardial protection, resulting in a negative trial.

Assessment and management of acute coronary syndromes (ACS): a Canadian perspective on current guideline-recommended treatment--part 1: non-ST-segment elevation ACS.

Despite the reduction of coronary heart disease mortality over the past 40 years, hospital admissions for acute coronary syndromes (ACS) continue to increase. The goal of this 2-part article is to review the issues at each stage of assessment and management of the ACS patient, and to propose an optimal treatment strategy for the individual patient in the context of the realities, culture, and delivery of healthcare in Canada. ACS patients are categorized as either ST segment elevation myocardial infarction (STEMI) or non-ST-elevation ACS (NSTE-ACS). For the patients with NSTE-ACS, prevention of recurrent ischemic events is the primary goal. Assessment of risk for recurrent ischemic and bleeding events helps to determine the net benefit of early cardiac catheterization and percutaneous coronary intervention (PCI) and intensive antiplatelet and anticoagulant treatment. Those with higher ischemic risk features should be considered for an early invasive strategy and receive both dual antiplatelet therapy and an anticoagulant at the time of first medical assessment. Patients without high-risk features could be considered for medical treatment and a selectively invasive strategy; with coronary angiography and revascularization only if high-risk features become apparent. Long-term vascular protection with lifestyle modification (especially smoking cessation), lipid lowering, blood pressure and glycemic control, and the use of renin angiotensin aldosterone system (RAAS) blockade to prevent recurrent ischemic events, is important in all patients with ACS.

Assessment and management of acute coronary syndromes (ACS): a Canadian perspective on current guideline-recommended treatment--part 2: ST-segment elevation myocardial infarction.

Acute ST-segment elevation myocardial infarction (STEMI) accounts for approximately 30% of all acute coronary syndromes (ACS). The high early mortality for patients with STEMI is largely due to the extent of the ischemic injury. However, immediate reperfusion either pharmacologically with fibrinolysis or mechanically by primary percutaneous coronary intervention (PCI) limits the size of the infarction and reduces mortality. Reperfusion therapy by primary PCI reduces mortality and the risk of reinfarction, beyond the benefits achieved by fibrinolysis, especially when the primary PCI is initiated within 90 minutes of first medical contact. The use of adjuvant therapy with antiplatelet and anticoagulant agents is essential to enhance the results of reperfusion, and/or maintain vessel patency following either mode of reperfusion. This review discusses the assessment and management of the patient with an acute STEMI, using recommendations from the most recent American College of Cardiology/American Heart Association, European Society of Cardiology, and existing Canadian guidelines. It provides an updated perspective and critical appraisal with practical application of the recommendations within the Canadian Healthcare system.

Predicting chronic left ventricular dysfunction 90 days after ST-segment elevation myocardial infarction: An Assessment of Pexelizumab in Acute Myocardial Infarction (APEX-AMI) Substudy.

OBJECTIVES: The purpose of this study was to determine predictors of 90-day left ventricular function following acute ST-segment elevation myocardial infarction (STEMI) using variables from clinical presentation, biomarker testing, and cardiovascular magnetic resonance imaging (CMR). BACKGROUND: Identifying patients with acute STEMI who experience adverse remodeling and develop left ventricular dysfunction 3 months post-MI is a priority for guiding subsequent therapy. METHODS: The Assessment of Pexelizumab in Acute Myocardial Infarction trial tested pexelizumab treatment in STEMI patients presenting within 6 hours of symptom onset who were to undergo primary percutaneous coronary intervention. We studied 64 patients within this trial according to a prespecified substudy that included paired core laboratory delayed-enhancement CMR at days 3 and 90 as well as plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP; in picograms per milliliter) measured at randomization and 24 hours. A multivariable model predicting day 90 left ventricular ejection fraction (LVEF) was developed from clinical, biomarker, and imaging findings. RESULTS: Patients had a median age of 60 years (52-68), 89% were male, and 60% had anterior STEMI. Time from symptom onset to percutaneous coronary intervention was 3 hours. The median baseline LVEF was 48% (38%-56%) and was 50% (40%-54%) at 90 days: 7 patients (11%) had an LVEF <35% at 90 days. Patients with a lower 90-day LVEF (as a continuous variable) had a higher 24-hour NT-proBNP (P = .02) and a larger baseline infarct size by CMR (median 15% LV [8%-20% LV]) (P < .01). Microvascular obstruction (no reflow) was greater as measured by CMR (median 2.8% [1.4%-6.1%]) in patients with a lower 90-day LVEF (P < .01). Median baseline and 24-hour NT-proBNP levels were 94 pg/mL (54-292 pg/mL) and 1,448 pg/mL (958-2,599 pg/mL), respectively. In a multivariable model with clinical, biomarker, and imaging variables, only 3 variables independently predicted 90-day LVEF: 24-hour NT-proBNP, baseline CMR infarct size, and microvascular obstruction. CONCLUSIONS: Three key pathophysiologic variables of the post-STEMI myocardium measuring baseline infarct size and the extent of microvascular obstruction on CMR and wall tension (24-hour NT-proBNP) independently predicted 90-day LVEF. Further studies linking these measures with earlier use of clinical therapies may be warranted.

Cost-effectiveness of enoxaparin compared with unfractionated heparin in ST elevation myocardial infarction patients undergoing pharmacological reperfusion: a Canadian analysis of the Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial Infarction Treatment - Thrombolysis in Myocardial Infarction (ExTRACT-TIMI) 25 trial.

OBJECTIVE: To evaluate the cost-effectiveness of enoxaparin versus unfractionated heparin in conjunction with fibrinolysis in ST elevation myocardial infarction patients within Canada. DESIGN: Based on the Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial Infarction Treatment - Thrombolysis in Myocardial Infarction (ExTRACT-TIMI) 25 trial, a model was created to analyze the cost-effectiveness of enoxaparin compared with unfractionated heparin in conjunction with fibrinolysis among ST elevation myocardial infarction patients within Canada. Clinical outcomes were derived from published results of the main trial. Resource use costs were first assessed based on United States Diagnosis-Related Group values for hospitalizations and Current Procedural Terminology codes for outpatient visits and tests. Both were then converted using Canadian local costs. Survival and life expectancy were estimated from Framingham survival data. The incremental cost-effectiveness ratio was expressed as cost per life year gained. RESULTS: Through 30 days after random assignment, the primary composite end point favoured the enoxaparin group over the unfractionated heparin group (death or recurrent myocardial infarction rate 9.9% versus 12.0%, P<0.001), and was associated with a modest increased cost of $169.50 ($8,757.00 versus $8,587.50, respectively). Life years gained as a result of treatment with enoxaparin was increased by 0.11 years (P<0.05). Enoxaparin was found to be cost-effective, as indicated by an incremental cost-effectiveness ratio of $4,930 with a 99% probability of costing less than $20,000. CONCLUSIONS: Although associated with modest increased direct medication costs, enoxaparin following fibrinolysis improved the clinical efficacy in STEMI patients and increased the life years gained.

Assessment of activity status and survival according to the Canadian Cardiovascular Society angina classification.

BACKGROUND: Despite its widespread use, limited data on the validity of the Canadian Cardiovascular Society angina (CCSA) classification relative to other measures of functional status have been reported. OBJECTIVE: To assess the validity of the CCSA classification by comparing it with the Duke Activity Status Index (DASI) and evaluate its prognostic significance with respect to long-term mortality. METHODS: The study population consisted of 1407 patients who underwent cardiac catheterization between 1992 and 1996. The median follow-up period was 9.7 years (interquartile range 6.1 to 11.1 years) and the mortality status as of December 31, 2004 was available for all patients. RESULTS: The first three CCSA classes were inversely related to the DASI. The mean (+/- SD) scores were as follows: class I, 31.4+/-16.7; class II, 22.5+/-15.4; class III, 14.7+/-14.3; and class IV, 15.5+/-14.9 (P<0.01). Increasing CCSA class was associated with increased long-term mortality, even after adjusting for baseline characteristics. Chest pain course was also an important modulator of mortality among class III and IV patients; one-year mortality rates were 8.1% among unstable patients compared with 4.8% among patients with stable or progressing course. CONCLUSION: CCSA classes I to III were inversely related to DASI scores and linearly associated with mortality. The similarity in outcomes among class III and IV patients is probably explained by the confounding effect of the stability of the patients' symptoms. The higher mortality risk among class III and IV patients with an unstable course provides impetus for a revised CCSA definition incorporating this information.