Quantitative troponin elevation does not provide incremental prognostic value beyond comprehensive risk stratification in patients with non-ST-segment elevation acute coronary syndromes.

BACKGROUND: The aim of this study was to evaluate whether quantitative cardiac troponin (cTn) assessment can improve risk stratification in a spectrum of patients with non-ST-segment elevation (NSTE) acute coronary syndrome (ACS) using the validated Global Registry of Acute Cardiac Events (GRACE) risk model. METHODS: The Canadian ACS Registry II is a prospective, multicenter study that enrolled patients admitted to hospital with a suspected NSTE ACS within 24 hours of symptom onset. Of the total 2297 patients, those with elevated cTn (n = 1013) were further stratified into tertiles of cTn ranges. Our primary end point was death and our secondary end point was a composite of death or/and recurrent myocardial infarction at 1-year follow-up. RESULTS: Multivariable analysis adjusting for validated predictors of death confirmed the independent prognostic value of any abnormal cTn (vs normal) for death (adjusted odds ratio 2.28, 95% CI 1.49-3.49, P < .001) and for the composite outcome (adjusted odds ratio 2.18, 95% CI 1.61-2.95, P < .001) at 1 year. With quantitative assessment, the gradient of mortality risk with increasing cTn level was not evident after adjusting for other prognosticators. Quantitative (compared to qualitative) assessment of cTn level did not improve either the GRACE risk model discrimination for 1-year death. CONCLUSIONS: Any cTn elevation is associated with higher rate of death at 1 year, but its quantitative assessment did not prove as important as its mere presence as an independent long-term prognosticator in a nonclinical trial, "real-world" NSTE ACS population.

Clinical implications of a next-day follow-up electrocardiogram in patients with non-ST elevation acute coronary syndromes.

BACKGROUND: The prognostic value of admission ST-segment changes in patients with non-ST elevation acute coronary syndromes (NSTE ACS) is well established; however, the value of a next-day follow-up electrocardiogram (ECG) is unclear. METHOD: We evaluated ST-depression (ST(downward arrow)) and Q-wave status on the admission and 24 to 36-hour follow-up ECG in 2,743 patients in a prospective Canadian ACS registry. RESULTS: Of patients with ST(downward arrow) > or =1 mm on admission (n = 533 [19.4%]), 366 (68.7%) normalized their ST segment on follow-up ECG. Among patients without ST(downward arrow) on admission (n = 2,110), 97 (4.4%) developed new ST(downward arrow) at follow-up. Patients with normalized ST(downward arrow) at follow-up had higher 1-year myocardial infarction (MI) (10.1% vs 5.7%, odds ratio [OR] 1.77, 95% CI 1.12-2.81, P = .015) and death/MI rates (19.5% vs 10.2%, OR 1.69, 95% CI 1.18-2.41, P = .004), respectively, as compared to those who never had ST(downward arrow). Patients with persistent ST(downward arrow) had higher 1-year MI (10.8% vs 5.7%, OR 1.95, 95% CI 1.09-3.51, P = .025) and death/MI rates (25.6% vs 10.2%, OR 1.78, 95% CI 1.13-2.79, P = .013), respectively. In multivariable analysis, ST(downward arrow) on baseline ECG was an independent predictor of 1-year mortality; however, ST(downward arrow) on the follow-up ECG did not provide additional prognostic value. There were no differences in outcomes between the 4 different Q-wave status groups. CONCLUSIONS: Although dynamic and persistent ST(downward arrow) are associated with worse unadjusted outcome in patients with NSTE ACS, there was no incremental prognostic value of a follow-up ECG evaluating ST depression and/or Q-wave status beyond that already provided by the initial ECG together with established prognostic factors.

Comparison of effectiveness of enoxaparin versus unfractionated heparin to reduce silent and clinically apparent acute myocardial infarction in patients presenting with non-ST-segment elevation acute coronary syndrome.

Electrocardiographic (ECG) estimates of myocardial infarct size based on the Selvester ECG score have been shown to predict mortality and left ventricular function after acute myocardial infarction (AMI). This score has also been used to identify not clinically apparent AMI ("silent" AMI) and to determine treatment effect, suggesting it could serve as a clinical trial end point. The objective of this study was to compare the rate of silent AMI as measured by the Selvester QRS score in patients with a non-ST-segment elevation acute coronary syndrome treated with enoxaparin versus intravenous unfractionated heparin who were participating in a continuous ECG monitoring substudy of the Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-wave Coronary Events study (ESSENCE) and INTegrelin and Enoxaparin Randomized Assessment of acute Coronary syndrome Treatment trial (INTERACT). Enoxaparin was associated with a 56% relative risk decrease in silent AMI at 96 hours compared with unfractionated heparin (2.7% vs 6.1% p = 0.03). Similarly, enoxaparin decreased Holter-detected myocardial ischemia compared with unfractionated heparin (18.7% vs 35.9%, p = 0.03). In conclusion, enoxaparin significantly decreased the composite of silent AMI or clinical AMI and death at 1 year (9.3% vs 21%, p = 0.0001).

Missed opportunities for the secondary prevention of cardiovascular disease in Canada.

BACKGROUND: Strong evidence supports the use of antithrombotic agents (antiplatelets or oral anticoagulants), statins and angiotensin-converting enzyme inhibitors in patients with atherosclerotic cardiovascular disease; beta-blockers are additionally indicated in patients with coronary artery disease. OBJECTIVES: The investigators sought to determine the extent to which guideline-recommended treatments and target goals are adopted in ambulatory patients with cardiovascular disease in Canada. METHODS: Two large, prospective, community-based registries (the Vascular Protection Registry and the Guideline Oriented Approach to Lipid Lowering Registry) enrolled 9809 outpatients with coronary artery disease, cerebrovascular disease, peripheral vascular disease or multiple cardiovascular risk factors from primary care settings in nine provinces across Canada between 2001 and 2004. This analysis focused primarily on patients with cardiovascular disease (n=6296). RESULTS: At baseline, antithrombotics, statins and angiotensin-converting enzyme inhibitors were used in 92%, 80% and 57% of patients, respectively; beta-blockers were used in 59% of patients with coronary artery disease. The dosing of most drug therapies was suboptimal compared with guideline-recommended dosing derived from clinical trials. Treatment goals for cardiovascular risk factors were suboptimally attained: low-density lipoprotein cholesterol in 50% of patients, total to high-density lipoprotein cholesterol ratio in 51% of patients, systolic and diastolic blood pressure in 58% and 78% of patients, respectively, and waist circumference and body mass index in 45% and 19%, respectively. CONCLUSIONS: These data suggest specific opportunities for improving the care of patients with cardiovascular disease in Canada. The focus must now shift from awareness of treatment gaps to implementation of effective solutions.

Randomized evaluation of the efficacy of enoxaparin versus unfractionated heparin in high-risk patients with non-ST-segment elevation acute coronary syndromes receiving the glycoprotein IIb/IIIa inhibitor eptifibatide. Long-term results of the Integrilin and Enoxaparin Randomized Assessment of Acute Coronary Syndrome Treatment (INTERACT) trial.

BACKGROUND: Patients with high-risk non-ST-segment elevation acute coronary syndromes (NSTE ACS) benefit from the early administration of aspirin, a small molecule glycoprotein IIb/IIIa inhibitor such as eptifibatide, and heparin. The INTERACT trial demonstrated that in high-risk patients with ACS receiving aspirin and eptifibatide, the use of enoxaparin compared with unfractionated heparin (UFH) was associated with less bleeding, less early myocardial ischemia, and improved 30-day outcomes. OBJECTIVE: The aim of our study was to determine whether the short-term benefits of enoxaparin compared with UFH observed in high-risk patients with NSTE ACS are maintained over a prolonged period of follow-up. METHODS: Six hundred thirty-nine patients that were representative of the total population of subjects in the INTERACT trial were followed up for a median period of 2.5 years. RESULTS: In this group, the early benefit of enoxaparin was maintained. The incidence of death or myocardial infarction at the time of long-term follow-up was 39% lower in patients receiving enoxaparin compared with those who received UFH (8.9% vs 14.7%, P = .024). There was no difference in the frequency of cardiac catheterization in the groups receiving either enoxaparin or UFH. CONCLUSIONS: The early treatment of high-risk patients with NSTE ACS receiving aspirin and eptifibatide with enoxaparin is associated with early outcome benefits that are sustained over a prolonged follow-up period. This trial supports the concept that early treatment directed against platelet and thrombin formation is associated with better short- and long-term outcomes.

Prognostic significance of admission heart failure in patients with non-ST-elevation acute coronary syndromes (from the Canadian Acute Coronary Syndrome Registries).

We evaluated the in-hospital and 1-year outcomes and predictors of admission heart failure in patients with non-ST-elevation acute coronary syndromes (NSTE-ACSs) without previous heart failure. We analyzed 4,825 patients with NSTE-ACS without a history of congestive heart failure who were included in the multicenter Canadian ACS Registries. Patients in Killip's class II/III on admission (n = 559, 11.6%) were compared with patients in Killip's class I. Patients with heart failure on admission were older (72 [64, 79] vs 64 [54, 73] years, p < 0.0001), with higher baseline creatinine levels (96 vs 88 mmol/dl, p <0.0001), more diabetes (32.2% vs 22.8%, p < 0.0001), hypertension (58% vs 52.4%, p = 0.014), previous myocardial infarction (MI; 38.9% vs 30.3%, p < 0.0001), previous stroke (13.5% vs 7.4%, p < 0.0001), and had more ST depression on admission (27.7% vs 17.3%, p < 0.0001). In-hospital treatment was similar except for a lower rate of aspirin therapy and fewer coronary interventions. Crude event rates were significantly higher in patients with heart failure (in-hospital death 3.6% vs 1.1%, p < 0.0001; death or MI 7.9% vs 4.7%, p = 0.0011; stroke 1.1% vs 0.4%, p = 0.03). One-year event rates were also higher in patients with heart failure (death 14.6% vs 4.4%, p < 0.0001; MI 9.3% vs 6.6%, p = 0.03; death or MI 21.5% vs 10.3%, p < 0.0001). Variables independently associated with heart failure were age (odds ratio 1.57, 95% confidence interval 1.43 to 1.73), diabetes mellitus (odds ratio 1.53, 95% confidence interval 1.24 to 1.89), admission ST depression (odds ratio 1.52, 95% confidence interval 1.22 to 1.90), previous MI, and baseline creatinine. Heart failure on admission was an independent predictor of in-hospital death, death or MI, and stroke and of 1-year death and death or MI. In conclusion, in patients with NSTE-ACS, heart failure on admission is associated with increased short- and long-term rates of death and MI.

Non-alcoholic fatty liver disease and outcomes in persons with acute coronary syndromes: insights from the GRACE-ALT analysis.

OBJECTIVE: Non-alcoholic fatty liver disease (NAFLD) is associated with a higher risk of cardiovascular disease, but no data exist about the relation between NAFLD and adverse outcomes in persons with acute coronary syndromes (ACS). We evaluated elevated serum alanine aminotransferase (ALT) as a marker of NAFLD, in association adverse outcomes following ACS. METHODS: We conducted a retrospective cohort study of participants enrolled in the Global Registry of Acute Coronary Events (GRACE) admitted for ACS to St Michael's Hospital, Toronto, between 1999 and 2007. Multivariable linear regression was used to determine the change in maximum measured cardiac troponin I (cTnI) per each 1 IU/l increase in serum ALT concentration. The association between an elevated ALT >90th centile, and adverse outcomes in-hospital and at 6 months were calculated using multiple logistic regression analyses, adjusting for age, sex, body mass index, serum creatinine, glucose, triglycerides and LDL-C, as well as chronic statin or other lipid-lowering agent use. RESULTS: 528 participants were included. Each 1 IU/l increase in ALT was associated with an increase in maximum measured cTnI of 0.16 µg/l (95% CI 0.10 to 0.22). An elevated ALT concentration >90th percentile was associated with a maximum measured cTnI in the highest quartile (adjusted OR 7.07, 95% CI 1.83 to 27.37). An elevated ALT >90th percentile was also significantly associated with all-cause mortality in-hospital, and up to 6 months after discharge (adjusted OR 8.96, 95% CI 3.28 to 24.49). CONCLUSIONS: NAFLD, determined by an elevated serum ALT, is associated with a higher risk of adverse outcomes in persons with ACS. Whether ALT is a valid and independent prognostic marker in ACS remains to be determined.

Use of a treatment optimization algorithm involving statin-ezetimibe combination aids in achievement of guideline-based low-density lipoprotein targets in patients with dyslipidemia at high vascular risk Guideline-based Undertaking to Improve Dyslipidemia Management in Canada (GUIDANC).

BACKGROUND: Despite the well-established benefits of strategies to reduce low-density lipoprotein cholesterol (LDL-C), many patients fail to achieve the guideline recommended targets. The objective of this study was to evaluate the impact of an enhanced 26-week algorithm-based treatment optimization strategy, involving titration of statin monotherapy and/or combination therapy with statin and ezetimibe, on achievement of guideline-based LDL-C targets in patients at high risk for atherosclerotic disease. METHODS AND RESULTS: In this national (172-physician) quality enhancement research initiative involving 2334 Canadian men and women (median age, 65 years) at high vascular risk who were not at the guideline-recommended LDL-C target despite statin therapy, 36.6% and 45.5% of patients achieved an LDL-C <2.0 mmol/L at visit 2 and visit 3, respectively, using the treatment optimization algorithm. The percentage of patients achieving the 2009 Canadian Cardiovascular Society (CCS)-recommended target of either LDL-C <2.0 mmol/L or a 50% or greater reduction from baseline increased from 6.8% at visit 1 to 43.3% at visit 2 and to 52.1% at visit 3. Attainment of LDL-C targets increased significantly with consecutive visits (P < .001). Use of ezetimibe in combination with statin therapy was associated with greater target achievement. CONCLUSIONS: Use of a structured treatment optimization algorithm, based on titration of statin dosages and incorporation of ezetimibe therapy when required, enabled the majority of high-risk patients to achieve guideline-recommended targets, thereby narrowing the care gap that exists in dyslipidemia management.

Usefulness of statin-ezetimibe combination to reduce the care gap in dyslipidemia management in patients with a high risk of atherosclerotic disease.

Lowering of low-density lipoprotein (LDL) cholesterol is a fundamental step in the comprehensive management of patients at high risk for cardiovascular events. The combination of a statin with ezetimibe usually provides additional LDL cholesterol lowering compared to statin monotherapy. This open-label observational study evaluated the impact of a 26-week treatment program with uptitration of statin dosages and incorporation of ezetimibe 10 mg therapy in 2,577 men and women (median age 64 years) with hypercholesterolemia and an LDL cholesterol level >2.5 mmol/L (97 mg/dl). Attainment of an LDL cholesterol target of 2.5 mmol/L (97 mg/dl) increased with consecutive visits (63%, 67%, and 71% at the second, third, and final visits, respectively). Current guideline-recommended LDL cholesterol value <2.0 mmol/L (77 mg/dl) was achieved by 36%, 40%, and 41% of the group at the same consecutive follow-up sessions. Median LDL cholesterol decreased from 3.0 mmol/L (116 mg/dl) at baseline to 2.1 mmol/L (81 mg/dl) at the end of the 26-week monitoring period. Favorable changes were concomitantly observed for median total cholesterol (5.1 to 4.1 mmol/L [197 to 159 mg/dl]), total cholesterol/high-density lipoprotein cholesterol ratio (4.2 to 3.3), and triglyceride (1.6 to 1.4 mmol/L [142 to 124 mg/dl]). Of those who attended visit 4, 48% exhibited LDL cholesterol lowering of > or =1 mmol/L (39 mg/dl) compared to baseline levels. In conclusion, an algorithm-based statin uptitration/ezetimibe combination regimen is useful to increase LDL cholesterol lowering where statin monotherapy has not achieved target lipid values.

Risk factors and outcome of in-hospital ischemic stroke in patients with non-ST elevation acute coronary syndromes.

OBJECTIVES: To identify predictors of ischemic stroke in patients with suspected non-ST elevation (NSTE) acute coronary syndrome (ACS) and to evaluate in-hospital and 1-year outcomes. METHODS: We analyzed 5842 patients with diagnosed NSTE ACS included in the multi-center Canadian ACS registries. Patients with in-hospital stroke (n=28, 0.5%) were compared to patients without stroke. Risk factors and short- and long-term outcome were evaluated. RESULTS: Baseline characteristics of patients with and without stroke were similar except for a significantly higher proportion of women, higher rates of in-hospital CABG, and greater use of unfractionated heparin. Crude event rates were significantly higher in patients with stroke: in-hospital death 21.4% vs. 1.6% (p<0.0001), MI 10.7% vs. 4.0% (p=0.10), and death or MI 32.1% vs. 5.1% (p<0.0001). One-year event rates were also higher in patients with stroke: death 32.1% vs. 7.4% (p<0.0001), and death or MI 39.3% vs. 13.5% (p<0.001). In multivariable analysis, independent predictors for stroke were female gender (OR 3.12, 95%CI 1.36-7.14, p=0.007), and Killip class >/=2 on admission (OR 2.87, 1.18-6.99, p=0.02). Stroke was an independent predictor of in-hospital death (OR 14.52, 4.57-46.12, p<0.0001), death or MI (6.0, 2.44-14.75, p<0.0001), as well as 1-year death (5.50, 1.94-15.60, p=0.0014), and death or MI (2.89, 1.15-7.27, p=0.025). CONCLUSIONS: In patients with NSTE ACS, stroke is associated with increased short- and long-term rates of death and MI. Stroke is highly predicted by female gender and Killip class on admission.

B-type natriuretic peptide and serum unbound free fatty acid levels after contemporary percutaneous coronary intervention.

OBJECTIVES: To determine the frequency and timing of B-type natriuretic peptide (BNP) and unbound free fatty acid (FFAu) elevation after percutaneous coronary intervention (PCI). DESIGN AND METHODS: Blood samples were collected from 55 patients undergoing PCI within 1 hour prior to PCI, immediately after PCI, 6 hours and 18-24 hours after PCI, and were analyzed for BNP and FFAu. RESULTS: There was a trend toward a rise in BNP levels at 18-24 hours post-PCI (65 vs. 45 pg/ml; p = 0.056). FFAu levels rose immediately after PCI and returned to baseline by 6 hours postprocedure (2.0 nM pre-PCI, 6.4 nM immediately post-PCI, 1.9 nM 6 hours post-PCI, and 2.2 nM 18-24 hours post-PCI; p < 0.0001). BNP and FFAu levels were elevated post-PCI in 17% and 82% of cases. CONCLUSIONS: PCI using short inflation times and coronary stenting are associated with a trend toward increased BNP levels at 18-24 hours post-PCI and a transient significant rise in FFAu levels.

Discordance between physicians' estimation of patient cardiovascular risk and use of evidence-based medical therapy.

Despite clinical trial evidence supporting the use of antiplatelets, angiotensin-converting enzyme inhibitors, and statins for cardiovascular risk reduction in high-risk patients, use of such therapies in real-world outpatients in the prospective Vascular Protection Registry and the Guidelines Oriented Approach to Lipid Lowering Registry was suboptimal (78%, 55%, and 75%, respectively). The most frequent reason physicians cited for nonprescription of statins (33%) was that patients were not high risk enough and/or current guidelines did not support statin use. In conclusion, outpatients at high cardiovascular risk continue to be undertreated as a result of a combination of physician underestimation of cardiovascular risk (knowledge gap) and barriers to implementation of evidence-based therapy (practice gap).