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Troponin T levels in patients with acute coronary syndromes, with or without renal dysfunction
Efficacy Assessment of Meloxicam, a Preferential Cyclooxygenase-2 Inhibitor, in Acute Coronary Syndromes Without ST-Segment Elevation. The Nonsteroidal Anti-Inflammatory Drugs in Unstable Angina Treatment-2 (NUT-2) Pilot Study
vascular and coronary deaths without affecting nonfatal coronary events in survivors of a recent MI (⬍3 months). This study analyzed the time course of the benefit to explore the hypothesis of an antiarrhythmic effect of the fish oil on sudden death? Methods: 11,323 post MI patients were randomized to 1000 mg of fish oil, 300 mg vitamin E, both or neither and followed for up to 3.5 years. The investigators did an ad hoc reanalysis of all causes of death without knowledge of treatments and characterized the time of death by months after entry and intention to treat. Results: The average age was 59 years, 15% were female and the median time to randomization was 16 days from the MI. 86% of patients had an LVEF ⬎40%, 13.5% had ⬎10 PVCs/hour and 23.5% significant ventricular arrhythmias. At baseline ⬎90% had anti-platelet Rx, 47% were treated with ACEi, 44% beta-blockers, and by 42 months, 45.5% were on lipid-lowering drugs. There was a total of 680 CV deaths. 265 patients had sudden coronary death, 85 died of CHF, 57 of stroke and 98 of AMI. Survival curves for fish oil treatment diverged for total mortality by 3 months [RR 0.59, p⫽0.03], explained primarily by reduction in sudden deaths which were significant at 4 months. A significant but delayed pattern of benefit of treatment was observed for CV and coronary deaths after 6 – 8 months. Conclusion: The early effect of 1000 mg of n-3 PUFAs as fish oil on total mortality and sudden death supports the hypothesis of an antiarrhythmic effect and is consistent with animal models, epidemiological and clinical studies. Perspective: The GISSI patients were under-treated with respect to secondary prevention, yet the evidence in support of a high intake of cold water fish or supplemental fish oil capsules following an AMI is convincing. There is accumulating evidence for a similar value in CAD with ICDs and possibly other CAD at high risk for sudden death. Many patients and physicians see fish oil as a low-cost and lowrisk supplement. As with many other “good ideas,” the risk is not clear. While I am an advocate, the antiplatelet effect of fish oil superimposed on ASA may result in increased bleeding and hemorrhagic strokes—another case of caveat emptor. MR
Altman R, Luciardi HL, Muntaner J, et al. Circulation 2002;106: 191–5. Study Question: Is the combination of Meloxicam with heparin and aspirin superior to heparin and aspirin alone in the treatment of patients with Non–ST-elevation acute coronary syndrome? Methods: Patients with acute coronary syndromes without ST-segment elevation were randomized in open-labeled fashion to aspirin and heparin treatment (n⫽60) or aspirin, heparin and meloxicam (n⫽60) during coronary care unit stay followed by aspirin or aspirin plus meloxicam for 30 days. Results: The primary outcome (recurrent angina, myocardial infarction or death) was significantly lower in the patients receiving meloxicam (15.0% vs. 38.3%, p⫽0.007) during the stay in coronary care unit. The secondary outcome (coronary revascularization procedures, myocardial infarction and death) was also significantly lower in meloxicam-treated patients (10.0% vs. 26.7%, p⫽0.034). The beneficial effects of meloxicam on the primary (21.7% vs. 48.3%, p⫽0.004), as well as secondary (13.3% vs. 33.3%, p⫽0.015) end points persisted at 90 days. Similarly, the need for revascularization alone was lower in meloxicam group at 90 days (11.7% vs. 30.0%, p⫽0.025). This benefit of meloxicam occurred without any increase in the risk of adverse side effects. Conclusions: A combination of meloxicam with heparin and aspirin was associated with significant reductions in adverse outcomes in acute coronary syndrome patients without ST-segment elevation. Perspective: Recurrent angina and the need for coronary revascularization (generally driven by recurrent symptoms) were the only end points of the outcomes cluster reduced among the composite primary and secondary end points. There was no evident impact on death or recurrent MI. Much larger studies are needed. RM
Troponin T Levels in Patients With Acute Coronary Syndromes, With or Without Renal Dysfunction
Early Protection Against Sudden Death by n-3 Polyunsaturated Fatty Acids After Myocardial Infarction. Time-Course Analysis of the Results of the Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarcto Miocardico (GISSI)Prevenzione
Aviles RJ, Askari AT, Lindahl B, et al. N Engl J Med 2002;346: 2047–52. Study Question: What is the prognostic value of cardiac troponin in patients with suspected acute coronary syndromes and renal dysfunction? Methods: Patients enrolled in the Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) IV trial with complete data on troponin T levels (elevated if ⬎0.1 ng/mL) and creatinine clearance rates (n⫽7033) were analyzed to evaluate the prognostic significance of troponin T.
Marchioli R, Barzi F, Bomba E, et al. Circulation 2002;105:18097–103. Study Question: The GISSI Prevenzione study demonstrated that 1000 mg of fish oil reduced sudden death, total cardio-
ACC CURRENT JOURNAL REVIEW Nov/Dec 2002
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Results: Death or MI within 30 days (primary end point) occurred in 581 patients. Among patients with a creatinine clearance above the 25th percentile value of 58.4 mL per minute, the risk of composite of MI and mortality was significantly higher in patients with an elevated troponin T compared to those without any troponin elevation (7% vs. 5%; adjusted odds ratio [OR] 1.7; 95% confidence interval [CI] 1.3 to 2.2; p⬍0.001). An elevated troponin T level was similarly predictive of increased risk even among patients with creatinine clearance in the lowest quartile (those with creatinine clearance ⱕ58.4 mL/minute, 20% vs. 9%; adjusted OR 2.5; 95% CI 1.8 to 3.3; p⬍0.001). Elevation of the troponin T level remained an independent predictor of risk across the entire spectrum of renal function after accounting for other confounders (age, sex, ST segment depression, heart failure, previous revascularization, diabetes, etc). Conclusions: Elevated cardiac troponin T levels independently predict short-term death and MI in patients with acute coronary syndromes regardless of their level of creatinine clearance. Perspective: The greater specificity of the newer generation troponin T assays have increased the precision of the diagnosis of myocardial necrosis (particularly when it is small) and thereby improved the prognostic value of troponin T among patients with acute coronary syndromes and decreased renal function as seen in the current study. The prognostic value of small elevations of troponin T in patients with renal failure without any symptoms suggestive of acute coronary syndromes needs to be evaluated in future studies. RM
Results: Of the 475 studies identified on the subject, 42 met the study criteria and 15 of these (that included ⬎35,000 subjects) had symptoms of depression, fatigue and sexual dysfunction reported and thereby were selected for inclusion. Beta-blocker therapy was not associated with a significant absolute annual increase in risk of reported depressive symptoms (6 per 1000 patients; 95% confidence interval [CI], ⫺7 to 19) but was associated with a small significant increase in the risk of reported fatigue (18 per 1000 patients; 95% CI, 5–30) as well as a small increase in the risk of reported sexual dysfunction (5 per 1000 patients; 95% CI, 2– 8). Lipid-solubility did not impact the risks of any adverse effects, but the risk of reported fatigue was significantly higher for early-generation than for late-generation– blockers (p⫽0.04). Conclusions: The data from clinical trials do not support the popular belief that beta-blocker therapy is associated with substantial risks of depressive symptoms, fatigue and sexual dysfunction. As such, these agents should be utilized appropriately in context of there documented benefits. Perspective: The current study should help clear the common myth among physicians that the use of beta-blockers is associated with a substantial increase in the risk of depressive symptoms, fatigue and sexual dysfunction. Thus, these findings should stimulate them to refrain from withholding these agents among appropriate patients with acute coronary syndromes, heart failure and hypertension. RM
Baseline Characteristics, Management Practices, and In-hospital Outcomes of Patients Hospitalized With Acute Coronary Syndromes in the Global Registry of Acute Coronary Events (GRACE)
Beta-Blocker Therapy and Symptoms of Depression, Fatigue, and Sexual Dysfunction
Steg PG, Goldberg RJ, Gore JM, et al., for the GRACE Investigators. Am J Cardiol 2002;90:358 – 63.
Ko DT, Hebert PR, Coffey CS, Sedrakyan A, Curtis JP, Krumholz HM. JAMA 2002;288:351–7.
Study Question: What are the present clinical characteristics, management and in-hospital outcomes of unselected patients with acute coronary syndromes (ACS) around the globe? Methods: Data on 11,543 patients with ACS enrolled n GRACE from 95 hospitals in 14 countries were analyzed to obtain information on the current epidemiology, management and outcomes of patients with ACS. Results: Patients with ST-segment elevation myocardial infarction (STEMI), non–ST-segment elevation myocardial infarction (NSTEMI), and unstable angina pectoris represented 30%, 25% and 38% of the study population, respectively, while the remaining (7%) had other cardiac or noncardiac diagnoses. Over half of these patients (53%) were 65 years of age or older. Reperfusion therapy was used in 62% of patients with STEMI, while 40% of patients underwent percutaneous coronary intervention during the index admission. Intravenous glycoprotein IIb/IIIa blockers were used most frequently in STEMI patients (23%) followed by those with NSTEMI (20%) and unstable angina (7%). Pa-
Study Question: What is the association of beta-blocker use with symptoms of depression, fatigue and sexual dysfunction? Methods: Randomized trials that evaluated beta-blockers in the management of patients with myocardial infarction, heart failure and hypertension were identified using MEDLINE search for articles published between 1966 to 2001 as well as the reference lists of published trials and reviews of beta-blockers. For the purpose of this review, studies were included if they were in English and if trials had random allocation of study treatments with placebo control and enrolled at least 100 patients with a minimum of 6 months of follow-up. Two different types of data on side effects were abstracted: report by patient of symptoms and withdrawal of therapy due to a specified symptom. Beta-blockers were categorized by generation (early vs. late) and by their lipid solubility (high vs. low to moderate).
ACC CURRENT JOURNAL REVIEW Nov/Dec 2002
16
vascular and coronary deaths without affecting nonfatal coronary events in survivors of a recent MI (⬍3 months). This study analyzed the time course of the benefit to explore the hypothesis of an antiarrhythmic effect of the fish oil on sudden death? Methods: 11,323 post MI patients were randomized to 1000 mg of fish oil, 300 mg vitamin E, both or neither and followed for up to 3.5 years. The investigators did an ad hoc reanalysis of all causes of death without knowledge of treatments and characterized the time of death by months after entry and intention to treat. Results: The average age was 59 years, 15% were female and the median time to randomization was 16 days from the MI. 86% of patients had an LVEF ⬎40%, 13.5% had ⬎10 PVCs/hour and 23.5% significant ventricular arrhythmias. At baseline ⬎90% had anti-platelet Rx, 47% were treated with ACEi, 44% beta-blockers, and by 42 months, 45.5% were on lipid-lowering drugs. There was a total of 680 CV deaths. 265 patients had sudden coronary death, 85 died of CHF, 57 of stroke and 98 of AMI. Survival curves for fish oil treatment diverged for total mortality by 3 months [RR 0.59, p⫽0.03], explained primarily by reduction in sudden deaths which were significant at 4 months. A significant but delayed pattern of benefit of treatment was observed for CV and coronary deaths after 6 – 8 months. Conclusion: The early effect of 1000 mg of n-3 PUFAs as fish oil on total mortality and sudden death supports the hypothesis of an antiarrhythmic effect and is consistent with animal models, epidemiological and clinical studies. Perspective: The GISSI patients were under-treated with respect to secondary prevention, yet the evidence in support of a high intake of cold water fish or supplemental fish oil capsules following an AMI is convincing. There is accumulating evidence for a similar value in CAD with ICDs and possibly other CAD at high risk for sudden death. Many patients and physicians see fish oil as a low-cost and lowrisk supplement. As with many other “good ideas,” the risk is not clear. While I am an advocate, the antiplatelet effect of fish oil superimposed on ASA may result in increased bleeding and hemorrhagic strokes—another case of caveat emptor. MR
Altman R, Luciardi HL, Muntaner J, et al. Circulation 2002;106: 191–5. Study Question: Is the combination of Meloxicam with heparin and aspirin superior to heparin and aspirin alone in the treatment of patients with Non–ST-elevation acute coronary syndrome? Methods: Patients with acute coronary syndromes without ST-segment elevation were randomized in open-labeled fashion to aspirin and heparin treatment (n⫽60) or aspirin, heparin and meloxicam (n⫽60) during coronary care unit stay followed by aspirin or aspirin plus meloxicam for 30 days. Results: The primary outcome (recurrent angina, myocardial infarction or death) was significantly lower in the patients receiving meloxicam (15.0% vs. 38.3%, p⫽0.007) during the stay in coronary care unit. The secondary outcome (coronary revascularization procedures, myocardial infarction and death) was also significantly lower in meloxicam-treated patients (10.0% vs. 26.7%, p⫽0.034). The beneficial effects of meloxicam on the primary (21.7% vs. 48.3%, p⫽0.004), as well as secondary (13.3% vs. 33.3%, p⫽0.015) end points persisted at 90 days. Similarly, the need for revascularization alone was lower in meloxicam group at 90 days (11.7% vs. 30.0%, p⫽0.025). This benefit of meloxicam occurred without any increase in the risk of adverse side effects. Conclusions: A combination of meloxicam with heparin and aspirin was associated with significant reductions in adverse outcomes in acute coronary syndrome patients without ST-segment elevation. Perspective: Recurrent angina and the need for coronary revascularization (generally driven by recurrent symptoms) were the only end points of the outcomes cluster reduced among the composite primary and secondary end points. There was no evident impact on death or recurrent MI. Much larger studies are needed. RM
Troponin T Levels in Patients With Acute Coronary Syndromes, With or Without Renal Dysfunction
Early Protection Against Sudden Death by n-3 Polyunsaturated Fatty Acids After Myocardial Infarction. Time-Course Analysis of the Results of the Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarcto Miocardico (GISSI)Prevenzione
Aviles RJ, Askari AT, Lindahl B, et al. N Engl J Med 2002;346: 2047–52. Study Question: What is the prognostic value of cardiac troponin in patients with suspected acute coronary syndromes and renal dysfunction? Methods: Patients enrolled in the Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) IV trial with complete data on troponin T levels (elevated if ⬎0.1 ng/mL) and creatinine clearance rates (n⫽7033) were analyzed to evaluate the prognostic significance of troponin T.
Marchioli R, Barzi F, Bomba E, et al. Circulation 2002;105:18097–103. Study Question: The GISSI Prevenzione study demonstrated that 1000 mg of fish oil reduced sudden death, total cardio-
ACC CURRENT JOURNAL REVIEW Nov/Dec 2002
15
Results: Death or MI within 30 days (primary end point) occurred in 581 patients. Among patients with a creatinine clearance above the 25th percentile value of 58.4 mL per minute, the risk of composite of MI and mortality was significantly higher in patients with an elevated troponin T compared to those without any troponin elevation (7% vs. 5%; adjusted odds ratio [OR] 1.7; 95% confidence interval [CI] 1.3 to 2.2; p⬍0.001). An elevated troponin T level was similarly predictive of increased risk even among patients with creatinine clearance in the lowest quartile (those with creatinine clearance ⱕ58.4 mL/minute, 20% vs. 9%; adjusted OR 2.5; 95% CI 1.8 to 3.3; p⬍0.001). Elevation of the troponin T level remained an independent predictor of risk across the entire spectrum of renal function after accounting for other confounders (age, sex, ST segment depression, heart failure, previous revascularization, diabetes, etc). Conclusions: Elevated cardiac troponin T levels independently predict short-term death and MI in patients with acute coronary syndromes regardless of their level of creatinine clearance. Perspective: The greater specificity of the newer generation troponin T assays have increased the precision of the diagnosis of myocardial necrosis (particularly when it is small) and thereby improved the prognostic value of troponin T among patients with acute coronary syndromes and decreased renal function as seen in the current study. The prognostic value of small elevations of troponin T in patients with renal failure without any symptoms suggestive of acute coronary syndromes needs to be evaluated in future studies. RM
Results: Of the 475 studies identified on the subject, 42 met the study criteria and 15 of these (that included ⬎35,000 subjects) had symptoms of depression, fatigue and sexual dysfunction reported and thereby were selected for inclusion. Beta-blocker therapy was not associated with a significant absolute annual increase in risk of reported depressive symptoms (6 per 1000 patients; 95% confidence interval [CI], ⫺7 to 19) but was associated with a small significant increase in the risk of reported fatigue (18 per 1000 patients; 95% CI, 5–30) as well as a small increase in the risk of reported sexual dysfunction (5 per 1000 patients; 95% CI, 2– 8). Lipid-solubility did not impact the risks of any adverse effects, but the risk of reported fatigue was significantly higher for early-generation than for late-generation– blockers (p⫽0.04). Conclusions: The data from clinical trials do not support the popular belief that beta-blocker therapy is associated with substantial risks of depressive symptoms, fatigue and sexual dysfunction. As such, these agents should be utilized appropriately in context of there documented benefits. Perspective: The current study should help clear the common myth among physicians that the use of beta-blockers is associated with a substantial increase in the risk of depressive symptoms, fatigue and sexual dysfunction. Thus, these findings should stimulate them to refrain from withholding these agents among appropriate patients with acute coronary syndromes, heart failure and hypertension. RM
Baseline Characteristics, Management Practices, and In-hospital Outcomes of Patients Hospitalized With Acute Coronary Syndromes in the Global Registry of Acute Coronary Events (GRACE)
Beta-Blocker Therapy and Symptoms of Depression, Fatigue, and Sexual Dysfunction
Steg PG, Goldberg RJ, Gore JM, et al., for the GRACE Investigators. Am J Cardiol 2002;90:358 – 63.
Ko DT, Hebert PR, Coffey CS, Sedrakyan A, Curtis JP, Krumholz HM. JAMA 2002;288:351–7.
Study Question: What are the present clinical characteristics, management and in-hospital outcomes of unselected patients with acute coronary syndromes (ACS) around the globe? Methods: Data on 11,543 patients with ACS enrolled n GRACE from 95 hospitals in 14 countries were analyzed to obtain information on the current epidemiology, management and outcomes of patients with ACS. Results: Patients with ST-segment elevation myocardial infarction (STEMI), non–ST-segment elevation myocardial infarction (NSTEMI), and unstable angina pectoris represented 30%, 25% and 38% of the study population, respectively, while the remaining (7%) had other cardiac or noncardiac diagnoses. Over half of these patients (53%) were 65 years of age or older. Reperfusion therapy was used in 62% of patients with STEMI, while 40% of patients underwent percutaneous coronary intervention during the index admission. Intravenous glycoprotein IIb/IIIa blockers were used most frequently in STEMI patients (23%) followed by those with NSTEMI (20%) and unstable angina (7%). Pa-
Study Question: What is the association of beta-blocker use with symptoms of depression, fatigue and sexual dysfunction? Methods: Randomized trials that evaluated beta-blockers in the management of patients with myocardial infarction, heart failure and hypertension were identified using MEDLINE search for articles published between 1966 to 2001 as well as the reference lists of published trials and reviews of beta-blockers. For the purpose of this review, studies were included if they were in English and if trials had random allocation of study treatments with placebo control and enrolled at least 100 patients with a minimum of 6 months of follow-up. Two different types of data on side effects were abstracted: report by patient of symptoms and withdrawal of therapy due to a specified symptom. Beta-blockers were categorized by generation (early vs. late) and by their lipid solubility (high vs. low to moderate).
ACC CURRENT JOURNAL REVIEW Nov/Dec 2002
16