Further information: Medical Treatment of Unstable Angina, Acute Non–ST-Elevation Myocardial Infarction, and Coronary Artery Spasm (see p937), Pathophysiology and Clinical Impact of Diastolic Heart Failure (see p1201) and Dilated Cardiomyopathy (see p1233) from Cardiovascular Medicine, 3rd Edn*

This article [1] contains observations from the Metabolic Efficiency with Ranolazine for Less Ischemia in Non-ST Elevation Acute Coronary-Thrombolysis in Myocardial Infarction 36) Trial (MERLIN-TIMI 36), a trial conducted at 440 sites between 2004 and 2007 to determine the efficacy and safety of ranolazine in long-term treatment of 6500 patients with non-ST segment elevation acute coronary syndromes (ACS). As part of the MERLIN-TIMI 36 trial, investigators designed a prospective evaluation of the interaction between B-type natriuretic peptide (BNP) and the effect of ranolazine in patients with ACS. Because elevated BNP and the N-terminal portion of BNP prohormone identify patients at high risk of death and heart failure (HF), intense effort is being made to find treatments that would mitigate the risk of elevated BNP. There were 4543 baseline samples in which BNP had been measured from patients who had been randomized to ranolazine or placebo, and the patients were followed for 343 days. BNP elevation was defined as >80 pg/ml. The primary end point was a composite of cardiovascular (CV) death, myocardial infarction (MI), and recurrent ischemia.

Results showed that in 1935 patients with elevated BNP (>80 pg/ml), the risk of the primary end-point was higher (26.4% vs. 20.4%, P=0.0001), higher for CV death (8.0% vs. 2.1%, P<0.001, and higher for MI (10.6% vs. 5.8%, P<0.001) at 1 year. The primary end-point was reduced by ranolazine (hazard ratio [HR]; 0.79; 95% confidence internal [CI]: 0.66–0.94, P=0.009). For recurrent ischemia in patients with elevated BNP, the effect of ranolazine was directionally similar (HR: 0.78; 95% CI: 0.62–0.98; P=0.04) and CV death or MI (HR: 0.83; 95% CI: 0.66–1.05, P=0.12). Ranolazine had no effect on patients without elevated BNP, did not reduce BNP concentration over time, and did not reduce the clinical end-point for patients with new or worsening HF. Nevertheless, it did identify patients at high risk of recurrent myocardial ischemia ameliorated by ranolazine. Therefore, the investigators concluded that the effects of ranolazine warrant additional study.

In an editorial [2] in this same issue of JACC, the authors stated that while this carefully done study does not provide conclusive evidence that ranolazine should be used in patients with ACS and elevated BNP levels, it does lay the groundwork for a prospective clinical trial.

[1] Morrow DA, Scirica BM, Sabatine MS, et al. B-Type Natriuretic Peptide and the Effect of Ranolazine in Patients with Non-ST Segment Elevation Acute Coronary Syndromes. J Am Coll Cardiol 2009;55:1189-96

[2] Califf RM, Shah SH, Newby LK. Biomarker Bonanza? J Am Coll Cardiol 2009;55:1197-99
 
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Further information: Regulation of Cardiac Contraction and Relaxation (see p1189) from Cardiovascular Medicine, 3rd Edn*

From 1996 to 2000, 8290 patients were enrolled in a clinical trial titled, “Prevention of Events with Angiotensin Converting Enzyme Inhibition (PEACE),” [1] to evaluate the use of ACE inhibitors in patients with stable coronary artery disease (CAD). Recently, the PEACE investigators used a subset of those patients to determine whether or not the risk of future cardiovascular events could be detected in patients who had stable coronary artery disease (CAD), but not heart failure or left ventricular systolic dysfunction, when a recently developed and highly sensitive assay was used to measure cardiac troponin T [2]. The highly sensitive assay can measure troponin levels that are lower than a factor of 10 than those measured with conventional assays. From the original group of patients, this study used stored plasma samples from 3679 patients for whom baseline troponin T measurements were available, and results were analyzed relative to the occurrence of cardiovascular events during a median follow-up period of 5.2 years. Results showed that in 3593 (97.7%) patients with stable CAD, the concentrations of troponin T when measured with the highly sensitive assay were at or above the limit of detection (0.001 µg/l), and equal to or greater than the 99th percentile for apparently healthy patients (0.0133 µg/l) in 407 patients (11.1%).

In the compilation of data after adjustments were made for other prognostic risk factors, a strong increase was shown in the incidence of cardiovascular death (adjusted hazard ratio [AHR] per unit increase in the natural logarithm of the troponin T level, 2.09; 95% confidence interval [CI], 1.60–2.74; P<0.001) and of heart failure (AHR, 2.20; 95% CI, 1.66–2.90; P<0.001) in this group. However, in regard to myocardial infarction (MI), there were 233 fatal or nonfatal acute MIs with a weak but significant increase in the cumulative incidence of MIs with increasing troponin T levels, but after adjustment, the association was no longer considered significant (HR, 1.16; 95% CI, 0.97–1.40; P=0.11). Also shown was a weak association between risk of MI and increasing quartiles of troponin T, but after adjustment, the association was not significant. Authors concluded that in patients with stable CAD whose troponin T levels were well below the detection limit of previous assays, but with increased troponin T values compared to normal controls, there was a strong association with the incidence of cardiovascular death and heart failure, but troponin T levels were not independently associated with incidence of MI.

Readers may also wish to read summaries posted in October on the this website of articles published in the August 27, 2009 issue of The New England Journal of Medicine regarding the use of sensitive troponin assays for the detection of acute MI [3,4,5,6].

[1] The PEACE Trial Investigators. Angiotensin-converting-enzyme inhibition in stable coronary artery disease. N Engl J Med 2009;351:2058-68

[2] Omland T, de Lemos JA, Sabatine MS, et al. A sensitive cardiac troponin T assay in stable coronary artery disease (PEACE trial investigators) N Engl J Med 2009;361:2538-47

[3] New generation sensitive troponin assays. http://cardiovascular-medicine.com/?p=189 (Accessed 3.2.10)

[4] Schouten O, Boersma E, Hoeks SE, et al. Fluvastatin and perioperative events in patients undergoing vascular surgery. N Engl J Med 2009;361:980-9

[5] Keller T, Zeller T, Peetz D, et al. Sensitive troponin I assay in early diagnosis of acute myocardial infarction. N Engl J Med 2009;361:868-77

[6] Morrow D. Clinical application of sensitive troponin assays. N Engl J Med 2009;361:913-15

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* To view the online text from the book, please navigate to SpringerLink or use the DVD to access electronic content. SpringerLink is a subscription service. For further information, click here.

Further information: Regulation of Cardiac Contraction and Relaxation (see p1189) from Cardiovascular Medicine, 3rd Edn*

In the August 27, 2009 issue of the New England Journal of Medicine, two original articles and an editorial were published regarding the advantages and limitations of the new generation of sensitive troponin assays. The articles by Reichlin et al [1] and Keller et al [2] both concur that with the sensitive assays, the accuracy of troponin for the diagnosis of myocardial infarction (MI) was improved over the older assays. In an editorial, David Morrow [3] stated that differentiation between tissue specificity of troponin for cardiomyocyte injury and myocardial infarction caused by ischemia is diminished with new, more sensitive assays, but the overall diagnostic accuracy is a major step forward in MI detection.

The Advantageous Predictors of Acute Coronary Syndromes Evaluation (APACE) [1] was a prospective, international, multicenter study, and from April 2006 through April 2008, 786 patients were recruited. These patients had presented to the emergency department of a participating hospital with symptoms of myocardial infarction (MI), such as chest pain or angina pectoris. Onset or peak of symptoms had occurred 12 hours before presentation. Four sensitive cardiac troponin assays, Abbott-Architect Troponin I, Roche High-Sensitive Troponin T, Roche Troponin I and Siemens Troponin I Ultra, plus a standard assay, Roche Troponin T, were used to determine cardiac troponin levels at presentation. In patients for whom AMI was the final diagnosis, cardiac troponin levels were significantly higher at presentation in all five assays than in patients who had a different diagnosis. In the case of non-ST-segment elevation MI (NSTEMI) and in the case of ST-segment elevation MI (STEMI), the diagnostic performance of the cardiac troponin levels was similar. However, for patients whose final diagnosis was unstable angina, the cardiac troponin levels were significantly lower than for patients with MI. Patients with chest pain that was from other cardiac causes had similar levels to those with unstable angina, but both were significantly higher than those patients whose chest pain was from noncardiac causes. Results showed that when patients presented with a recent onset of chest pain, the four sensitive cardiac troponin assays used in the study had an early and excellent diagnostic performance. Early diagnosis of MI by the sensitive cardiac troponin assays substantially improves a patient’s prognosis, not only for patients with MI, but also in order to begin proper medical management for patients with unstable angina.

The second paper [2] reports on a study on the use of a newer sensitive troponin assay, the investigators enrolled 1818 consecutive patients from January 2007 to December 2008 who presented with new-onset chest pain at chest-pain units in three German study centers. For this study, one sensitive troponin assay was used. To obtain a primary diagnosis of acute myocardial infarction (AMI), the following conventional assays also used were Roche Troponin T and Seimens Dimension RxL Troponin I. To assess the diagnostic value of the sensitive troponin I assay alone, as well as to determine how soon a diagnosis could be made, two criteria were used to classify patients with AMI, unstable angina, and patients who had an elevated troponin level from causes other than coronary in origin. Investigators concluded that of the two assessments, the diagnostic accuracy was highest with the sensitive troponin I assay (area under the receiver-operating-characteristic curve [AUC], 0.96), as compared with the troponin T assay (AUC, 0.85) and traditional myocardial necrosis markers. Use of the sensitive troponin I assay significantly improved early diagnosis of AMI and could be safely used to rule out or rule in the coronary causes of chest pain.

In an editorial [3] in the same issue of the New England Journal of Medicine on the latest generation of sensitive troponin assays, David Morrow evaluates the advantages and limitations of the assays as reported in two articles. Dr. Morrow agreed that the investigators had shown that the new generation of sensitive troponin assays improved overall diagnostic accuracy and functioned as better tests. However, he warned that the results also showed a trade-off of superior clinical sensitivity for diminished clinical specificity for diagnosis of AMI, and thus, additional and larger studies are warranted.

[1] Reichlin T, Hochholzer W, Bassetti S, et al. Early diagnosis of myocardial infarction with sensitive cardiac troponin assays. N Engl J Med 2009;361:858-67.

[2] Keller T, Zeller T, Peetz D, et al. Sensitive troponin I assay in early diagnosis of acute myocardial infarction. N Engl J Med 2009;361:868-77.

[3] Morrow, D. Clinical application of sensitive troponin assays. N Engl J Med 2009;361:913-15.

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* To view the online text from the book, please navigate to SpringerLink or use the DVD to access electronic content. SpringerLink is a subscription service. For further information, click here.