Robert L. Jesse

Risk of adverse outcomes associated with concomitant use of clopidogrel and proton pump inhibitors following acute coronary syndrome.

CONTEXT Prior mechanistic studies reported that omeprazole decreases the platelet inhibitory effects of clopidogrel, yet the clinical significance of these findings is not clear. OBJECTIVE To assess outcomes of patients taking clopidogrel with or without a proton pump inhibitor (PPI) after hospitalization for acute coronary syndrome (ACS). DESIGN, SETTING, AND PATIENTS Retrospective cohort study of 8205 patients with ACS taking clopidogrel after discharge from 127 Veterans Affairs hospitals between October 1, 2003, and January 31, 2006. Vital status information was available for all patients through September 30, 2006. MAIN OUTCOME MEASURES All-cause mortality or rehospitalization for ACS. RESULTS Of 8205 patients taking clopidogrel after discharge, 63.9% (n = 5244) were prescribed PPI at discharge, during follow-up, or both and 36.1% (n = 2961) were not prescribed PPI. Death or rehospitalization for ACS occurred in 20.8% (n = 615) of patients taking clopidogrel without PPI and 29.8% (n = 1561) of patients taking clopidogrel plus PPI. In multivariable analyses, use of clopidogrel plus PPI was associated with an increased risk of death or rehospitalization for ACS compared with use of clopidogrel without PPI (adjusted odds ratio [AOR], 1.25; 95% confidence interval [CI], 1.11-1.41). Among patients taking clopidogrel after hospital discharge and prescribed PPI at any point during follow-up (n = 5244), periods of use of clopidogrel plus PPI (compared with periods of use of clopidogrel without PPI) were associated with a higher risk of death or rehospitalization for ACS (adjusted hazard ratio, 1.27; 95% CI, 1.10-1.46). In analyses of secondary outcomes, patients taking clopidogrel plus PPI had a higher risk of hospitalizations for recurrent ACS compared with patients taking clopidogrel without PPI (14.6% vs 6.9%; AOR, 1.86 [95% CI, 1.57-2.20]) and revascularization procedures (15.5% vs 11.9%; AOR, 1.49 [95% CI, 1.30-1.71]), but not for all-cause mortality (19.9% vs 16.6%; AOR, 0.91 [95% CI, 0.80-1.05]). The association between use of clopidogrel plus PPI and increased risk of adverse outcomes also was consistent using a nested case-control study design (AOR, 1.32; 95% CI, 1.14-1.54). In addition, use of PPI without clopidogrel was not associated with death or rehospitalization for ACS among patients not taking clopidogrel after hospital discharge (n = 6450) (AOR, 0.98; 95% CI, 0.85-1.13). CONCLUSION Concomitant use of clopidogrel and PPI after hospital discharge for ACS was associated with an increased risk of adverse outcomes than use of clopidogrel without PPI, suggesting that use of PPI may be associated with attenuation of benefits of clopidogrel after ACS.

National Academy of Clinical Biochemistry Laboratory Medicine Practice Guidelines: Clinical Characteristics and Utilization of Biochemical Markers in Acute Coronary Syndromes

I. OVERVIEW OF THE ACUTE CORONARYSYNDROME e357A. Definition of Terms e357B. Pathogenesis and Management of ACS e357II. USE OF BIOCHEMICAL MARKERS IN THEINITIAL EVALUATION OF ACS e358A. Diagnosis of Myocardial Infarction e3581. Biochemical Markers of MyocardialNecrosis e3582. Optimal Timing of Sample Acquisition.......e3593. Criteria for Diagnosis of MI e3604. Additional Considerations in the Use ofBiomarkers for Diagnosis of MI e360B. Early Risk Stratification e3611. Biochemical Markers of Cardiac Injury.......e361a. Pathophysiology e361b. Relationship to Clinical Outcomes.........e361c. Decision-Limits e362d. Therapeutic Decision-Making e3622. Natriuretic Peptides e362a. Pathophysiology e362b. Relationship to Clinical Outcomes.........e363c. Decision-Limits e364d. Therapeutic Decision-Making e3653. Biochemical Markers of Inflammation........e365a. Pathophysiology e365b. Relationship to Clinical Outcomes.........e365c. Decision-Limits e365d. Therapeutic Decision-Making e3674. Biochemical Markers of Ischemia e3675. Multimarker Approach e3676. Other Novel Markers e368III. USE OF BIOCHEMICAL MARKERS IN THEMANAGEMENT OF NSTEACS e368A. Clinical Decision-Making e3681. Biochemical Markers of Cardiac Injury.......e3682. Other Biochemical Markers e369

Comprehensive Strategy for the Evaluation and Triage of the Chest Pain Patient

STUDY OBJECTIVE To evaluate the safety and efficacy of a systematic evaluation and triage strategy including immediate resting myocardial perfusion imaging in patients presenting to the emergency department with chest pain of possible ischemic origin. METHODS We conducted an observational study of 1,187 consecutive patients seen in the ED of an urban tertiary care hospital with the chief complaint of chest pain. Within 60 minutes of presentation, each patient was assigned to one of five levels on the basis of his or her risk of myocardial infarction (MI) or unstable angina (UA): level 1, MI; level 2, MI/UA; level 3, probable UA; level 4, possible UA; and level 5, noncardiac chest pain. In the lower risk levels (3 and 4), immediate resting myocardial perfusion imaging was used as a risk-stratification tool alone (level 4) or in combination with serial markers (level 3). RESULTS Acute MI, early revascularization indicative of acute coronary syndrome, or both were consistent with risk designations: level 1: 96% MI, 56% revascularization; level 2: 13% MI, 29% revascularization; level 3: 3% MI, 17% revascularization; level 4: .7% MI; 2.5% revascularization. Sensitivity of immediate resting myocardial perfusion imaging for MI was 100% (95% confidence interval [CI], 64% to 100%) and specificity 78% (74% to 82%). In patients with abnormal imaging findings, risk for MI (7% versus 0%, P < .001; relative risk [RR], 50; 95% CI, 2.8 to 889) and for MI or revascularization (32% vs 2%, P < .001; RR, 15.5; 95% CI, 6.4 to 36) were significantly higher than in patients with normal imaging findings. During 1-year follow-up, patients with normal imaging findings (n = 338) had an event rate of 3% (revascularization) with no MI or death (combined events: negative predictive value, 97%; 95% CI, 95% to 98%). Patients with abnormal imaging findings (n = 100) had a 42% event rate (combined events: RR, 14.2; 95% CI, 6.5 to 30; P < .001), with 11% experiencing MI and 8% cardiac death. CONCLUSION This strategy is a safe, effective method for rapid triage of chest pain patients. Rapid perfusion imaging plays a key role in the risk stratification of low-risk patients, allowing discrimination of unsuspected high risk patients who require prompt admission and possible intervention from those who are truly at low risk.

National Academy of Clinical Biochemistry Laboratory Medicine Practice Guidelines: Clinical Utilization of Cardiac Biomarker Testing in Heart Failure

### A. Context of Biochemical Marker Testing in Heart Failure Biochemical marker testing has revolutionized the approach to diagnosis and management of heart failure over the past decade. There is an unsurpassed excitement in the heart failure community that significant advances in our understanding of currently available and future cardiac biomarkers will facilitate improved characterization of heart failure disease states and promote individualized therapy in heart failure and beyond. However, like most novel diagnostic tests, the promising findings from pivotal trials have met with ongoing challenges when applied in the clinical setting. The material discussed in this guidelines document addresses clinical use of BNP/NT-proBNP and cardiac troponin testing in the context of heart failure diagnosis, risk stratification and management, including therapeutic guidance in adult (>18 year-old) patients. Together with the associated document titled “ National Academy of Clinical Biochemistry and IFCC Committee for Standardization of Markers of Cardiac Damage Laboratory Medicine Practice Guidelines: Analytical Issues for Biomarkers of Heart Failure ”, …

ACCF 2012 Expert Consensus Document on Practical Clinical Considerations in the Interpretation of Troponin Elevations: A Report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents

This document has been developed as an Expert Consensus Document (ECD) by the American College of Cardiology Foundation (ACCF), American Association for Clinical Chemistry (AACC), American College of Chest Physicians (ACCP), American College of Emergency Physicians (ACEP), American College of

Value of acute rest sestamibi perfusion imaging for evaluation of patients admitted to the emergency department with chest pain.

OBJECTIVES This study sought to determine the ability of early perfusion imaging using technetium-99m sestamibi to predict adverse cardiac outcomes in patients who present to the emergency department with possible cardiac ischemia and nondiagnostic electrocardiograms (ECGs). BACKGROUND Evaluation of patients presenting to the emergency department with possible acute coronary syndromes and nondiagnostic ECGs is problematic. Accurate risk stratification is necessary to prevent serious adverse outcomes. Initial results suggest that early perfusion imaging using technetium-99m sestamibi enables reliable risk stratification. METHODS Patients presenting to the emergency department with a low to moderate probability of acute coronary syndromes underwent rapid sestamibi injection with gated single-photon emission computed tomographic imaging. Studies showing perfusion defects with associated wall motion abnormalities were considered positive. RESULTS A total of 532 consecutive patients underwent serial myocardial marker analysis and rest perfusion imaging. Of these patients, perfusion imaging was positive in 171 (32%). Positive perfusion imaging was the only multivariate predictor of myocardial infarction (MI) (p < 0.0001, odds ratio [OR] 33, 95% confidence interval [CI] 7.7 to 141) and was the most important independent predictor of MI or revascularization (p < 0.0001, OR 14, 95% CI 7.3 to 25), followed by diabetes (p < 0.01, OR 2.8, 95% CI 1.5 to 5.1), typical angina (p = 0.01, OR 2.1, 95% CI 1.2 to 3.7) and male gender (p = 0.03, OR 1.9, 95% CI 1.1 to 3.5). The sensitivity of positive perfusion imaging for MI was 93% (95% CI 77% to 98%), and for MI or revascularization it was 81% (95% CI 71% to 88%), with negative predictive values of 99% (95% CI 98% to 100%) and 95% (95% CI 92% to 97%), respectively. CONCLUSIONS Positive rest perfusion imaging accurately identified patients at high risk for adverse cardiac outcomes, whereas negative perfusion imaging identified a low risk patient group. Early perfusion imaging allows for rapid and accurate risk stratification of emergency department patients with possible cardiac ischemia and nondiagnostic ECGs.

Comparison of Myocardial Perfusion Imaging and Cardiac Troponin I in Patients Admitted to the Emergency Department With Chest Pain

BACKGROUND Identification of patients with acute coronary syndromes (ACS) among those who present to emergency departments with possible myocardial ischemia is difficult. Myocardial perfusion imaging with 99mTc sestamibi and measurement of serum cardiac troponin I (cTnI) both can identify patients with ACS. METHODS AND RESULTS Patients considered at low to moderate risk for ACS underwent gated single-photon emission CT sestamibi imaging and serial myocardial marker measurements of creatine kinase-MB, total creatine kinase activity, and cTnI over 8 hours. Positive perfusion imaging was defined as a perfusion defect with associated abnormalities in wall motion or thickening. cTnI >/=2.0 ng/mL was considered abnormal. Among the 620 patients studied, 59 (9%) had myocardial infarction and 81 (13%) had significant coronary disease; of these patients, 58 underwent revascularization. Perfusion imaging was positive in 241 patients (39%), initial cTnI was positive in 37 (6%), and cTnI was >/=2.0 ng/mL in 74 (12%). Sensitivity for detecting myocardial infarction was not significantly different between perfusion imaging (92%) and cTnI (90%), and both were significantly higher than the initial cTnI (39%). Sensitivity for predicting revascularization or significant coronary disease was significantly higher for perfusion imaging than for serial cTnI, although specificity for all end points was significantly lower. Lowering the cutoff value of cTnI to 1.0 ng/mL did not significantly change the results. CONCLUSIONS Early perfusion imaging and serial cTnI have comparable sensitivities for identifying myocardial infarction. Perfusion imaging identified more patients who underwent revascularization or who had significant coronary disease, but it had lower specificity. The 2 tests can provide complementary information for identifying patients at risk for ACS.

Modulation of purified phospholipase A2 activity from human platelets by calcium and indomethacin

A membrane bound phospholipase A2 (phosphatide 2-acylhydrolase, EC 3.1.1.4) from human platelets has been purified 3500-fold, and partially characterized. Phospholipase A2 activity was assayed using [1(-14)C] oleate-labeled Escherichia coli or sonicated dispersions of synthetic phospholipids. The 2-acyl specificity of the phospholipase activity was confirmed using phosphatidylethanolamine labeled in the C-1 position as substrate. The purified enzyme was maximally active between pH 8.0 and 10.5, and had an absolute requirement for low concentrations of Ca2+. Indomethacin, but not aspirin, inhibited phospholipase A2 activity.

Impact of the troponin standard on the prevalence of acute myocardial infarction

BACKGROUND Recent recommendations are that troponin should replace creatine kinase (CK)-MB as the diagnostic standard for myocardial infarction (MI). The impact of this change has not been well described. Our objective was to determine the impact of a troponin standard on the prevalence of acute non-ST-elevation MI. METHODS The current study was a retrospective analysis of consecutive patients without ST-segment elevation admitted for exclusion of myocardial ischemia to an inner city urban tertiary care center. All patients underwent serial marker sampling (CK, CK-MB, and cardiac troponin I [cTnI]). Patients with ST elevation consistent with acute MI (n = 130) or who did not have an 8 hour cTnI (n = 124) were excluded. The impact of 3 different cTnI diagnostic values were examined in 2181 patients: the lower limit of detectability (LLD); an optimal diagnostic value (OPT), chosen using receiver operator characteristic curve analysis; and the manufacturers suggested upper reference level (URL), when compared to a gold standard CK-MB MI definition. In addition, MI prevalence was assessed using different CK-MB MI definitions and evaluated in patients with ischemic changes only. RESULTS The prevalence CK-MB MI was 7.8%. Using the various cTnI diagnostic values, the incidence of MI increased the prevalence by 28% to 195%. Using the optimal diagnostic value for cTnI, patients with cTnI elevations not meeting CK-MB MI criteria had an intermediate 30-day mortality (5.4%) compared to those with CK-MB MI (7.1%). Grouping the cTnI positive, CK-MB MI negative patients with the CK-MB MI patients rather than the non-CK-MB MI patients reduced mortality for both the MI (to 5.9%) and non-MI groups (from 1.9% to 1.6%). CONCLUSIONS Changing to a troponin standard will have a substantial impact on the number of patients diagnosed with MI. The revised definition for MI will have important clinical and health care implications.

Sustain inhibition of nitric oxide by NG-nitro-l-arginine improves myocardial function following ischemia/reperfusion in isolated perfused rat heart

It has been postulated nitric oxide (NO) can react with superoxide anion (·O − 2 ) to generate hydroxyl (·OH) radical. If this is correct inhibition of NO synthesis could attenuate ·OH radical mediated ischemia/reperfusion injury. Therefore we studied the effects of N G -nitro- l -arginine ( l -NNA), a competitive inhibitor of the NO synthase enzyme on ischemia/reperfusion injury in isolated perfused rat hearts. Three groups of rats ( n = 12–15) were studied. Group I: Untreated ischemia/reperfusion control (37.5 min of global ischemia follows by 20 min reperfusion); Group II: ischemia/reperfusion with 25μm N G -nitro- l -arginine; and Group III: ischemia/reperfusion in the presence of l -NNA and 2m m l -arginine, the substrate for NO synthase. Coronary flow (in ml/min) and ventricular developed pressure +dP/dt and -dP/dt were measured 5 min prior to ischemia and at the end of reperfusion. Baseline preischemic developed pressure was significantly lower in l -NNA perfused hearts than controls (76.8±5.9 v 97.6±2.9 mmHg, P l -NNA perfused hearts (57.4±7.4 v 20.8±6.4 mmHg in control). This protective effect was reversed by the addition of l -arginine. Preischemic coronary flow was decreased significantly in the l -NNa group (6.4±0.5ml/min) compared to controls (11.6±0.7ml/min). The duration of sinus rhythm was significantly improved from 3.8±1.2 min in controls to 15.1±0.8 min in l-NNA perfused hearts. A corresponding significantly lower incidence of arrhythmias was observed (10.2±1.5 in ischemia/reperfusion group v 1.7±0.8 min with l -NNA). Again, hearts perfused with l -NNA plus l -arginine had more arrhythmias and a shorter duration of sinus rhythm. The results show that despite the reduction of myocardial contractility and coronary flow prior to ischemia l -NNA significantly preserved myocardial contractility and reduced arrhythmias following reperfusion. Electron spin resonance or cytochrome c reduction assay demonstrated that l -NNA did not scavenge ·OH nor ·O − 2 radical directly. These results suggest that ischemia/reperfusion injury observed in this model may in part be due to ·OH radical formed as a result of NO interaction with ·O − 2 and that inhibition of this pathway by l -NNA leads to recovery of myocardial function.