Michael C. Kontos

2014 AHA/ACC Guideline for the Management of Patients With Non-ST-Elevation Acute Coronary Syndromes A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines

Preamble e346 1. Introduction e347 2. Overview of Acs e349 3. Initial Evaluation and Management e350 4. Early Hospital Care e359

Clinical Practice Guideline2014 AHA/ACC Guideline for the Management of Patients With Non–ST-Elevation Acute Coronary Syndromes: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines

Circulation is available at http://circ.ahajournals.org DOI: 10.1161/CIR.0000000000000134 The writing committee gratefully acknowledges the memory of Dr. Francis M. Fesmire (representative of the American College of Emergency Physicians), who died during the development of this document but contributed immensely to our understanding of non–ST-elevation acute coronary syndromes. *Writing committee members are required to recuse themselves from voting on sections to which their specific relationships with industry and other entities may apply; see Appendix 1 for recusal information. †ACC/AHA Representative. ‡ACC/AHA Task Force on Practice Guidelines Liaison. §American College of Physicians Representative. ║American Academy of Family Physicians Representative. ¶Society of Thoracic Surgeons Representative. #ACC/AHA Task Force on Performance Measures Liaison. **Society for Cardiovascular Angiography and Interventions Representative. ††Former Task Force member; current member during the writing effort. This document was approved by the American Heart Association Science Advisory and Coordinating Committee and the American College of Cardiology Board of Trustees in August 2014. The online-only Comprehensive Relationships Data Supplement is available with this article at http://circ.ahajournals.org/lookup/suppl/ doi:10.1161/CIR.0000000000000134/-/DC1. The online-only Data Supplement files are available with this article at http://circ.ahajournals.org/lookup/suppl/doi:10.1161/ CIR.0000000000000134/-/DC2. The American Heart Association requests that this document be cited as follows: Amsterdam EA, Wenger NK, Brindis RG, Casey DE Jr, Ganiats TG, Holmes DR Jr, Jaffe AS, Jneid H, Kelly RF, Kontos MC, Levine GN, Liebson PR, Mukherjee D, Peterson ED, Sabatine MS, Smalling RW, Zieman SJ. 2014 ACC/AHA guideline for the management of patients with non–ST-elevation acute coronary syndromes: a report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines. Circulation. 2014;130:e344–e426. This article is copublished in the Journal of the American College of Cardiology. Copies: This document is available on the World Wide Web sites of the American Heart Association (my.americanheart.org) and the American College of Cardiology (www.cardiosource.org). A copy of the document is available at http://my.americanheart.org/statements by selecting either the “By Topic” link or the “By Publication Date” link. To purchase additional reprints, call 843-216-2533 or e-mail kelle.ramsay@wolterskluwer.com. Expert peer review of AHA Scientific Statements is conducted by the AHA Office of Science Operations. For more on AHA statements and guidelines development, visit http://my.americanheart.org/statements and select the “Policies and Development” link. Permissions: Multiple copies, modification, alteration, enhancement, and/or distribution of this document are not permitted without the express permission of the American Heart Association. Instructions for obtaining permission are located at http://www.heart.org/HEARTORG/General/ Copyright-Permission-Guidelines_UCM_300404_Article.jsp. A link to the “Copyright Permissions Request Form” appears on the right side of the page. 2014 AHA/ACC Guideline for the Management of Patients With Non–ST-Elevation Acute Coronary Syndromes A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines

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.

Use of evidence-based therapies in short-term outcomes of ST-segment elevation myocardial infarction and non-ST-segment elevation myocardial infarction in patients with chronic kidney disease: a report from the National Cardiovascular Data Acute Coronary Treatment and Intervention Outcomes Network registry.

Background Chronic kidney disease (CKD) is a risk factor for myocardial infarction (MI) and death. Our goal was to characterize the association between CKD severity and short-term outcomes and the use of in-hospital evidence-based therapies among patients with STEMI and NSTEMI.Background— Chronic kidney disease (CKD) is a risk factor for myocardial infarction (MI) and death. Our goal was to characterize the association between CKD severity and short-term outcomes and the use of in-hospital evidence-based therapies among patients with ST-segment elevation MI (STEMI) and non–ST-segment elevation MI (NSTEMI). Methods and Results— The study sample was drawn from the Acute Coronary Treatment and Intervention Outcomes Network registry, a nationwide sample of STEMI (n=19 029) and NSTEMI (n=30 462) patients. Estimated glomerular filtration rate was calculated with the Modification of Diet in Renal Disease equation in relation to use of immediate (first 24 hours) therapies and early (first 48 hours) cardiac catheterization as well as in-hospital major bleeding events and death. Overall, 30.5% and 42.9% of patients with STEMI and NSTEMI, respectively, had CKD. Regardless of MI type, patients with progressively more severe CKD had higher rates of death. For STEMI, the odds ratio for stage 3a, 3b, 4, and 5 CKD compared with patients with no CKD was 2.49, 3.72, 4.82, and 7.97, respectively (Ptrend<0.0001). For NSTEMI, the analogous odds ratios were 1.81, 2.41, 3.50, and 4.09 (P for trend <0.0001). In addition, patients with progressively more severe CKD were less likely to receive immediate evidence-based therapies including aspirin, &bgr;-blockers, or clopidogrel, were less likely to undergo any reperfusion (STEMI) or revascularization (NSTEMI), and had higher rates of bleeding. Conclusions— Reports over the past decade have highlighted the importance of CKD among patients with MI. Data from this contemporary cohort suggest that patients with CKD still receive fewer evidence-based therapies and have substantially higher mortality rates.

Interleukin-1 Blockade With Anakinra to Prevent Adverse Cardiac Remodeling After Acute Myocardial Infarction (Virginia Commonwealth University Anakinra Remodeling Trial [VCU-ART] Pilot Study)

Acute myocardial infarction (AMI) initiates an intense inflammatory response in which interleukin-1 (IL-1) plays a central role. The IL-1 receptor antagonist is a naturally occurring antagonist, and anakinra is the recombinant form used to treat inflammatory diseases. The aim of the present pilot study was to test the safety and effects of IL-1 blockade with anakinra on left ventricular (LV) remodeling after AMI. Ten patients with ST-segment elevation AMI were randomized to either anakinra 100 mg/day subcutaneously for 14 days or placebo in a double-blind fashion. Two cardiac magnetic resonance (CMR) imaging and echocardiographic studies were performed during a 10- to 14-week period. The primary end point was the difference in the interval change in the LV end-systolic volume index (LVESVi) between the 2 groups on CMR imaging. The secondary end points included differences in the interval changes in the LV end-diastolic volume index, and C-reactive protein levels. A +2.0 ml/m(2) median increase (interquartile range +1.0, +11.5) in the LVESVi on CMR imaging was seen in the placebo group and a -3.2 ml/m(2) median decrease (interquartile range -4.5, -1.6) was seen in the anakinra group (p = 0.033). The median difference was 5.2 ml/m(2). On echocardiography, the median difference in the LVESVi change was 13.4 ml/m(2) (p = 0.006). Similar differences were observed in the LV end-diastolic volume index on CMR imaging (7.6 ml/m(2), p = 0.033) and echocardiography (9.4 ml/m(2), p = 0.008). The change in C-reactive protein levels between admission and 72 hours after admission correlated with the change in the LVESVi (R = +0.71, p = 0.022). In conclusion, in the present pilot study of patients with ST-segment elevation AMI, IL-1 blockade with anakinra was safe and favorably affected by LV remodeling. If confirmed in larger trials, IL-1 blockade might represent a novel therapeutic strategy to prevent heart failure after AMI.

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.

Utilization and Impact of Pre-Hospital Electrocardiograms for Patients With Acute ST-Segment Elevation Myocardial Infarction: Data From the NCDR (National Cardiovascular Data Registry) ACTION (Acute Coronary Treatment and Intervention Outcomes Network) Registry

OBJECTIVES This study sought to determine the association of pre-hospital electrocardiograms (ECGs) and the timing of reperfusion therapy for patients with ST-segment elevation myocardial infarction (STEMI). BACKGROUND Pre-hospital ECGs have been recommended in the management of patients with chest pain transported by emergency medical services (EMS). METHODS We evaluated patients with STEMI from the NCDR (National Cardiovascular Data Registry) ACTION (Acute Coronary Treatment and Intervention Outcomes Network) registry who were transported by EMS from January 1, 2007, through December 31, 2007. Patients were stratified by the use of pre-hospital ECGs, and timing of reperfusion therapy was compared between the 2 groups. RESULTS A total of 7,098 of 12,097 patients (58.7%) utilized EMS, and 1,941 of these 7,098 EMS transport patients (27.4%) received a pre-hospital ECG. Among the EMS transport population, primary percutaneous coronary intervention was performed in 92.1% of patients with a pre-hospital ECG versus 86.3% with an in-hospital ECG, whereas fibrinolytic therapy was used in 4.6% versus 4.2% of patients. Median door-to-needle times for patients receiving fibrinolytic therapy (19 min vs. 29 min, p = 0.003) and median door-to-balloon times for patients undergoing primary percutaneous coronary intervention (61 min vs. 75 min, p < 0.0001) were significantly shorter for patients with a pre-hospital ECG. A suggestive trend for a lower risk of in-hospital mortality was observed with pre-hospital ECG use (adjusted odds ratio: 0.80, 95% confidence interval: 0.63 to 1.01). CONCLUSIONS Only one-quarter of these patients transported by EMS receive a pre-hospital ECG. The use of a pre-hospital ECG was associated with a greater use of reperfusion therapy, faster reperfusion times, and a suggested trend for a lower risk of mortality.

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.

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.