The NEW ENGLAND JOURNAL f MEDICINE REATMENT OF PATIENTS WITH ACUTE tial CCTA or standard evaluation without CCTA chest pain but an inconclusive initial evalu- patient care in both groups was not mandated by ation with the use of biomarkers and elec the study protocol but instead was at the discretio agnos it nging and majori ihed in ne disease.Contrast-enhanced this article at NEIM.org coronary computed tomographic angiogra phy (CCTA)has high sensitivity and specificity for the STUDY POPULATION detection of clinically significant coronary artery Patient enrollment began on April 23,2010,and on January 30 at nine on Un 。25 Rule out my dial e n to p n the ter Assisted Tomography (ROMICAT-D).a ROMICAT-I study6 with the goal of enrolling blinded observational study involving patients in population with a similar prevalence of acute the emergency departmen with suspected acute coronary syndromes (approximately 8%).Eligibl coronary syndromes and other studies? hav patients were 40 to 74 years of age,presented to wn th A have e emergency depar che pain ng out acu es thin 24 bou ion and the occurrence of maior adverse cardio ency department.we in sinus rhythn vascular events over the next 2 years.The results and wa arranted further risk stratification to rule of two previous randomized,multicenter trials out acute coronary syndromes,as determined by suggest that CCTA may facilitate safe and earlie an attending physician in the emergency depart triage of low-risk patients and that CCTA can ru ment.Major ex story o out co th stres is coronary arte th tile ures and greater costs than functional tes the local impaired t ngThus.equipoise exists regarding the effec nine level,>1.5 mg per deciliter [132.6 umol per tiveness of incorporating CCTA into an evaluation liter)),hemodynamic or clinical instability,known e allergy to an iodinated contrast agen the .comp nass index weight in kilograms divided b n stra th that of 0 me sthgreater tha egy dep ment for ants with s stive of an acute coronary syndrome and to STUDY PROTOCOL evaluate the downstream testing.cost,and radia- Eligible patients were identified,provided writter tion exposure associated with CCTA. informed consent,and were randomly assigned at their initial evaluation in th emergency depar METHODS ng 1e er CCT STUDY DESIGN AND OVERSIGHT itial ROMICAT-II was designed as arandomized.cor artme at or the standard evaluatio trolled,multicenter trial in which an evaluation and in the emergency department at that site all tes management strategy that included CCTA as a results were provided to emergency department first diagnostic test performed as early as possi physicians in real tim wa compa rgency mand Hated by the study protocol in partment evalua nts with acu an nt.Tas base ed on the lo 300 N ENGLJ MED 367:4 NEJM.ORG JULY 26,201
T h e n e w e ngl a nd j o u r na l o f m e dic i n e 300 n engl j med 367;4 nejm.org july 26, 2012 Treatment of patients with acute chest pain but an inconclusive initial evaluation with the use of biomarkers and electrocardiographic (ECG) testing is often diagnostically challenging and inefficient. The majority of patients with acute coronary syndromes have underlying coronary artery disease.1 Contrast-enhanced coronary computed tomographic angiography (CCTA) has high sensitivity and specificity for the detection of clinically significant coronary artery disease, as compared with invasive coronary angiography, in patients in stable condition with suspected or known coronary artery disease.2-5 Rule Out Myocardial Infarction/Ischemia Using Computer Assisted Tomography (ROMICAT-I),6 a blinded observational study involving patients in the emergency department with suspected acute coronary syndromes, and other studies7,8 have shown that normal findings on CCTA have a very high negative predictive value for ruling out acute coronary syndromes during the index hospitalization and the occurrence of major adverse cardiovascular events over the next 2 years.7,9 The results of two previous randomized, multicenter trials10,11 suggest that CCTA may facilitate safe and earlier triage of low-risk patients and that CCTA can rule out coronary artery disease faster than stress myocardial-perfusion imaging. However, imaging the coronary anatomy with CCTA can involve more procedures and greater costs than functional testing.12 Thus, equipoise exists regarding the effectiveness of incorporating CCTA into an evaluation strategy in the emergency department. The objectives of this study were to compare the effectiveness of a CCTA-based evaluation strategy with that of standard evaluation in the emergency department for patients with symptoms suggestive of an acute coronary syndrome and to evaluate the downstream testing, cost, and radiation exposure associated with CCTA. Me thods Study Design and Oversight ROMICAT-II was designed as a randomized, controlled, multicenter trial in which an evaluation and management strategy that included CCTA as a first diagnostic test performed as early as possible was compared with a standard emergency department evaluation for patients with acute chest pain suggestive of an acute coronary syndrome. After random assignments had been made to initial CCTA or standard evaluation without CCTA, patient care in both groups was not mandated by the study protocol but instead was at the discretion of local physicians. The design of ROMICAT-II has been described in detail previously,13 and the study protocol is available with the full text of this article at NEJM.org. Study Population Patient enrollment began on April 23, 2010, and ended on January 30, 2012, at nine hospitals in the United States. All patients provided written informed consent to participate in the study. Eligibility criteria were chosen according to the ROMICAT-I study,6 with the goal of enrolling a population with a similar prevalence of acute coronary syndromes (approximately 8%). Eligible patients were 40 to 74 years of age, presented to the emergency department with chest pain (or the anginal equivalent) of at least 5 minutes’ duration within 24 hours before presentation in the emergency department, were in sinus rhythm, and warranted further risk stratification to rule out acute coronary syndromes, as determined by an attending physician in the emergency department. Major exclusion criteria were a history of known coronary artery disease, new diagnostic ischemic changes on the initial ECG, an initial troponin level in excess of the 99th percentile of the local assay, impaired renal function (creatinine level, >1.5 mg per deciliter [132.6 µmol per liter]), hemodynamic or clinical instability, known allergy to an iodinated contrast agent, a bodymass index (the weight in kilograms divided by the square of the height in meters) greater than 40, or currently symptomatic asthma. Study Protocol Eligible patients were identified, provided written informed consent, and were randomly assigned at their initial evaluation in the emergency department during weekday daytime hours. Patients were randomly assigned in a 1:1 ratio to either CCTA as part of the initial evaluation in the emergency department or the standard evaluation strategy in the emergency department at that site. All test results were provided to emergency department physicians in real time. Additional care was not mandated by the study protocol in either randomization group. The discharge diagnosis was based on the local physicians’ assessment. The discharge diag-
CORONARY CT ANGIOGRAPHY FOR ACUTE CHEST PAIN noses were adjudicated separately by a clinical 242 patients.which included all patients with acute coronary syndromes,the first 8 patients enrolled each site,4%o f patients dis rge with cardia ecte subgroup of patients.The ided reasons y sy To ascertain n tentially undetected acute cor 1000 Un nary syndromes and as a safety measure,patients discharged within 24 hours after presentation in the eme d by tele urs to as the ucal st tus.A fo ow-up telephone ca evongrgnopeam telenhone calls information on re at visits to the emergency department or rehospitalizations for recurrent chest pain (including diagnostic testing,interventions,and clinical nts during the 1.Screening.Randomizatio and Folt up of the Study Patien coronary compu angiograph CCTA Before the start of the study.participating site were not routinely performing CCTA in patients presentation in the emergency department to the in the emergency department to detect acute cor- final test that was used to rule out an acute coro- onary syndromes,but they were required to use nary syndrome.The rate of direct discharge fron at least 64-slic for patient as the em t wa as th mitte with use accordin vation unit or the hospital.Resource utilization guidelines.The use of tube modulation to lower was defined as any diagnostic testing (CcTa ex- radiation exposure was strongly encouraged.CCTA ercise treadmill testing,nuclear imaging,stress images were interpreted on-site in real time,and echocardiography,or cardiac catheterization)or interventions from the ent in th y department to v-up at 28 END POINTS cu der The pr pecified primary end point was the le recurrent chest pain.Cumulative radiation expo sure was defined as radiation exposure from presentation in the emergency department to the testing,including CCTA,nuclear perfusion im- time of the discharge order.This end point was aging,and in sive coronary angiography,me chosen because it re ts th of act e St sure thth taken in respo dur to the degal consider tio s in n and ho pitalization)and fol Health Secondary effective ness end points included the costs during the index care episode were assessed time to diagnosis.defined as the time from pre from reports from hospital cost-accounting sys sentation in the emergency department until the tems and physician billing records and were ad first diagnostic test that led to the diagnosis of an ted to 2011 ars. n costs to acute coronary synd rome,or as the time fror diagnostic testing,and inte ventions ring th N ENGLJ MED 367:4 NEJM.ORG JULY 26,2012 301
coronary CT Angiogr aphy for Acute Chest Pain n engl j med 367;4 nejm.org july 26, 2012 301 noses were adjudicated separately by a clinical end-points committee in a predefined sample of 242 patients, which included all patients with acute coronary syndromes, the first 8 patients enrolled at each site, 4% of patients discharged with cardiac symptoms, and a randomly selected subgroup of 10% of all patients. The definitions of acute coronary syndromes are provided in the Supplementary Appendix, available at NEJM.org. To ascertain potentially undetected acute coronary syndromes and as a safety measure, patients discharged within 24 hours after presentation in the emergency department were contacted by telephone within 72 hours to assess their clinical status. A follow-up telephone call to all patients was also conducted 28 days after discharge. During telephone calls, information on repeat visits to the emergency department or rehospitalizations for recurrent chest pain (including diagnostic testing, interventions, and clinical events during follow-up) was obtained and verified by the collection of medical records. CCTA Before the start of the study, participating sites were not routinely performing CCTA in patients in the emergency department to detect acute coronary syndromes, but they were required to use at least 64-slice CT technology for patient assessment. Protocols involving both retrospectively ECG-gated and prospectively ECG-triggered CCTA were permitted, with use according to published guidelines.14 The use of tube modulation to lower radiation exposure was strongly encouraged. CCTA images were interpreted on-site in real time, and the results were communicated to the responsible clinician. End Points The prespecified primary end point was the length of the hospital stay, defined as the time from presentation in the emergency department to the time of the discharge order. This end point was chosen because it reflects the summary of actions taken in response to clinical information and test results, as well as logistical, cost, and medical and legal considerations in participating centers. Secondary effectiveness end points included the time to diagnosis, defined as the time from presentation in the emergency department until the first diagnostic test that led to the diagnosis of an acute coronary syndrome, or as the time from presentation in the emergency department to the final test that was used to rule out an acute coronary syndrome. The rate of direct discharge from the emergency department was defined as the proportion of patients discharged from the emergency department without admission to an observation unit or the hospital. Resource utilization was defined as any diagnostic testing (CCTA, exercise treadmill testing, nuclear imaging, stress echocardiography, or cardiac catheterization) or interventions from the index assessment in the emergency department to follow-up at 28 days, and it included resources used during repeat visits to the emergency department or hospitalization for recurrent chest pain. Cumulative radiation exposure was defined as radiation exposure from testing, including CCTA, nuclear perfusion imaging, and invasive coronary angiography, measured in millisieverts and calculated with the use of standard methods15 during the index care episode (the visit to the emergency department and hospitalization) and follow-up. Health care costs during the index care episode were assessed from reports from hospital cost-accounting systems and physician billing records and were adjusted to 2011 dollars. Mean costs for patient care, diagnostic testing, and interventions during the 1000 Underwent randomization 1273 Patients were assessed for eligibility 273 Were excluded 228 Declined to participate 45 Had administrative reasons 501 Were assigned to CCTA (473 [94%] underwent CCTA as a first test) 499 Were assigned to standard evaluation in emergency department 497 (99%) Were included in 28-day follow-up 490 (98%) Were included in 28-day follow-up Figure 1. Screening, Randomization, and Follow-up of the Study Patients. CCTA denotes coronary computed tomographic angiography
The NEW ENGLAND JOURNAL f MEDICINE index care episode were used to estimate the are presented as means tSD and medians with costs during follow-up. interquartile ranges.Comparisons between groups Safety variables prespecified as secondary were performed with the use of an in end points inc undetecte acute cor sample est for con nuou unex discharee in patients with a hos nital stay of 24 sided pvalue of less than 005 wa hours)to ensure that potentially earlier discharge indicate statistical significance concordance be in the CCTA group was not associated with in-tween the discharge diagnosis made at the study creased adverse events,major adverse cardiovas- site and the independently adjudicated diagnosi ined as death,myocardial in- n a select subpopula was assessed with urgent coronary the app o ha ter or renal failure).These variables mnificance level if the true betw were adjudicated by an external,independent difference in the length of stay in the hospital was clinical-events committee. at least 8.3 hours.Details of the simulation are described elsewhere. E The study did not ave predefined yses we e performed by yanin rules or b ect t o-t-Connouat Table 1.Baseline Demographic and Clinical Chara ristics of the Patients.* Standard Variable 499 Mean age-yr 54± 54 Female sex-% 8 46 0.57 Race or ethnic group-no.(96) Black 14128 141(28) 1.00 White 330166 330(66) 只 Asian 323 Non-Hispanic 435(87 422(85) Cardiovascular risk factors-no.(% Hypertension 26954 27254) Diabetes mellitus 8617刀 870刀 093 Dyslipidemia 230(46 2445 0.75 2439 Family history of premature coronary artery disease 13627 0 No.of cardiovascular risk factors- 0.63 Oor1 38 2or3 52 y 0 10 Relevant prior medication-. Aspirin 152 Beta-blocker 88(18) 82(16) Statin 143(28) 151(30) 0.58 N ENGLJ MED 367:4 NEJM.ORG JULY 26,2012
T h e n e w e ngl a nd j o u r na l o f m e dic i n e 302 n engl j med 367;4 nejm.org july 26, 2012 index care episode were used to estimate the costs during follow-up. Safety variables prespecified as secondary end points included an undetected acute coronary syndrome (defined as an unexpected cardiovascular event within 72 hours after hospital discharge in patients with a hospital stay of <24 hours), to ensure that potentially earlier discharge in the CCTA group was not associated with increased adverse events, major adverse cardiovascular events (defined as death, myocardial infarction, unstable angina, or urgent coronary revascularization within 28 days), and periprocedural complications (stroke, bleeding, anaphylaxis, or renal failure). These predefined safety variables were adjudicated by an external, independent clinical-events committee. Statistical Analyses All statistical analyses were performed by an independent data coordinating center on the basis of an intention-to-treat analysis. Continuous data are presented as means ±SD and medians with interquartile ranges. Comparisons between groups were performed with the use of an independentsample t-test for continuous variables, Fisher’s exact test for categorical variables, and the Wilcoxon rank-sum test for ordinal variables. A twosided P value of less than 0.05 was considered to indicate statistical significance. Concordance between the discharge diagnosis made at the study site and the independently adjudicated diagnosis in a selected subpopulation was assessed with the use of the kappa statistic. The study was designed to have greater than 83% power with the use of a t-test at a two-sided 5% significance level if the true between-group difference in the length of stay in the hospital was at least 8.3 hours. Details of the simulation are described elsewhere.13 The study did not have predefined stopping rules or boundaries with respect to the primary end point or safety end points. Rather, the data and safety monitoring board was responsible for Table 1. Baseline Demographic and Clinical Characteristics of the Patients.* Variable CCTA (N=501) Standard Evaluation (N=499) P Value Mean age — yr 54±8 54±8 0.44 Female sex — % 48 46 0.57 Race or ethnic group — no. (%) Black 141 (28) 141 (28) 1.00 White 330 (66) 330 (66) 0.95 Asian 18 (4) 13 (23) 0.47 Other 12 (2) 18 (4) 0.27 Non-Hispanic 435 (87) 422 (85) 0.57 Cardiovascular risk factors — no. (%) Hypertension 269 (54) 272 (54) 0.80 Diabetes mellitus 86 (17) 87 (17) 0.93 Dyslipidemia 230 (46) 224 (45) 0.75 Former or current smoker 249 (50) 243 (49) 0.75 Family history of premature coronary artery disease 135 (27) 136 (27) 0.94 No. of cardiovascular risk factors — % 0.68 0 or 1 36 38 2 or 3 54 52 ≥4 10 10 Relevant prior medication — no. (%) Aspirin 115 (23) 113 (23) 0.94 Beta-blocker 88 (18) 82 (16) 0.67 Statin 143 (28) 151 (30) 0.58
CORONARY CT ANGIOGRAPHY FOR ACUTE CHEST PAIN Table 1.(Continued.) ( PValu Initial presentation in emergency departmen Chief symptom一no.%) 0.47 Radiating or nonradiating chest pain or anginal equivalent 44489 452(91) Arm,jaw,shoulder.or epigastric pain 2】14 163) Shortness of breath 71 102 Other Heart rate-beats/min 0.58 Blood pressure一mmHe Systolic 144±23 144±23 Diastolic 83±13 83±13 0.94 RMI 29.4±5.3 29.1±4.8 041 0.16 Noncardiac chest pain 426(85 445(89 Noncoronary cardiac pair 71) 8(2) Coronary chest pain not asso with syndrome 255 1431 Acute syndrome 9) 32(同 Unstable angina pectori 35 Myocardial infarction 82) 15(3) sSD.BMI denotes body-mass index(the om ded byeof in which coronary site and inder enden adjudication for the disch ordanc, 242 patients]:kappa,0.94). RESULTS PRIMARY A STUDY POPUL Of100 e ts,501were randomly a e effectiv end points are shown in Table2. toed to domy a: ndard evalua since the ment.All patients were included in the inte the hospital stay in the group of patients ran- to-treat analysis (Fig.1).CCTA was not performed domly assigned to CCTA was decreased by 7.6 in 28 patients(6%)because of the patient's deci-hours,as compared with the group randomly as- patients),safety concerns signed to a sta dard emergency de partment eval ty or CCIA (5 pa .00 ws th 1000 The riginal medical the atients in th ere disch records for repeat visits to the eme gency depart-within 86 hours after presentation as comp red ment or hospitalizations were available inall cases.with 10%of the patients randomly assigned toa Baseline charact eristics of the study population standard evaluation in the emergen depart are shown in Table 1 After a complete evalua- ment.In the subgroup of patients with a fina final or an cor Agreement between the N ENGLJ MED 367:4 NEJM.ORG JULY 26,2012
coronary CT Angiogr aphy for Acute Chest Pain n engl j med 367;4 nejm.org july 26, 2012 303 assessing every case in which an acute coronary syndrome might have been undetected. R esult s Study Population Of 1000 enrolled patients, 501 were randomly assigned to CCTA and 499 were randomly assigned to a standard evaluation in the emergency department. All patients were included in the intentionto-treat analysis (Fig. 1). CCTA was not performed in 28 patients (6%) because of the patient’s decision to decline CCTA (9 patients), safety concerns (5 patients), unavailability of CCTA (5 patients), or technical difficulties (9 patients). Overall, 987 of 1000 randomly assigned patients (99%) had complete follow-up at 28 days. The original medical records for repeat visits to the emergency department or hospitalizations were available in all cases. Baseline characteristics of the study population are shown in Table 1. After a complete evaluation, 75 patients (8%) had a final diagnosis of an acute coronary syndrome. Agreement between the site and independent adjudication for the discharge diagnosis was very high (concordance, 98% [236 of 242 patients]; kappa, 0.94). Primary and Secondary Effectiveness End Points The effectiveness end points are shown in Table 2. The primary end point met the prespecified criterion for significance, since the average length of the hospital stay in the group of patients randomly assigned to CCTA was decreased by 7.6 hours, as compared with the group randomly assigned to a standard emergency department evaluation (P<0.001). Figure 2 shows the cumulative distribution of discharged patients with lengthof-stay data in the two groups. Notably, 50% of the patients in the CCTA group were discharged within 8.6 hours after presentation, as compared with 10% of the patients randomly assigned to a standard evaluation in the emergency department. In the subgroup of patients with a final diagnosis of an acute coronary syndrome, the length of stay in the hospital was similar after Table 1. (Continued.) Variable CCTA (N=501) Standard Evaluation (N=499) P Value Initial presentation in emergency department Chief symptom — no. (%) 0.47 Radiating or nonradiating chest pain or anginal equivalent 444 (89) 452 (91) Arm, jaw, shoulder, or epigastric pain 21 (4) 16 (3) Shortness of breath 7 (1) 10 (2) Other 29 (6) 21 (4) Heart rate — beats/min 78±14 77±14 0.58 Blood pressure — mm Hg Systolic 144±23 144±23 0.80 Diastolic 83±13 83±13 0.94 BMI 29.4±5.3 29.1±4.8 0.41 Discharge diagnosis after index emergency department visit or hospitalization — no. (%) 0.16 Noncardiac chest pain 426 (85) 445 (89) Noncoronary cardiac pain 7 (1) 8 (2) Coronary chest pain not associated with acute coronary syndrome 25 (5) 14 (3) Acute coronary syndrome 43 (9) 32 (6) Unstable angina pectoris 35 (7) 17 (3) Myocardial infarction 8 (2) 15 (3) * Plus–minus values are means ±SD. BMI denotes body-mass index (the weight in kilograms divided by the square of the height in meters), and CCTA coronary computed tomographic angiography
The NEW ENGLAND JOURNAL O MEDICINE Table 2.Primary and Secondary Effectiveness and Safety End Points. End Point 6 PValue Length of ospital stay-h 232470 Median Time to diagnosis-hr a s with final diagnosis other than acute coronary syndrome s with final diagnosis of acute coronary syndrome Interquartile range Discharge status一 1o.(% harge from emergency department against medical advice 器 up for recurrent chest pain within 28 days-no Repeat visit to emergency departmen 4 19 0.38 ry syndrome rocedural compli Major adverse cardiova ular events at dayso. 8 Plus-minus values are meansSD. CCTA and after standard evaluation in the emer- acute coronary syndr the mean time to diag gency departm s was sig all cohor groups sis o group wer ctly dis 304 N ENGLJ MED 367:4 NEJM.ORG JULY 26,2012
T h e n e w e ngl a nd j o u r na l o f m e dic i n e 304 n engl j med 367;4 nejm.org july 26, 2012 CCTA and after standard evaluation in the emergency department. In the overall cohort and also in the subgroups with or without a final diagnosis of an acute coronary syndrome, the mean time to diagnosis was significantly decreased with CCTA as compared with a standard evaluation. Patients in the CCTA group were more often directly disTable 2. Primary and Secondary Effectiveness and Safety End Points.* End Point CCTA (N=501) Standard Evaluation (N=499) P Value Length of hospital stay — hr All patients in intention-to-treat analysis <0.001 Mean 23.2±37.0 30.8±28.0 Median 8.6 26.7 Interquartile range 6.4–27.6 21.4–30.6 Patients with final diagnosis other than acute coronary syndrome <0.001 Mean 17.2±24.6 27.2±19.5 Median 8.1 26.3 Interquartile range 6.2–24.6 20.6–29.5 Patients with final diagnosis of acute coronary syndrome 0.87 Mean 86.3±72.3 83.8±61.3 Median 56.9 71.8 Interquartile range 46.2–95.9 45.2–96.7 Time to diagnosis — hr All patients in intention-to-treat analysis <0.001 Mean 10.4±12.6 18.7±11.8 Median 5.8 21.0 Interquartile range 4.0–9.0 8.5–23.8 Patients with final diagnosis other than acute coronary syndrome <0.001 Mean 10.6±12.3 18.8±12.0 Median 6.1 21.1 Interquartile range 4.0–9.6 8.7–23.8 Patients with final diagnosis of acute coronary syndrome 0.002 Mean 8.0±15.1 17.1±9.5 Median 4.4 14.9 Interquartile range 3.3–5.6 7.4–25.1 Discharge status — no. (%) <0.001 Direct discharge from emergency department 233 (47) 62 (12) Admission to observation unit 153 (30) 301 (60) Admission to hospital 107 (21) 125 (25) Left against medical advice 8 (2) 11 (2) Follow-up for recurrent chest pain within 28 days — no. Repeat visit to emergency department 14 19 0.38 Repeat hospitalization 7 7 Safety — no. Undetected acute coronary syndrome 0 0 Periprocedural complications 2 0 0.50 Major adverse cardiovascular events at 28 days — no. 2 6 0.18 * Plus–minus values are means ±SD