THERAPEUTIC HYPOTHERMIA AND TEMPERATURE MANAGEMENT Volume 2, Number 2, 2012 ª Mary Ann Liebert, Inc. DOI: 10.1089/ther.2012.0012
Initial Clinical Predictors of Significant Coronary Lesions After Resuscitation from Cardiac Arrest Mariana R. Gonzalez, B.A.,1 Emily C. Esposito, B.A.,1 Marion Leary, B.S.N., R.N.,1 David F. Gaieski, M.D.,1 Daniel M. Kolansky, M.D.,2 Gene Chang, M.D.,2 Lance B. Becker, M.D.,1 Brendan G. Carr, M.D., MSCE,1 Anne V. Grossestreuer, M.S.,1 and Benjamin S. Abella, M.D., M.Phil1,3
Urgent coronary angiography following cardiac arrest is an important consideration as part of a therapeutic hypothermia/postresuscitation care bundle. Few data exist to guide the selection of patients who should receive postarrest angiography. This investigation sought to evaluate patient-level variables on initial postarrest presentation and their association with significant coronary lesions on subsequent angiography. Clinical and angiographic data were collected on consecutive postarrest patients from July 2007 to April 2012 who underwent coronary angiography during hospitalization. Univariate and multivariable analyses were performed to determine the relationship between patient characteristics, clinical data, and the outcome measure, defined as the presence of at least one coronary lesion with > 75% stenosis. Of 527 cardiac arrest patients, 267 achieved return of spontaneous circulation; 106 of these initial survivors received coronary angiography. This cohort had a mean age of 58.1 – 13.5 years and a survival to discharge of 73/106 (69%), with therapeutic hypothermia utilized in 79/ 106 (75%) patients. Significant coronary lesions were found on angiography in 68/106 (64%) patients. Multivariable adjusted analysis demonstrated that significant lesions were associated with a prior known history of coronary disease and/or prior myocardial infarction (odds ratio [OR] 6.2, 95% confidence interval [CI] 1.6–24.4, p = 0.009), and with initial rhythm of ventricular fibrillation/ventricular tachycardia (OR 2.9, 95% CI 1.1–7.7, p = 0.033), but not with hypertension, tobacco use, age, or initial troponin measurements. Prior known history of coronary disease and a shockable arrest rhythm were associated with significant coronary lesions on subsequent angiography. Normal initial troponin values and younger age did not exclude clinically relevant lesions postarrest.
ers and the clinical risk of angiographic procedures may contribute to the documented underutilization of this therapy in the immediate postarrest setting (Merchant et al., 2008). Little data exist to guide clinical decision-making with regard to patient selection for urgent coronary angiography. Several observational studies have suggested that isolated clinical findings, such as chest pain preceding arrest or ST segment elevation on postarrest electrocardiography (ECG), may be associated with significant coronary lesions, but investigations have not tested multiple potential predictors in multivariable models (Spaulding et al., 1997; Dumas et al., 2010). In the current investigation, we sought to evaluate the association of immediately available and common clinical variables (age, past medical history parameters, initial ECG, serologic markers of cardiac injury, and initial rhythm of arrest) with subsequent significant coronary lesions upon postarrest angiography, in both univariate analysis and multivariable models.
Introduction
U
rgent coronary angiography is a crucial consideration immediately following successful resuscitation from cardiac arrest, as part of a postresuscitation/therapeutic hypothermia (TH) bundle of care (Sunde et al., 2007). While cardiac arrest survival remains low (Nichol et al., 2008; LloydJones et al., 2010), a number of investigations have demonstrated the feasibility and potential effectiveness of urgent percutaneous coronary intervention (PCI) to improve patient outcomes following cardiac arrest (Sunde et al., 2007; Sagalyn et al., 2009; Gaieski et al., 2009; Stub et al., 2011). The use of PCI has been shown to have potential benefit with or without associated use of TH in postarrest cohorts (Bernard et al., 2002; Noc, 2008; Stub et al., 2011; Strote et al., 2012). Despite these encouraging data suggesting a role for early coronary angiography following resuscitation, logistical barri1
Department of Emergency Medicine, Center for Resuscitation Science, University of Pennsylvania, Philadelphia, Pennsylvania. Cardiovascular Division, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. Division of Pulmonary, Allergy and Critical Care, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
2 3
73
74 Methods Study design A retrospective chart review was performed on consecutive adult (age q18) patients suffering out-of-hospital cardiac arrest between July 2007 and April 2012, from two urban U.S. teaching hospitals with 24-hour emergency cardiac catheterization capability and active postarrest care/TH protocols. Patients were included in this analysis if they achieved return of spontaneous circulation (ROSC) and received diagnostic coronary angiography and/or PCI during subsequent postarrest hospitalization. Patients who arrested in the emergency department setting, or were transferred to the study hospitals for postcardiac arrest care following out-of-hospital arrest were also included in this investigation. Patients were included for analysis whether or not they underwent TH. The decision to perform cardiac catheterization was made at the time of treatment by clinicians without involvement of study investigators. This study was approved by the Institutional Review Board of the University of Pennsylvania. Data collection and variable definitions Patient demographic data were collected, and information pertaining to the cardiac arrest event (e.g., initial arrest rhythm and location of arrest) was obtained from patient medical records. Patient past medical history (specifically, a prior diagnosis of coronary artery disease and/or myocardial infarction [MI], diabetes mellitus, hypertension, and history of tobacco use) was included if it was known at the time of cardiac arrest presentation. Diagnostic coronary angiography reports were obtained for each patient, and data regarding angiographic findings and any PCIs performed were recorded. A significant coronary lesion, for the purpose of this study, was defined a priori as at least one lesion characterized by > 75% stenosis as described by the performing interventional cardiologist, consistent with definitions from prior literature (Virmani et al., 2000; Surmely et al., 2006). Additionally, patient laboratory data were reviewed to identify the first-available postcardiac arrest troponin T or troponin I blood levels. Troponin values were dichotomized for the purposes of this investigation, with ‘‘abnormal’’ defined as troponin I > 0.4 ng/mL and/or troponin T > 0.030 ng/ mL, following hospital consensus cut-off values at the participating institutions. Data from first-available cardiologistinterpreted ECGs were also abstracted, specifically including data regarding the presence of right or left bundle branch block, presence of ST segment elevation or other ST segment/ T wave abnormalities, and suspected MI; the presence or absence of these features was based on the cardiologist interpretation text and confirmed by study investigators (B.S.A., L.B.B.). For patients with a first-confirmed ECG that occurred greater than 24 hours after the date and time of arrest (four patients), the first-available unconfirmed ECG was identified and interpreted by a study investigator, boardcertified in emergency medicine (B.S.A.).
GONZALEZ ET AL. ography) was assessed through univariate and multivariable logistic regression analyses, performed using a statistical software package (STATA 11, Statacorp, College Station, TX). Logistic regression included the following variables in the model: age, dichotomized at a cut-point of > 50 years, prior history of coronary disease and/or MI, tobacco use, diabetes mellitus or hypertension, abnormal postarrest troponin, and ST/T wave abnormalities. Significance of relationships between dichotomized variables and the outcome variable was analyzed in terms of adjusted odds ratios. Significance was set at an alpha of < 0.05. Results A total of 527 cardiac arrest patients with resuscitation attempts were identified during the study period, and 267 patients achieved ROSC. Of these, 106 subjects underwent postarrest diagnostic coronary angiography during initial hospitalization; this subset represents the study cohort of this investigation (Fig. 1). Mean age was 58.1 – 13.5 years and 31/ 106 (29%) were women. In 75/103 (73%) the initial arrest rhythm was ventricular fibrillation/pulseless ventricular tachycardia (VF/VT) with three subjects excluded due to missing initial rhythm data; 79/106 (75%) patients received postarrest therapeutic hypothermia, and a total of 73/106 (69%) patients achieved survival to discharge. Evaluation of past medical history data revealed that 29/106 (27%) patients had a reported history of coronary artery disease and/or MI, while 61/106 (58%) had a history of hypertension and 54/106 (51%) had a history of tobacco use. Postarrest troponin values were available for 104 of the 106 patients included in this analysis (98%); 55/104 patients (53%) had abnormal troponin levels. ECG analysis identified 49/105 (47%) patients with ST or T wave abnormalities apparent on first-confirmed postarrest ECG, with one ECG not available for analysis. Demographic and clinical data from our cohort are shown in Table 1. Coronary angiography demonstrated significant lesions ( > 75% stenosis) in 68/106 (64%) of the total patient cohort
Statistical analysis The relationship between patient characteristics, clinical data, and the a priori outcome variable (the presence of at least one > 75% stenosis on postarrest diagnostic coronary angi-
FIG. 1. Schematic of subject inclusion in the current investigation, showing the derivation of the final study cohort (n = 106). ROSC, return of spontaneous circulation.
POSTARREST CARDIAC CATHETERIZATION
75
Table 1. Subject Demographic and Clinical Data (n = 106) Characteristics Patient age (years), mean – SD Gender Female Past medical history Coronary artery disease and/or prior MI Hypertension Tobacco use Diabetes mellitus Initial rhythm of arrest VF/VT PEA and asystole Abnormal initial troponin ST/T wave abnormalities on ECG Therapeutic hypothermia treatment Survival to discharge
Value 58.1 – 13.5
Discussion
31 (29%)
In this observational investigation at two urban teaching hospitals, we tested the association between readily available patient-level clinical variables and significant coronary lesions, in the context of a postarrest care bundle including TH in most patients. This work has shown that a reported prior medical history of coronary artery disease and/or MI and a shockable initial rhythm of arrest were significantly associated with clinically relevant coronary lesions in our postarrest patient cohort. Of note, no clear association was found between age, other past medical history, or initial ECG findings and significant coronary lesions. Given that significant coronary lesions are present in as many as 75% of patients resuscitated from cardiac arrest (Spaulding et al., 1997; Dumas et al., 2010; Cronier et al., 2011) and that postarrest catheterization is broadly underutilized (Merchant et al., 2008), a number of investigations have attempted to clarify factors predictive of treatable coronary lesions, with limited success. In the landmark study of Spaulding et al. (1997), the presence of ST segment elevation on postarrest ECG or chest pain prior to arrest was associated with coronary lesions, with a positive predictive value of 0.63 and negative predictive value of 0.74. In a more recent investigation, a more broad set of ECG criteria (for example, ST elevation of depression and/or QRS widening) allowed for a negative predictive value of 1.0 but a positive predictive value of only 0.52 (Sideris et al., 2011). Using this approach, the authors suggest that up to 30% of postarrest patients might be safely excluded from angiography, but many patients without significant disease might still be selected for the procedure following these criteria. Other recent cohort studies found that prior chest pain (Helton et al., 2011) and ST segment elevation on postarrest ECG (Anyfantakis et al., 2009) were moderately predictive of coronary lesions. Compounding the problem of using ST segment elevation alone as a predictor, another angiographic investigation found that 58% of postarrest patients without ST segment elevation on initial postarrest ECG were found to have significant coronary lesions (Dumas et al., 2010). In our study population, no association was found between a number of clinical parameters and significant coronary lesions—including age, initial troponin values, or ECG abnormalities—after multivariable adjustment. In particular, it is important to note the lack of statistical association with both postarrest ECG findings and initial troponin elevation. However, our work does support the reasoning of other literature pertaining to postarrest catheterization, in which some studies only considered patients with shockable initial arrest rhythms as eligible for urgent angiography (Cronier et al., 2011; Helton et al., 2011; Nanjayya and Nayyar, 2012). The current international resuscitation guidelines suggest that urgent coronary angiography be considered for resuscitated patients with a presumed ‘‘cardiac’’ etiology of arrest (Peberdy et al., 2010). The results of the current work suggest that historical medical factors, specifically a history of coronary disease and/or prior MI, and a shockable initial arrest rhythm may be important criteria to help make this subjective
29 61 54 23
(27%) (58%) (51%) (22%)
75 28 55 49 79 73
(73%) (27%) (53%) (47%) (75%) (69%)
Missing data: initial arrest rhythm (n = 3); initial troponin (n = 2); ECG data (n = 1). SD, standard deviation; MI, myocardial infarction; VF/VT, ventricular fibrillation/ventricular tachycardia; PEA, pulseless electrical activity; ECG, electrocardiogram.
(Table 2). Of these patients who received diagnostic coronary angiography, a total of 43 individuals received PCI intervention (defined as balloon angioplasty and/or placement of a coronary stent). Twenty-eight (65%) of the 43 patients who received PCI survived to discharge, compared with 45/63 (71%) who did not receive any intervention (p = NS). Univariate analysis demonstrated that significant lesions were most strongly associated with a prior known history of coronary artery disease/prior MI (odds ratio [OR] 7.2, 95% confidence interval [CI] 2.0–25.9, p = 0.002) and shockable (VF/VT) initial rhythm of arrest (OR 3.0, 95% CI 1.2–7.3, p = 0.018). No statistically significant correlation was observed with respect to subject age, presence of diabetes mellitus, hypertension, tobacco use, abnormal initial troponin, or ST/T wave abnormalities on initial postarrest ECG (Table 3). Different age cut-points were tested without any change in our findings (data not shown). Multivariate regression analysis confirmed that a past medical history of coronary disease/prior MI (OR 6.2, 95% CI 1.6–24.4, p = 0.009) and shockable initial rhythm of arrest (OR Table 2. Findings on Postarrest Coronary Angiography (n = 106) Characteristics Angiographic findings > 75% stenosis > 95% stenosis PCI performed PCI pts: survival to discharge Timing of catheterization < 24 h postarrest 24–48 h postarrest > 48 h postarrest PCI, percutaneous coronary intervention.
2.9, 95% CI 1.1–7.7, p = 0.033) were the variables most strongly associated with significant coronary lesions on postarrest angiography.
Value 68 52 43 28/43
(64%) (49%) (41%) (65%)
67 (63%) 13 (12%) 26 (25%)
76
GONZALEZ ET AL. Table 3. Univariate and Multivariable Analyses of Clinical Variables and Association with Significant Coronary Lesions
Characteristics Age > 50 years Past medical history Coronary disease Hypertension Tobacco use Initial rhythm (VF/VT) Abnormal initial troponin ST/T wave abnormalities on initial postarrest ECG
Univariate analysis OR (95% CI)
p-Value
Adjusted analysis OR (95% CI)
p-Value
1.78 (0.7–4.4)
0.210
0.8 (0.3–2.3)
0.647
7.2 1.4 2.1 3.0 1.1 1.25
0.002 0.45 0.079 0.018 0.82 0.58
6.2 0.8 2.4 2.9 1.0 1.2
0.009 0.41 0.068 0.033 0.97 0.64
(2.0–25.9) (0.6–3.0) (0.9–4.6) (1.2–7.3) (0.5–2.5) (0.5–2.8)
(1.6–24.4) (0.3–2.0) (0.9–6.3) (1.1–7.7) (0.4–2.5) (0.5–3.1)
OR, odds ratio; CI, confidence interval.
and often difficult determination. These factors may especially be useful in the coronary angiography decision process when the postarrest ECG is non-diagnostic and serologic markers of cardiac injury are negative. A number of limitations should be noted in the current work. A crucial question that is not addressed in this investigation relates to the timing of postarrest angiography. It remains unclear whether angiography should be performed within hours of resuscitation or within several days of initial stabilization and after rewarming from TH. An initial investigation on the timing of angiography was inconclusive (Nanjayya and Nayyar, 2012) while another suggested benefit to earlier angiography (Strote et al., 2012). This remains an unresolved question in the resuscitation literature with important practical implications for the timing and priorities of postarrest care, as well as coordination with interventional cardiology teams. Another limitation rests in the retrospective nature of our work, with patients selected for angiography representing a biased cohort. That is, our population was limited to patients that the treating medical team considered appropriate for angiography, potentially based on factors unmeasured in our work. The high proportion of clinically significant lesions and favorable outcomes observed in this cohort may not necessarily be representative of the broader population of postarrest patients. Finally, our investigation represents patients from one metropolitan area treated at two hospitals, which may further limit generalizability. Future evaluation of coronary angiography using existing multicenter postarrest clinical registries (Nielsen et al., 2009; Brady et al., 2011; Grossestreuer et al., 2011) may provide broader perspectives in subsequent investigations. Conclusions In a cohort of postarrest patients treated at two urban U.S. hospitals, prior history of coronary disease and/or MI, as well as a shockable initial arrest rhythm, was associated with significant coronary disease on subsequent angiography. Other readily available clinical data, including initial postarrest ECG findings and serologic markers of cardiac injury, were not statistically associated with significant coronary lesions in multivariable adjusted analyses. Future research on postcardiac arrest angiography with larger patient populations will be required to clarify the relationship between patientlevel clinical factors, significant angiographic findings, and outcomes from cardiac arrest.
Acknowledgments This work was supported in part by the HeartRescue Pennsylvania project, an unrestricted grant from the Medtronic Foundation. The authors are grateful to Drs. Barry Fuchs and Josh Levine for participation in the design of our hospital postarrest care protocols. The authors also thank Dr. Douglas Wiebe for assistance with statistical calculations. Disclosure Statement Dr. Gaieski has received research funding and speaking honoraria from Stryker Corporation. Dr. Becker has received research funding from NHLBI, Benechill Medical, Philips Healthcare, Zoll Medical Systems, Medtronic Corporation, Gaymar Industries, Abbott Diagnostics, Cardiac Science, and the Medtronic Foundation. In addition, Dr. Becker holds patents related to hypothermia induction/reperfusion therapies and holds equity in Cold Core Therapeutics, Inc. Dr. Abella has received research funding from NHLBI, Philips Healthcare, the Medtronic Foundation, and the Doris Duke Foundation; serves on the advisory board of HeartSine Corporation; and has received speaking honoraria from Medivance Corporation. The other authors do not declare any relevant conflicts of interest. References Anyfantakis ZA, Baron G, Aubry P, Himbert D, Feldman LJ, Juliard JM, Ricard-Hibon A, Burnod A, Cokkinos DV, Steg PG. Acute coronary angiographic findings in survivors of outof-hospital cardiac arrest. Am Heart J 2009;157:312–318. Bernard SA, Gray TW, Buist MD, Jones BM, Silvester W, Gutteridge G, Smith K. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med 2002;346:557–563. Brady WJ, Gurka KK, Mehring B, Peberdy MA, O’Connor RE; American Heart Association’s Get with the Guidelines (formerly, NRCPR) Investigators. In-hospital cardiac arrest: impact of monitoring and witnessed event on patient survival and neurologic status at hospital discharge. Resuscitation 2011;82:845–852. Cronier P, Vignon P, Bouferrache K, Aegerter P, Charron C, Templier F, Castro S, El Mahmoud R, Lory C, Pichon N, Dubourg O, Vieillard-Baron A. Impact of routine percutaneous coronary intervention after out-of-hospital cardiac arrest due to ventricular fibrillation. Crit Care 2011;15:R122.
POSTARREST CARDIAC CATHETERIZATION Dumas F, Cariou A, Manzo-Silberman S, Grimaldi D, Vivien B, Rosencher J, Empana JP, Carli P, Mira JP, Jouven X, Spaulding C. Immediate percutaneous coronary intervention is associated with better survival after out-of-hospital cardiac arrest: insights from the PROCAT (Parisian Region Out of hospital Cardiac ArresT) registry. Circ Cardiovasc Interv 2010;3: 200–207. Gaieski DF, Fuchs B, Carr BG, Merchant R, Kolansky DM, Abella BS, Becker LB, Maguire C, Whitehawk M, Levine J, Goyal M. Practical implementation of therapeutic hypothermia after cardiac arrest. Hosp Pract 2009;37:71–83. Grossestreuer AV, Abella BS, Leary M, Neumar RW, Becker LB, Gaieski DF. Penn alliance for therapeutic hypothermia: the first US registry of post-cardiac arrest hypothermia patients hemodynamics, mortality, and therapeutic hypothermia. Circulation 2011;124:A15463. Helton TJ, Nadig V, Subramanya SD, Menon V, Ellis SG, Shishehbor MH. Outcomes of cardiac catheterization and percutaneous coronary intervention for in-hospital ventricular tachycardia or fibrillation cardiac arrest. Catheter Cardiovasc Interv 2011. [Epub ahead of print]; DOI: 10.1002/ccd.23196. Lloyd-Jones D, Adams RJ, Brown TM, Carnethon M, Dai S, De Simone G, Ferguson TB, Ford E, Furie K, Gillespie C, Go A, Greenlund K, Haase N, Hailpern S, Ho PM, Howard V, Kissela B, Kittner S, Lackland D, Lisabeth L, Marelli A, McDermott MM, Meigs J, Mozaffarian D, Mussolino M, Nichol G, Roger VL, Rosamond W, Sacco R, Sorlie P, Roger VL, Thom T, Wasserthiel-Smoller S, Wong ND, Wylie-Rosett J; American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics—2010 update: a report from the American Heart Association. Circulation 2010;121:e46–e215. Merchant RM, Abella BS, Khan M, Huang KN, Beiser DG, Neumar RW, Carr BG, Becker LB, Vanden Hoek TL. Cardiac catheterization is underutilized after in-hospital cardiac arrest. Resuscitation 2008;79:398–403. Nanjayya VB, Nayyar V. Immediate coronary angiogram in comatose survivors of out-of-hospital cardiac arrest-An Australian study. Resuscitation 2012;83:699–704. Nichol G, Thomas E, Callaway CW, Hedges J, Powell JL, Aufderheide TP, Rea T, Lowe R, Brown T, Dreyer J, Davis D, Idris A, Stiell I; Resuscitation Outcomes Consortium Investigators. Regional variation in out-of-hospital cardiac arrest incidence and outcome. J Amer Med Assoc 2008;300:1423–1431. Nielsen N, Hovdenes J, Nilsson F, Rubertsson S, Stammet P, Sunde K, Valsson F, Wanscher M, Friberg H; Hypothermia Network. Outcome, timing and adverse events in therapeutic hypothermia after out-of-hospital cardiac arrest. Acta Anaesthesiol Scand 2009;53:926–934. Noc M. Urgent coronary angiography and percutaneous coronary intervention as a part of postresuscitation management. Crit Care Med 2008;36:S454–S457. Peberdy MA, Callaway CW, Neumar RW, Geocadin RG, Zimmerman JL, Donnino M, Gabrielli A, Silvers SM, Zaritsky AL,
77 Merchant R, Vanden Hoek TL, Kronick SL. Part 9: post-cardiac arrest care: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2010;122:S768–S786. Sagalyn E, Band RA, Gaieski DF, Abella BS. Therapeutic hypothermia after cardiac arrest in clinical practice: review and compilation of recent experiences. Crit Care Med 2009;37: S223–S226. Sideris G, Voicu S, Dillinger JG, Stratiev V, Logeart D, Broche C, Vivien B, Brun PY, Deye N, Capan D, Aout M, Megarbane B, Baud FJ, Henry P. Value of post-resuscitation electrocardiogram in the diagnosis of acute myocardial infarction in out-ofhospital cardiac arrest patients. Resuscitation 2011;82:1148– 1153. Spaulding CM, Joly LM, Rosenberg A, Monchi M, Weber SN, Dhainaut JF, Carli P. Immediate coronary angiography in survivors of out-of-hospital cardiac arrest. N Engl J Med 1997; 336:1629–1633. Strote JA, Maynard C, Olsufka M, Nichol G, Copass MK, Cobb LA, Kim F. Comparison of role of early (less than six hours) to later (more than six hours) or no cardiac catheterization after resuscitation from out-of-hospital cardiac arrest. Am J Cardiol 2012;109:451–454. Stub D, Hengel C, Chan W, Jackson D, Sanders K, Dart AM, Hilton A, Pellegrino V, Shaw JA, Duffy SJ, Bernard S, Kaye DM. Usefulness of cooling and coronary catheterization to improve survival in out-of-hospital cardiac arrest. Am J Cardiol 2011;107:522–527. Sunde K, Pytte M, Jacobsen D, Mangschau A, Jensen LP, Smedsrud C, Draegni T, Steen PA. Implementation of a standardised treatment protocol for post resuscitation care after out-of-hospital cardiac arrest. Resuscitation 2007;73: 29–39. Surmely JF, Nasu K, Fujita H, Terashima M, Matsubara T, Tsuchikane E, Ehara M, Kinoshita Y, Zheng QX, Tanaka N, Katoh O, Suzuki T. Coronary plaque composition of culprit/ target lesions according to the clinical presentation: a virtual histology intravascular ultrasound analysis. Eur Heart J 2006; 27:2939–2944. Virmani R, Kolodgie FD, Burke AP, Farb A, Schwartz SM. Lessons from sudden coronary death: a comprehensive morphological classification scheme for atherosclerotic lesions. Arterioscler Thromb Vasc Biol 2000;20:1262–1275.
Address correspondence to: Benjamin S. Abella, M.D., M.Phil. Department of Emergency Medicine Center for Resuscitation Science University of Pennsylvania 3400 Spruce Street, Ground Ravdin Philadelphia, PA 19104 E-mail: [email protected]
Initial Clinical Predictors of Significant Coronary Lesions After Resuscitation from Cardiac Arrest Mariana R. Gonzalez, B.A.,1 Emily C. Esposito, B.A.,1 Marion Leary, B.S.N., R.N.,1 David F. Gaieski, M.D.,1 Daniel M. Kolansky, M.D.,2 Gene Chang, M.D.,2 Lance B. Becker, M.D.,1 Brendan G. Carr, M.D., MSCE,1 Anne V. Grossestreuer, M.S.,1 and Benjamin S. Abella, M.D., M.Phil1,3
Urgent coronary angiography following cardiac arrest is an important consideration as part of a therapeutic hypothermia/postresuscitation care bundle. Few data exist to guide the selection of patients who should receive postarrest angiography. This investigation sought to evaluate patient-level variables on initial postarrest presentation and their association with significant coronary lesions on subsequent angiography. Clinical and angiographic data were collected on consecutive postarrest patients from July 2007 to April 2012 who underwent coronary angiography during hospitalization. Univariate and multivariable analyses were performed to determine the relationship between patient characteristics, clinical data, and the outcome measure, defined as the presence of at least one coronary lesion with > 75% stenosis. Of 527 cardiac arrest patients, 267 achieved return of spontaneous circulation; 106 of these initial survivors received coronary angiography. This cohort had a mean age of 58.1 – 13.5 years and a survival to discharge of 73/106 (69%), with therapeutic hypothermia utilized in 79/ 106 (75%) patients. Significant coronary lesions were found on angiography in 68/106 (64%) patients. Multivariable adjusted analysis demonstrated that significant lesions were associated with a prior known history of coronary disease and/or prior myocardial infarction (odds ratio [OR] 6.2, 95% confidence interval [CI] 1.6–24.4, p = 0.009), and with initial rhythm of ventricular fibrillation/ventricular tachycardia (OR 2.9, 95% CI 1.1–7.7, p = 0.033), but not with hypertension, tobacco use, age, or initial troponin measurements. Prior known history of coronary disease and a shockable arrest rhythm were associated with significant coronary lesions on subsequent angiography. Normal initial troponin values and younger age did not exclude clinically relevant lesions postarrest.
ers and the clinical risk of angiographic procedures may contribute to the documented underutilization of this therapy in the immediate postarrest setting (Merchant et al., 2008). Little data exist to guide clinical decision-making with regard to patient selection for urgent coronary angiography. Several observational studies have suggested that isolated clinical findings, such as chest pain preceding arrest or ST segment elevation on postarrest electrocardiography (ECG), may be associated with significant coronary lesions, but investigations have not tested multiple potential predictors in multivariable models (Spaulding et al., 1997; Dumas et al., 2010). In the current investigation, we sought to evaluate the association of immediately available and common clinical variables (age, past medical history parameters, initial ECG, serologic markers of cardiac injury, and initial rhythm of arrest) with subsequent significant coronary lesions upon postarrest angiography, in both univariate analysis and multivariable models.
Introduction
U
rgent coronary angiography is a crucial consideration immediately following successful resuscitation from cardiac arrest, as part of a postresuscitation/therapeutic hypothermia (TH) bundle of care (Sunde et al., 2007). While cardiac arrest survival remains low (Nichol et al., 2008; LloydJones et al., 2010), a number of investigations have demonstrated the feasibility and potential effectiveness of urgent percutaneous coronary intervention (PCI) to improve patient outcomes following cardiac arrest (Sunde et al., 2007; Sagalyn et al., 2009; Gaieski et al., 2009; Stub et al., 2011). The use of PCI has been shown to have potential benefit with or without associated use of TH in postarrest cohorts (Bernard et al., 2002; Noc, 2008; Stub et al., 2011; Strote et al., 2012). Despite these encouraging data suggesting a role for early coronary angiography following resuscitation, logistical barri1
Department of Emergency Medicine, Center for Resuscitation Science, University of Pennsylvania, Philadelphia, Pennsylvania. Cardiovascular Division, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. Division of Pulmonary, Allergy and Critical Care, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
2 3
73
74 Methods Study design A retrospective chart review was performed on consecutive adult (age q18) patients suffering out-of-hospital cardiac arrest between July 2007 and April 2012, from two urban U.S. teaching hospitals with 24-hour emergency cardiac catheterization capability and active postarrest care/TH protocols. Patients were included in this analysis if they achieved return of spontaneous circulation (ROSC) and received diagnostic coronary angiography and/or PCI during subsequent postarrest hospitalization. Patients who arrested in the emergency department setting, or were transferred to the study hospitals for postcardiac arrest care following out-of-hospital arrest were also included in this investigation. Patients were included for analysis whether or not they underwent TH. The decision to perform cardiac catheterization was made at the time of treatment by clinicians without involvement of study investigators. This study was approved by the Institutional Review Board of the University of Pennsylvania. Data collection and variable definitions Patient demographic data were collected, and information pertaining to the cardiac arrest event (e.g., initial arrest rhythm and location of arrest) was obtained from patient medical records. Patient past medical history (specifically, a prior diagnosis of coronary artery disease and/or myocardial infarction [MI], diabetes mellitus, hypertension, and history of tobacco use) was included if it was known at the time of cardiac arrest presentation. Diagnostic coronary angiography reports were obtained for each patient, and data regarding angiographic findings and any PCIs performed were recorded. A significant coronary lesion, for the purpose of this study, was defined a priori as at least one lesion characterized by > 75% stenosis as described by the performing interventional cardiologist, consistent with definitions from prior literature (Virmani et al., 2000; Surmely et al., 2006). Additionally, patient laboratory data were reviewed to identify the first-available postcardiac arrest troponin T or troponin I blood levels. Troponin values were dichotomized for the purposes of this investigation, with ‘‘abnormal’’ defined as troponin I > 0.4 ng/mL and/or troponin T > 0.030 ng/ mL, following hospital consensus cut-off values at the participating institutions. Data from first-available cardiologistinterpreted ECGs were also abstracted, specifically including data regarding the presence of right or left bundle branch block, presence of ST segment elevation or other ST segment/ T wave abnormalities, and suspected MI; the presence or absence of these features was based on the cardiologist interpretation text and confirmed by study investigators (B.S.A., L.B.B.). For patients with a first-confirmed ECG that occurred greater than 24 hours after the date and time of arrest (four patients), the first-available unconfirmed ECG was identified and interpreted by a study investigator, boardcertified in emergency medicine (B.S.A.).
GONZALEZ ET AL. ography) was assessed through univariate and multivariable logistic regression analyses, performed using a statistical software package (STATA 11, Statacorp, College Station, TX). Logistic regression included the following variables in the model: age, dichotomized at a cut-point of > 50 years, prior history of coronary disease and/or MI, tobacco use, diabetes mellitus or hypertension, abnormal postarrest troponin, and ST/T wave abnormalities. Significance of relationships between dichotomized variables and the outcome variable was analyzed in terms of adjusted odds ratios. Significance was set at an alpha of < 0.05. Results A total of 527 cardiac arrest patients with resuscitation attempts were identified during the study period, and 267 patients achieved ROSC. Of these, 106 subjects underwent postarrest diagnostic coronary angiography during initial hospitalization; this subset represents the study cohort of this investigation (Fig. 1). Mean age was 58.1 – 13.5 years and 31/ 106 (29%) were women. In 75/103 (73%) the initial arrest rhythm was ventricular fibrillation/pulseless ventricular tachycardia (VF/VT) with three subjects excluded due to missing initial rhythm data; 79/106 (75%) patients received postarrest therapeutic hypothermia, and a total of 73/106 (69%) patients achieved survival to discharge. Evaluation of past medical history data revealed that 29/106 (27%) patients had a reported history of coronary artery disease and/or MI, while 61/106 (58%) had a history of hypertension and 54/106 (51%) had a history of tobacco use. Postarrest troponin values were available for 104 of the 106 patients included in this analysis (98%); 55/104 patients (53%) had abnormal troponin levels. ECG analysis identified 49/105 (47%) patients with ST or T wave abnormalities apparent on first-confirmed postarrest ECG, with one ECG not available for analysis. Demographic and clinical data from our cohort are shown in Table 1. Coronary angiography demonstrated significant lesions ( > 75% stenosis) in 68/106 (64%) of the total patient cohort
Statistical analysis The relationship between patient characteristics, clinical data, and the a priori outcome variable (the presence of at least one > 75% stenosis on postarrest diagnostic coronary angi-
FIG. 1. Schematic of subject inclusion in the current investigation, showing the derivation of the final study cohort (n = 106). ROSC, return of spontaneous circulation.
POSTARREST CARDIAC CATHETERIZATION
75
Table 1. Subject Demographic and Clinical Data (n = 106) Characteristics Patient age (years), mean – SD Gender Female Past medical history Coronary artery disease and/or prior MI Hypertension Tobacco use Diabetes mellitus Initial rhythm of arrest VF/VT PEA and asystole Abnormal initial troponin ST/T wave abnormalities on ECG Therapeutic hypothermia treatment Survival to discharge
Value 58.1 – 13.5
Discussion
31 (29%)
In this observational investigation at two urban teaching hospitals, we tested the association between readily available patient-level clinical variables and significant coronary lesions, in the context of a postarrest care bundle including TH in most patients. This work has shown that a reported prior medical history of coronary artery disease and/or MI and a shockable initial rhythm of arrest were significantly associated with clinically relevant coronary lesions in our postarrest patient cohort. Of note, no clear association was found between age, other past medical history, or initial ECG findings and significant coronary lesions. Given that significant coronary lesions are present in as many as 75% of patients resuscitated from cardiac arrest (Spaulding et al., 1997; Dumas et al., 2010; Cronier et al., 2011) and that postarrest catheterization is broadly underutilized (Merchant et al., 2008), a number of investigations have attempted to clarify factors predictive of treatable coronary lesions, with limited success. In the landmark study of Spaulding et al. (1997), the presence of ST segment elevation on postarrest ECG or chest pain prior to arrest was associated with coronary lesions, with a positive predictive value of 0.63 and negative predictive value of 0.74. In a more recent investigation, a more broad set of ECG criteria (for example, ST elevation of depression and/or QRS widening) allowed for a negative predictive value of 1.0 but a positive predictive value of only 0.52 (Sideris et al., 2011). Using this approach, the authors suggest that up to 30% of postarrest patients might be safely excluded from angiography, but many patients without significant disease might still be selected for the procedure following these criteria. Other recent cohort studies found that prior chest pain (Helton et al., 2011) and ST segment elevation on postarrest ECG (Anyfantakis et al., 2009) were moderately predictive of coronary lesions. Compounding the problem of using ST segment elevation alone as a predictor, another angiographic investigation found that 58% of postarrest patients without ST segment elevation on initial postarrest ECG were found to have significant coronary lesions (Dumas et al., 2010). In our study population, no association was found between a number of clinical parameters and significant coronary lesions—including age, initial troponin values, or ECG abnormalities—after multivariable adjustment. In particular, it is important to note the lack of statistical association with both postarrest ECG findings and initial troponin elevation. However, our work does support the reasoning of other literature pertaining to postarrest catheterization, in which some studies only considered patients with shockable initial arrest rhythms as eligible for urgent angiography (Cronier et al., 2011; Helton et al., 2011; Nanjayya and Nayyar, 2012). The current international resuscitation guidelines suggest that urgent coronary angiography be considered for resuscitated patients with a presumed ‘‘cardiac’’ etiology of arrest (Peberdy et al., 2010). The results of the current work suggest that historical medical factors, specifically a history of coronary disease and/or prior MI, and a shockable initial arrest rhythm may be important criteria to help make this subjective
29 61 54 23
(27%) (58%) (51%) (22%)
75 28 55 49 79 73
(73%) (27%) (53%) (47%) (75%) (69%)
Missing data: initial arrest rhythm (n = 3); initial troponin (n = 2); ECG data (n = 1). SD, standard deviation; MI, myocardial infarction; VF/VT, ventricular fibrillation/ventricular tachycardia; PEA, pulseless electrical activity; ECG, electrocardiogram.
(Table 2). Of these patients who received diagnostic coronary angiography, a total of 43 individuals received PCI intervention (defined as balloon angioplasty and/or placement of a coronary stent). Twenty-eight (65%) of the 43 patients who received PCI survived to discharge, compared with 45/63 (71%) who did not receive any intervention (p = NS). Univariate analysis demonstrated that significant lesions were most strongly associated with a prior known history of coronary artery disease/prior MI (odds ratio [OR] 7.2, 95% confidence interval [CI] 2.0–25.9, p = 0.002) and shockable (VF/VT) initial rhythm of arrest (OR 3.0, 95% CI 1.2–7.3, p = 0.018). No statistically significant correlation was observed with respect to subject age, presence of diabetes mellitus, hypertension, tobacco use, abnormal initial troponin, or ST/T wave abnormalities on initial postarrest ECG (Table 3). Different age cut-points were tested without any change in our findings (data not shown). Multivariate regression analysis confirmed that a past medical history of coronary disease/prior MI (OR 6.2, 95% CI 1.6–24.4, p = 0.009) and shockable initial rhythm of arrest (OR Table 2. Findings on Postarrest Coronary Angiography (n = 106) Characteristics Angiographic findings > 75% stenosis > 95% stenosis PCI performed PCI pts: survival to discharge Timing of catheterization < 24 h postarrest 24–48 h postarrest > 48 h postarrest PCI, percutaneous coronary intervention.
2.9, 95% CI 1.1–7.7, p = 0.033) were the variables most strongly associated with significant coronary lesions on postarrest angiography.
Value 68 52 43 28/43
(64%) (49%) (41%) (65%)
67 (63%) 13 (12%) 26 (25%)
76
GONZALEZ ET AL. Table 3. Univariate and Multivariable Analyses of Clinical Variables and Association with Significant Coronary Lesions
Characteristics Age > 50 years Past medical history Coronary disease Hypertension Tobacco use Initial rhythm (VF/VT) Abnormal initial troponin ST/T wave abnormalities on initial postarrest ECG
Univariate analysis OR (95% CI)
p-Value
Adjusted analysis OR (95% CI)
p-Value
1.78 (0.7–4.4)
0.210
0.8 (0.3–2.3)
0.647
7.2 1.4 2.1 3.0 1.1 1.25
0.002 0.45 0.079 0.018 0.82 0.58
6.2 0.8 2.4 2.9 1.0 1.2
0.009 0.41 0.068 0.033 0.97 0.64
(2.0–25.9) (0.6–3.0) (0.9–4.6) (1.2–7.3) (0.5–2.5) (0.5–2.8)
(1.6–24.4) (0.3–2.0) (0.9–6.3) (1.1–7.7) (0.4–2.5) (0.5–3.1)
OR, odds ratio; CI, confidence interval.
and often difficult determination. These factors may especially be useful in the coronary angiography decision process when the postarrest ECG is non-diagnostic and serologic markers of cardiac injury are negative. A number of limitations should be noted in the current work. A crucial question that is not addressed in this investigation relates to the timing of postarrest angiography. It remains unclear whether angiography should be performed within hours of resuscitation or within several days of initial stabilization and after rewarming from TH. An initial investigation on the timing of angiography was inconclusive (Nanjayya and Nayyar, 2012) while another suggested benefit to earlier angiography (Strote et al., 2012). This remains an unresolved question in the resuscitation literature with important practical implications for the timing and priorities of postarrest care, as well as coordination with interventional cardiology teams. Another limitation rests in the retrospective nature of our work, with patients selected for angiography representing a biased cohort. That is, our population was limited to patients that the treating medical team considered appropriate for angiography, potentially based on factors unmeasured in our work. The high proportion of clinically significant lesions and favorable outcomes observed in this cohort may not necessarily be representative of the broader population of postarrest patients. Finally, our investigation represents patients from one metropolitan area treated at two hospitals, which may further limit generalizability. Future evaluation of coronary angiography using existing multicenter postarrest clinical registries (Nielsen et al., 2009; Brady et al., 2011; Grossestreuer et al., 2011) may provide broader perspectives in subsequent investigations. Conclusions In a cohort of postarrest patients treated at two urban U.S. hospitals, prior history of coronary disease and/or MI, as well as a shockable initial arrest rhythm, was associated with significant coronary disease on subsequent angiography. Other readily available clinical data, including initial postarrest ECG findings and serologic markers of cardiac injury, were not statistically associated with significant coronary lesions in multivariable adjusted analyses. Future research on postcardiac arrest angiography with larger patient populations will be required to clarify the relationship between patientlevel clinical factors, significant angiographic findings, and outcomes from cardiac arrest.
Acknowledgments This work was supported in part by the HeartRescue Pennsylvania project, an unrestricted grant from the Medtronic Foundation. The authors are grateful to Drs. Barry Fuchs and Josh Levine for participation in the design of our hospital postarrest care protocols. The authors also thank Dr. Douglas Wiebe for assistance with statistical calculations. Disclosure Statement Dr. Gaieski has received research funding and speaking honoraria from Stryker Corporation. Dr. Becker has received research funding from NHLBI, Benechill Medical, Philips Healthcare, Zoll Medical Systems, Medtronic Corporation, Gaymar Industries, Abbott Diagnostics, Cardiac Science, and the Medtronic Foundation. In addition, Dr. Becker holds patents related to hypothermia induction/reperfusion therapies and holds equity in Cold Core Therapeutics, Inc. Dr. Abella has received research funding from NHLBI, Philips Healthcare, the Medtronic Foundation, and the Doris Duke Foundation; serves on the advisory board of HeartSine Corporation; and has received speaking honoraria from Medivance Corporation. The other authors do not declare any relevant conflicts of interest. References Anyfantakis ZA, Baron G, Aubry P, Himbert D, Feldman LJ, Juliard JM, Ricard-Hibon A, Burnod A, Cokkinos DV, Steg PG. Acute coronary angiographic findings in survivors of outof-hospital cardiac arrest. Am Heart J 2009;157:312–318. Bernard SA, Gray TW, Buist MD, Jones BM, Silvester W, Gutteridge G, Smith K. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med 2002;346:557–563. Brady WJ, Gurka KK, Mehring B, Peberdy MA, O’Connor RE; American Heart Association’s Get with the Guidelines (formerly, NRCPR) Investigators. In-hospital cardiac arrest: impact of monitoring and witnessed event on patient survival and neurologic status at hospital discharge. Resuscitation 2011;82:845–852. Cronier P, Vignon P, Bouferrache K, Aegerter P, Charron C, Templier F, Castro S, El Mahmoud R, Lory C, Pichon N, Dubourg O, Vieillard-Baron A. Impact of routine percutaneous coronary intervention after out-of-hospital cardiac arrest due to ventricular fibrillation. Crit Care 2011;15:R122.
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Address correspondence to: Benjamin S. Abella, M.D., M.Phil. Department of Emergency Medicine Center for Resuscitation Science University of Pennsylvania 3400 Spruce Street, Ground Ravdin Philadelphia, PA 19104 E-mail: [email protected]
