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Timing of coronary angiography in survivors of out-of-hospital cardiac arrest without obvious extracardiac causes
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Clinical paper
Timing of coronary angiography in survivors of out-of-hospital cardiac arrest without obvious extracardiac causes Isabelle Irene Staudacher a , Corstiaan den Uil b , Lucia Jewbali b , Laurens van Zandvoort a , Felix Zijlstra a , Nicolas Van Mieghem a , Eric Boersma a , Joost Daemen a,∗ a b
Department of Cardiology, Thoraxcenter, Erasmus Medical Center, The Netherlands Deparment of Intensive Care Medicine, Erasmus Medical Center, The Netherlands
a r t i c l e
i n f o
Article history: Received 25 July 2017 Received in revised form 2 November 2017 Accepted 16 November 2017 Keywords: Out-of-hospital cardiac arrest Coronary angiography Percutaneous coronary intervention Cardiogenic shock Myocardial infarction
a b s t r a c t Background: Indications and timing of coronary angiography in patients surviving out-of-hospital cardiac arrest (OHCA) remain controversial. The aim of the present study was to assess the impact of an early invasive strategy in patients presenting with an OHCA and no obvious extracardiac cause. Methods: Between January 1st 2009 and December 31st 2014 a total 612 survivors of OHCA were admitted to our institution. Patients with no obvious extracardiac cause (n = 507) were stratified into two groups: patients that underwent cardiac catheterization ≤3 h (early invasive; n = 291) and patients not undergoing cardiac catheterization within 3 h (non-early invasive; n = 216). Primary endpoint was all-cause mortality at 30 days. Results: All-cause 30-day mortality was 28.9% in the early invasive group vs. 36.6% in the non-early invasive group (log-rank p = 0.071). After propensity analyses, an early invasive strategy, as compared to a non-early strategy, was not associated with 30-day mortality (adjusted Hazard ratio [HR] 0.69; 95% CI 0.35–1.37; p = 0.029). Cox multivariable regression analyses demonstrated age (HR 1.04/year; 95% CI 1.02–1.07) and presentation with cardiogenic shock (HR 5.1; 95% CI 1.8–14.0) to be the sole independent predictors of 30-day mortality. Conclusions: In this retrospective study, early coronary angiography (<3 h), as compared to a non-early invasive strategy, was not associated with reduced 30-day mortality in patients hospitalized after OHCA, irrespective of the presence of ST segment elevation or cardiogenic shock at presentation. © 2017 Elsevier B.V. All rights reserved.
Introduction Out-of-hospital cardiac arrest (OHCA) remains a challenging clinical problem frequently characterized by an unclear etiology and an overall poor survival [1]. Acute coronary thrombotic occlusion has been identified as the leading cause of OHCA and recent studies suggest that an early invasive strategy including immediate
Abbreviations: ACS, acute coronary syndrome; BMI, body mass index; CABG, coronary artery bypass surgery; CAD, coronary artery disease; CAG, coronary angiography; Cathlab, catheterization laboratory; CK, creatine kinase; CKMB, creatine kinase myocardial band; HR, hazard ratio; hsTnT, high sensitivity troponin T; MAP, mean arterial pressure; No-STE, No ST-segment elevation; OHCA, out-of-hospital cardiac arrest; PCI, percutaneous coronary intervention; ROSC, return of spontaneous circulation; SaO2, oxygen saturation; SD, standard deviation; STE, ST-segment elevation; ULN, upper limit of normal. ∗ Corresponding author at: Department of Cardiology, Room Ad-342, Erasmus University Medical Center, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands. E-mail address: [email protected] (J. Daemen).
percutaneous coronary intervention (PCI) might improve outcome in selected patients [2–5]. In practice though, identification of those likely to benefit from an early invasive strategy is difficult and there is currently no dedicated prospective study confirming a benefit of an immediate invasive strategy in comatose survivors of OHCA, irrespective of the presence of ST-segment elevation [3]. Most previous studies focused on patients already selected for an immediate invasive strategy precluding any statements on when and if a patient should be referred coronary angiography [2,6]. The aim of the present study was to assess differences in 30-day mortality rates of an early invasive strategy as compared to a nonearly invasive strategy in a large cohort of all-comer survivors of OHCA without obvious extracardiac causes presenting at a tertiary referral center.
https://doi.org/10.1016/j.resuscitation.2017.11.046 0300-9572/© 2017 Elsevier B.V. All rights reserved.
Please cite this article in press as: Staudacher II, et al. Timing of coronary angiography in survivors of out-of-hospital cardiac arrest without obvious extracardiac causes. Resuscitation (2017), https://doi.org/10.1016/j.resuscitation.2017.11.046
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Methods Patients and treatment This retrospective observational cohort study included 612 patients presenting with an OHCA at Erasmus Medical Centre Rotterdam (NL) between January 1st 2009 and December 31st 2014. Medical records review was performed by scrutinizing emergency room and intensive care admission reports, cathlab procedure reports, ECG data and laboratory results to acquire full patient data and to assess the presence of clear extracardiac causes (being mainly pulmonary embolism, stroke). All patient files were digitally available in our hospital throughout the entire study period. All other causes (ST-elevation, ST-depression, ventricular fibrillation and a history of coronary artery disease, new bundle branch block, AV block with suspicion of inferior myocardial infarction) were classified as possible ACS cases. Analyses were performed on those presenting with no obvious extracardiac cause of OHCA. Therapeutic hypothermia (33 ◦ C) on hospital admission was systematically implemented in all patients during the first 24 h unless contraindicated. A high-resolution CT scan at admission was made in all patients with a suspicion of (head) trauma, stroke or pulmonary embolism. The final decision to refer a patient for an early invasive strategy was left at the discretion of the involved team (cardiologist, anesthesiologist and interventional cardiologist oncall) with an overall low threshold for an early invasive strategy in case an acute coronary problem was deemed likely. This study was not subject to the Dutch Medical Research Involving Human Subjects Act. Consequently, approval from the local research ethics committee to conduct this retrospective observational cohort study was not required at the time of enrolment. Moreover, this study was conducted according to the Helsinki Declaration. Study endpoints The primary endpoint was all-cause mortality at 30 days. Secondary endpoint was all-cause mortality at one-year. Survival status was ascertained using hospital medical records or municipal civil registry. One-year follow-up was complete for 100% of the patients. Socio-demographic characteristics comprised age and gender. Clinical characteristics comprised cardiac history (previous myocardial infarction, previous stroke, previous coronary artery bypass surgery (CABG) or PCI), and cardiovascular risk factors (hypercholesterolemia, smoking, diabetes mellitus, hypertension, family history of coronary artery disease, and body mass index (BMI)). Clinical parameters at admission included blood pressure, heart rate, hemoglobin (mmol/L), SaO2 (Oxygen Saturation, %), pH, temperature (degrees Celsius), CK (U/L), CKMB (g/L), hsTnT (ng/L), lactate (mmol/L), time to ROSC, Cardiogenic shock). Cardiogenic shock was defined as a systolic blood pressure of <90 mmHg longer than 30 min or use of inotropic medication. Statistical data analysis Continuous variables are presented as mean ± standard deviation (SD) and categorical variables are expressed as percentages. Continuous variables were compared using Student’s t-test or oneway ANOVA. Pearson’s Chi-Square test was used for categorical variables. Patients were stratified into 2 groups; patients that underwent cardiac catheterization ≤3 h, and patients not undergoing cardiac catheterization within 3 h. The incidence of mortality over time was studied with the use of the Kaplan-Meier method, whereas the log-rank test was applied to evaluate differences between the treatment groups. Cox
proportional-hazards regression analyses were applied to adjust for potential confounders. Variables with p < 0.10 in the univariate analyses were entered in the multivariable Cox proportional hazards models. Control of potential confounders was attempted by constructing a propensity score using logistic regression. The propensity score was the probability that a patient would undergo an early invasive strategy, and was computed using an extensive, non-parsimonious, logistic regression model including the following variables: age, sex, body-mass index (BMI), smoking, previous myocardial infarction, previous CABG, time of OHCA, time until return of spontaneous circulation (ROSC), ST- segment elevation on the electrocardiogram, hemoglobin level at admission, saturation, mean arterial pressure at admission, temperature, lactate level at admission and pH at admission. The selection of the variables was made so as to get the best discriminating model as assessed by the C-statistics. Final results are presented as adjusted hazard ratios with 95% confidence interval. Statistical analyses were performed using SPSS (version 21.0). All statistical tests are 2-tailed. Sensitivity analyses were performed in order to test the heterogeneity of the treatment effect in patients presenting with STE, No-STE and shock as well as a definition of early invasive being 2 h and 6 h. Results This retrospective cohort consists of 612 patients presenting with an OHCA. Analyses were performed on those presenting with no obvious extracardiac cause of OHCA (n = 507) (Fig. 1). Of the 507 patients, 291 underwent cardiac catheterization ≤3 h (early invasive group) and 216 patients did not undergo cardiac catheterization ≤3 h (non-early invasive group. In the non-early invasive group, 100 patients underwent in-hospital cardiac catheterization later than 3 h after hospital admission at an average of 4120 ± 7116 min (corresponding to 69 ± 119 h). A total of 116 patients did not undergo coronary angiography. Timing of angiography Table 1 presents the differences between patients that underwent early invasive or non-early invasive treatment. In brief, patients in the early invasive group were younger and presented more often with ST-segment elevation and/or cardiogenic shock, had a lower MAP and temperature and higher cardiac enzymes at admission however, they also had a higher mean Hb and SaO2 at admission. Coronary artery disease was present in 84% of the patients in the early invasive group vs. 79% in the patients that underwent in-hospital angiography >3 h (n = 100) in the non-early invasive group. PCI was performed in 72% of the patients in the early invasive group versus 23% of the non-early group. All-cause 30-day mortality was 28.9% in the early invasive group and 36.6% in the non-early group (log-rank p-value 0.071) (Fig. 2). All-cause 1-year mortality was 32.3% in the early invasive group and 40.7% in the non-early group (p = 0.055). Propensity adjusted cox multivariable regression analyses demonstrated age (HR 1.04/year; 95% CI 1.02 −1.07) and presentation with cardiogenic shock (HR 5.1; 95% CI 1.8–14.0) to be the sole independent predictors of 30-day mortality while catheterization within 3 h was not associated with 30-day mortality (HR 0.69; 95% CI 0.35–1.37) (Table 2). Sensitivity analyses ST-segment elevation (STE) at presentation was present in 220 patients (43%) while ST-segment elevation was absent (No-STE) in the remaining 287 patients (57%). Cumulative 30-day all-cause mortality was 32.8% in patients presenting with No-STE vs. 31.4%
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OHCA n=612
Possible ACS n=507
No possible ACS (n=105) Non ischemic CMP
n=27
Primary arrhythmia
n=19
Asphyxia
n=12
Pulmonary embolism n=10
Early invasive (≤3 hours) n=291
Non-early invasive (>3 hours) n=216
Intoxication
n=9
AV block
n=7
Stroke
n=6
Other
n=15
Fig. 1. Selection and stratification of patients.
in STE patients (p = 0.869), increasing to 35.5% for STE patients and 36.2% for No-STE patients at 1-year (p = 0.965). All-cause 30-day mortality in STE patients was 28.7% in the early invasive group and 43.6% in the non-early group (log-rank p-value 0.033) (Fig. 3). All-cause 1-year mortality was 33.1% in the early invasive group and 46.2% in the non-early group (p = 0.058). In STE patients propensity adjusted Cox multivariable regression analyses demonstrated age (HR 1.05; 95% CI 1.02–1.08), Hb at admission (HR 0.61; 95% CI 0.41–0.90) and presentation with cardiogenic shock (HR 7.2; 95% CI 1.9–27.7) to be the sole independent predictors of 30-day mortality. An early invasive strategy was not associated with 30-day mortality (HR 0.90; 95% CI 0.34–2.37). All-cause 30-day mortality in No-STE patients was 29.1% in the early invasive group and 35.0% in the non-early group (log-rank p-value 0.348) (Fig. 4). All-cause 1-year mortality was 30.9% in the early invasive group and 39.5% in the non-early group (p = 0.19). In No-STE patients age (HR 1.04; 95% CI 1.01–1.07), lactate at admission (HR 1.15; 95% CI 1.0–1.3) and presentation with cardiogenic shock (HR 3.2; 95% CI 1.1–9.5) appeared to be the sole independent predictors of 30-day mortality while an early invasive strategy was not associated with 30-day mortality rates (HR 0.74; 95% CI 0.47–1.16). Also in patients presenting with cardiogenic shock (n = 275), an early invasive strategy did not significantly impact 30-day mortality rate (adjusted HR 0.83; 95 CI 0.47–1.47; p = 0.53). Final sensitivity analyses did not show a significant difference in the treatment effect when an early invasive strategy was defined as either 2 h (adjusted HR 0.69, 95% CI 0.32–1.48) or 6 h (adjusted HR 0.64, 95% CI 0.32–1.29).
Causes of death In the present study a total of 207 died. Only 9 patients (4.3%) died of a clear non-cardiac cause and 57 patients (27.5%) died of a direct cardiac cause. The largest contributor to mortality however appeared to be a poor neurological prognosis (88 patients, 42.5%) resulting in holding of from further treatment.
Discussion The principle outcome of this study was that early coronary angiography (<3 h), as compared to a non-early invasive strategy, was not associated with reduced 30-day mortality in patients hospitalized after OHCA, irrespective of the presence of ST segment elevation or cardiogenic shock at presentation. Defining the exact etiology of an OHCA is complex. Electrocardiographic findings in post CPR patients are most often abnormal, bundle branch block is frequently observed and ST segment elevation has proven to be a poor predictor of an actual STEMI. While an acute obstructive lesion is absent in up to 20% of patients presenting with STE, it can be found in nearly 25% of patients without STE [2,7–9]. The latter is demonstrated also by the present work in which coronary artery disease was absent in almost 20% of the cases referred for coronary angiography and PCI was not performed in 34% of the cases demonstrating that an invasive approach only could have led to an improvement in outcome in 66% of the cases, irrespective of the timing of angiography. Thereby the use of contrast, on top of the bolus of approximately 100cc used for excluding secondary causes of OHCA in the emergency department in a substantial number of patients undergoing CTA, significantly increases the risk of acute kidney injury [10]. To the best of our knowledge, there are currently no results available of dedicated randomized-controlled trials assessing the potential benefit of an early invasive strategy in patients presenting with OHCA. While the results of randomized prospective trials like COACT, PEARL and ARREST are still to be awaited, current guidelines [11] are mostly based on the result of relatively small retrospective studies, suggesting a potential benefit of an early invasive strategy. Spaulding et al, in 1997, concluded that immediate coronary angiography (CAG) in survivors of OHCA seemed to improve survival, based on the fact that successful PCI was performed in 28 out of 84 patients [2]. Also in the more recent PROCAT registry, including 435 survivors of OHCA without obvious extracardiac causes, successful immediate revascularization was associated with improved hospital survival, while the post resuscitation ECG pattern was not [3]. In the present however, we could not demonstrate a benefit of an early invasive strategy. A finding
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4 Table 1 Baseline characteristics for all ACS patients (n = 507).
Early invasive (n = 291)
Non-early invasive (n = 216)
p-value (early invasive vs. non-early invasive)
Gender, male Mean age (±SD)
82% (238/291) 63 (12)
75% (161/216) 67 (13)
0.049 0.001
Dyslipidemia Smoking Diabetes Mellitus Hypertension Family history for CAD
23% (67/288) 38% (83/221) 16% (47/289) 32% (92/289) 14% (39/289)
22% (47/213) 28% (42/150) 20% (43/213) 36% (76/213) 15% (31/213)
0.752 0.056 0.257 0.367 0.735
Prior infarction Prior stroke Prior PCI Prior CABG
22% (63/289) 6% (18/289) 12% (33/288) 5% (13/289)
29% (63/214) 11% (23/214) 13% (28/213) 12% (26/214)
0.051 0.067 0.568 0.002
BMI (±SD) ST elevation MAP at admission Heart rate at admission Hb at admission SaO2 at admission pH at admission Temperature at admission
28 (5) 62% (181/291) 87 (21) 91 (26) 8.8 (1.0) 94 (11) 7.2 (0.1) 35.4 (1.1)
27 (5) 18% (39/216) 93 (26) 93 (27) 8.4 (1.1) 90 (17) 7.2 (0.2) 35.7 (0.9)
0.545 <0.001 0.003 0.594 <0.001 0.005 0.677 0.037
CK admission ULN CK max ULN CKMB admission ULN CKMB max ULN hsTnT admission ULN hsTnT max ULN Lactate at admission
2.5 (4.3) 20.6 (24.5) 3.5 (12.9) 39.0 (49.9) 14.2 (28.6) 270.5 (612.6) 6.4 (3.5)
1.4 (2.4) 10.3 (13.3) 1.2 (2.0) 14.8 (30.1) 6.9 (9.8) 110.7 (270.6) 6.5 (3.8)
0.003 <0.001 0.012 <0.001 0.002 0.001 0.845
Shock Time to ROSC
60% (173/291) 18 (11)
47% (102/216) 16 (14)
0.006 0.119
ROSC > 30 min pH < 7.2 Lactate > 7 Age > 85
7% (20/291) 36% (105/291) 32% (93/291) 3% (9/291)
6% (12/216) 32% (70/216) 29% (62/216) 7% (16/216)
0.546 0.389 0.431 0.026
CAG during admission Time to Cathlab, (minutes ± SD); min-max CAG findings -1 vesseldisease -2 vesseldisease -3 vesseldisease -no CAD Invasive strategy - PCI - CABG - Conservative after CAG - No CAG
100% (291/291) 68 (37); 4–176
44% (100/226) 4120 (7116); 185 − 31878
30% (85/286) 25% (72/286) 29% (82/286) 16% (47/286)
41% (40/98) 20% (20/98) 17% (17/98) 21% (21/98)
0.043 0.340 0.027 0.264
72% (208/291) 1% (4/291) 27% (79/291) 0% (0/291)
23% (49/216) 2% (4/216) 22% (47/216) 54% (116/216)
<0.001 0.670 0.165 <0.001
Continuous variables are presented as mean ± standard deviation (SD) and categorical variables are expressed as percentages.
Adjusted HR 0.69; 95% CI 0.35-1.37; p=0.29
40
40.7% 36.6%
Early invasive
Death (%)
30 20
32.3%
28.9%
10 0 30
100
200
300
365
Time in days Early invasive
207
200
197
197
197
Fig. 2. Kaplan survival curve in patients with ACS stratified according to treatment strategy.
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Table 2 Univariate and multivariate analysis of the total study population by Cox proportional hazards model. Variable
Unadjusted HR (95% CI)
Propensity score adjusted HR (95% CI)
Age Gender Hypertension Diabetes Mellitus Dyslipidemia Smoking Family history of CAD Prior PCI Prior CABG Prior MI Prior stroke Shock BMI MAP Heart rate at admission Hemoglobin at admission Saturation pH at admission Temperature at admission Lactate at admission Time until ROSC Early invasive strategy
1.04 (1.03–1.06) 1.27 (0.89– 1.81) 1.23 (0.89–1.69) 1.52 (1.05–2.18) 0.83 (0.56–1.22) 0.84 (0.55–1.29) 0.32 (0.17–0.64) 0.82 (0.53–1.27) 1.11 (0.64–1.93) 1.39 (0.99–1.94) 1.99 (1.26–3.15) 7.77 (4.91–12.30) 1.00 (0.96–1.05) 0.99 (0.98–1.00) 1.00 (0.99–1.00) 0.66 (0.57–0.76) 0.97 (0.97–0.98) 0.01 (<0.01–0.03) 0.78 (0.63–0.96) 1.18 (1.13–1.22) 1.04 (1.03–1.05) 0.76 (0.56–1.03
1.04 (1.02–1.07)
1.23 (0.63–2.39)
0.19 (0.03–1.43)
1.41 (0.76–2.63) 1.10 (0.49–2.49) 5.05 (1.82–14.04) 0.99 (0.98–1.01) 0.85 (0.65–1.11) 1.01 (0.99–1.03) 0.26 (0.02–4.33) 1.06 (0.82–1.39) 1.07 (0.96–1.20) 1.02 (1.00–1.04) 0.69 (0.35–1.37)
that might have a multifactorial explanation. Significant differences exist in the definition of what is called “an early invasive approach” [2,5,12,13]. For the present study we used a cut-off of 3 h whereas in other studies the cut-off ranged from 2 h to 24 h [5,14]. Furthermore, when scrutinizing the results of previous work, significant differences emerge in the patients included and the capacities of sites involved. Callaway and colleagues advocated an early invasive strategy in survivors of OHCA, however, only 19% of 3981 all-comer survivors were referred for early coronary angiography (<24 h) in 151 sites [5]. Besides the fact that patients with obvious extracardiac causes were included, huge heterogeneity existed in the capacities and volumes of the sites – some referred 0% of their patients for early coronary angiography. Additionally, patients presenting with STE were not referred for coronary angiography within 24 h in 24% of the cases as compared to 6% in the present study. Furthermore, a significant number of studies were focused on patients already selected for an immediate invasive strategy and actually looked at the benefit of PCI, precluding any statements on when and if a patient should be referred for coronary angiography [2–4]. Instead, in the present work we aimed to assess the potential benefit of an early invasive strategy in patients presenting with an OHCA without obvious extracardiac causes in a high volume institution with PCI capabilities. The importance of the latter is
illustrated by the fact that overall 30-day survival rate for the total studied population in the present study was 67.9% as compared to results as low as 33.1% in previous work [5]. Unfortunately, the only question to be answered at admission, irrespective of the presence of STE, is whether or not to proceed for immediate or early coronary angiography. The question to perform a PCI or a delayed angiography, can only be answered at a later stage. In the present work, an attempt to perform a PCI within 3 h was made in 286/507 patients (56%) which is higher than in the vast majority of previous studies in which an acute CAG was performed in 41% of the cases [12]. Nevertheless, no significant survival benefit could be found when correcting for independent predictors of 30 day mortality. Multivariable analyses in the present study demonstrated that shock and a higher age at presentation were the only predictors of 30-day mortality, whereas STE and an early invasive approach were not. Additional sensitivity analyses demonstrated a consistency of these findings in patients presenting with STE, no-STE or shock, in which an early invasive treatment strategy did not appear to improve 30-day mortality rates. Extensive regression analyses revealed several multivariable predictors of 30 day mortality. Hb level at admission was an independent predictor of 30-day mortality among STE patients. This
Adjusted HR 0.90; 95% CI 0.34-2.37
40
46.2% 43.6%
Early invasive
Death (%)
30 33.1% 28.7%
20 10 0
0 30
100
200
300
365
Time in days Early invasive
129
123
121
121
121
Fig. 3. Kaplan survival curve in patients with STE stratified according to treatment strategy.
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Adjusted HR 0.74; 95% CI 0.47-1.16
40
39.5% 35.0%
Early invasive
Death (%)
30 30.9%
29.1%
20 10 0
0 30
100
200
300
365
Time in days Early inv asiv e
78
78
76
76
76
Fig. 4. Kaplan survival curve in patients with NSTE stratified according to treatment strategy.
finding is in line with several previous studies suggesting a potential detrimental outcome in patients with lower Hb levels at admission [15,16]. Lactate level at admission was shown to be an independent predictor of 30 days mortality in patients presenting with NSTE. Higher lactate levels at admission have been associated with higher mortality in OHCA patients while higher lactate clearance proved to be protective [17–20]. Furthermore, lower post-resuscitation lactate levels have even been associated with better neurological outcome among OHCA patients [17,18,20]. Finally, in our study, higher age and cardiogenic shock at presentation proved to be strong independent predictors of 30 day mortality, in line with previous work suggesting in detrimental outcome patients at higher age or those presenting in shock [3,21–24]. Finally, severe ischemic brain injury with severe neurologic deficit was the leading cause of mortality in 42.5% of the patients dying in the present study, and even accounted for 54% of the causes of death within 30 days. It is likely that the latter might have mitigated to potential effect of an early revascularization strategy in survivors of OHCA with a suspected ACS. The results of our study might have been biased by several limitations. As in all previous non-randomized studies, selection bias might have played an important role. Although it is impossible to correct for all variables clinicians take into account when selecting patients for early invasive or non-early invasive treatment we used propensity score adjusted analyses in order to account for the likelihood that a patients was referred for an early invasive strategy. Nevertheless, the results of the present study question the need for an early invasive approach in patients with an OHCA without obvious extracardiac causes and warrant further research to determine which patients will benefit from an early invasive strategy. If confirmed, these findings might have important implications for resource management and cost given the fact that the vast majority of OHCA patients arrive outside working hours. Conclusion In this retrospective study, early coronary angiography (<3 h), as compared to a −non-early invasive strategy, was not associated with reduced 30-day mortality in patients hospitalized after OHCA, irrespective of the presence of ST segment elevation or cardiogenic shock at presentation. Funding sources No external funding.
Conflict of interest statement None. References [1]. Atwood C, Eisenberg MS, Herlitz J, Rea TD. Incidence of EMS-treated out-ofhospital cardiac arrest in Europe. Resuscitation 2005;67:75–80. [2]. Spaulding CM, Joly LM, Rosenberg A, Monchi M, Weber SN, Dhainaut JF, et al. Immediate coronary angiography in survivors of out-of-hospital cardiac arrest. N Engl J Med 1997;336:1629–33. [3]. Dumas F, Cariou A, Manzo-Silberman S, Grimaldi D, Vivien B, Rosencher J, et al. 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;3:200–7. [4]. Garot P, Lefevre T, Eltchaninoff H, Morice MC, Tamion F, Abry B, et al. Six-month outcome of emergency percutaneous coronary intervention in resuscitated patients after cardiac arrest complicating ST-elevation myocardial infarction. Circulation 2007;115:1354–62. [5]. Callaway CW, Schmicker RH, Brown SP, Albrich JM, Andrusiek DL, Aufderheide TP, et al. Early coronary angiography and induced hypothermia are associated with survival and functional recovery after out-of-hospital cardiac arrest. Resuscitation 2014;85:657–63. [6]. Davies MJ. Anatomic features in victims of sudden coronary death. Coronary artery pathology. Circulation 1992;85:I19–24. [7]. Hosmane VR, Mustafa NG, Reddy VK, Reese CLt, DiSabatino A, Kolm P, et al. Survival and neurologic recovery in patients with ST-segment elevation myocardial infarction resuscitated from cardiac arrest. J Am Coll Cardiol 2009;53:409–15. [8]. Radsel P, Knafelj R, Kocjancic S, Noc M. Angiographic characteristics of coronary disease and postresuscitation electrocardiograms in patients with aborted cardiac arrest outside a hospital. Am J Cardiol 2011;108:634–8. [9]. Anyfantakis ZA, Baron G, Aubry P, Himbert D, Feldman LJ, Juliard JM, et al. Acute coronary angiographic findings in survivors of out-of-hospital cardiac arrest. Am Heart J 2009;157:312–8. [10]. Mehran R, Aymong ED, Nikolsky E, Lasic Z, Iakovou I, Fahy M, et al. A simple risk score for prediction of contrast-induced nephropathy after percutaneous coronary intervention: development and initial validation. J Am Coll Cardiol 2004;44:1393–9. [11]. Roffi M, Patrono C, Collet JP, Mueller C, Valgimigli M, Andreotti F, et al. 2015 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: Task Force for the Management of Acute Coronary Syndromes in Patients Presenting without Persistent ST-Segment Elevation of the European Society of Cardiology (ESC). Eur Heart J 2016;37:267–315. [12]. Larsen JM, Ravkilde J. Acute coronary angiography in patients resuscitated from out-of-hospital cardiac arrest – a systematic review and meta-analysis. Resuscitation 2012;83:1427–33. [13]. Rab T, Kern KB, Tamis-Holland JE, Henry TD, McDaniel M, Dickert NW, et al. Cardiac Arrest: A Treatment Algorithm for Emergent Invasive Cardiac Procedures in the Resuscitated Comatose Patient. J Am Coll Cardiol 2015;66:62–73. [14]. Strote JA, Maynard C, Olsufka M, Nichol G, Copass MK, Cobb LA, et al. 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;109:451–4. [15]. Albaeni A, Eid SM, Akinyele B, Kurup LN, Vaidya D, Chandra-Strobos N. The association between post resuscitation hemoglobin level and survival with good
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[21]. Hemradj VV, Ottervanger JP, van ’t Hof AW, Dambrink JH, Gosselink M, Kedhi E, et al. Cardiogenic shock predicts long-term mortality in hospital survivors of STEMI treated with primary percutaneous coronary intervention. Clin Cardiol 2016;39:665–9. [22]. Yamanaka F, Jeong MH, Saito S, Ahn Y, Chae SC, Hur SH, et al. Comparison of clinical outcomes between octogenarians and non-octogenarians with acute myocardial infarction in the drug-eluting stent era: analysis of the Korean Acute Myocardial Infarction Registry. J Cardiol 2013;62:210–6. [23]. Seder DB, Patel N, McPherson J, McMullan P, Kern KB, Unger B, et al. Geriatric experience following cardiac arrest at six interventional cardiology centers in the United States 2006–2011: interplay of age, do-not-resuscitate order, and outcomes. Crit Care Med 2014;42:289–95. [24]. Kobayashi Y, Mehran R, Mintz GS, Dangas G, Moussa I, Lansky AJ, et al. Comparison of in-hospital and one-year outcomes after multiple coronary arterial stenting in patients > or = 80 years old versus those <80 years old. Am J Cardiol 2003;92:443–6.
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Clinical paper
Timing of coronary angiography in survivors of out-of-hospital cardiac arrest without obvious extracardiac causes Isabelle Irene Staudacher a , Corstiaan den Uil b , Lucia Jewbali b , Laurens van Zandvoort a , Felix Zijlstra a , Nicolas Van Mieghem a , Eric Boersma a , Joost Daemen a,∗ a b
Department of Cardiology, Thoraxcenter, Erasmus Medical Center, The Netherlands Deparment of Intensive Care Medicine, Erasmus Medical Center, The Netherlands
a r t i c l e
i n f o
Article history: Received 25 July 2017 Received in revised form 2 November 2017 Accepted 16 November 2017 Keywords: Out-of-hospital cardiac arrest Coronary angiography Percutaneous coronary intervention Cardiogenic shock Myocardial infarction
a b s t r a c t Background: Indications and timing of coronary angiography in patients surviving out-of-hospital cardiac arrest (OHCA) remain controversial. The aim of the present study was to assess the impact of an early invasive strategy in patients presenting with an OHCA and no obvious extracardiac cause. Methods: Between January 1st 2009 and December 31st 2014 a total 612 survivors of OHCA were admitted to our institution. Patients with no obvious extracardiac cause (n = 507) were stratified into two groups: patients that underwent cardiac catheterization ≤3 h (early invasive; n = 291) and patients not undergoing cardiac catheterization within 3 h (non-early invasive; n = 216). Primary endpoint was all-cause mortality at 30 days. Results: All-cause 30-day mortality was 28.9% in the early invasive group vs. 36.6% in the non-early invasive group (log-rank p = 0.071). After propensity analyses, an early invasive strategy, as compared to a non-early strategy, was not associated with 30-day mortality (adjusted Hazard ratio [HR] 0.69; 95% CI 0.35–1.37; p = 0.029). Cox multivariable regression analyses demonstrated age (HR 1.04/year; 95% CI 1.02–1.07) and presentation with cardiogenic shock (HR 5.1; 95% CI 1.8–14.0) to be the sole independent predictors of 30-day mortality. Conclusions: In this retrospective study, early coronary angiography (<3 h), as compared to a non-early invasive strategy, was not associated with reduced 30-day mortality in patients hospitalized after OHCA, irrespective of the presence of ST segment elevation or cardiogenic shock at presentation. © 2017 Elsevier B.V. All rights reserved.
Introduction Out-of-hospital cardiac arrest (OHCA) remains a challenging clinical problem frequently characterized by an unclear etiology and an overall poor survival [1]. Acute coronary thrombotic occlusion has been identified as the leading cause of OHCA and recent studies suggest that an early invasive strategy including immediate
Abbreviations: ACS, acute coronary syndrome; BMI, body mass index; CABG, coronary artery bypass surgery; CAD, coronary artery disease; CAG, coronary angiography; Cathlab, catheterization laboratory; CK, creatine kinase; CKMB, creatine kinase myocardial band; HR, hazard ratio; hsTnT, high sensitivity troponin T; MAP, mean arterial pressure; No-STE, No ST-segment elevation; OHCA, out-of-hospital cardiac arrest; PCI, percutaneous coronary intervention; ROSC, return of spontaneous circulation; SaO2, oxygen saturation; SD, standard deviation; STE, ST-segment elevation; ULN, upper limit of normal. ∗ Corresponding author at: Department of Cardiology, Room Ad-342, Erasmus University Medical Center, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands. E-mail address: [email protected] (J. Daemen).
percutaneous coronary intervention (PCI) might improve outcome in selected patients [2–5]. In practice though, identification of those likely to benefit from an early invasive strategy is difficult and there is currently no dedicated prospective study confirming a benefit of an immediate invasive strategy in comatose survivors of OHCA, irrespective of the presence of ST-segment elevation [3]. Most previous studies focused on patients already selected for an immediate invasive strategy precluding any statements on when and if a patient should be referred coronary angiography [2,6]. The aim of the present study was to assess differences in 30-day mortality rates of an early invasive strategy as compared to a nonearly invasive strategy in a large cohort of all-comer survivors of OHCA without obvious extracardiac causes presenting at a tertiary referral center.
https://doi.org/10.1016/j.resuscitation.2017.11.046 0300-9572/© 2017 Elsevier B.V. All rights reserved.
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Methods Patients and treatment This retrospective observational cohort study included 612 patients presenting with an OHCA at Erasmus Medical Centre Rotterdam (NL) between January 1st 2009 and December 31st 2014. Medical records review was performed by scrutinizing emergency room and intensive care admission reports, cathlab procedure reports, ECG data and laboratory results to acquire full patient data and to assess the presence of clear extracardiac causes (being mainly pulmonary embolism, stroke). All patient files were digitally available in our hospital throughout the entire study period. All other causes (ST-elevation, ST-depression, ventricular fibrillation and a history of coronary artery disease, new bundle branch block, AV block with suspicion of inferior myocardial infarction) were classified as possible ACS cases. Analyses were performed on those presenting with no obvious extracardiac cause of OHCA. Therapeutic hypothermia (33 ◦ C) on hospital admission was systematically implemented in all patients during the first 24 h unless contraindicated. A high-resolution CT scan at admission was made in all patients with a suspicion of (head) trauma, stroke or pulmonary embolism. The final decision to refer a patient for an early invasive strategy was left at the discretion of the involved team (cardiologist, anesthesiologist and interventional cardiologist oncall) with an overall low threshold for an early invasive strategy in case an acute coronary problem was deemed likely. This study was not subject to the Dutch Medical Research Involving Human Subjects Act. Consequently, approval from the local research ethics committee to conduct this retrospective observational cohort study was not required at the time of enrolment. Moreover, this study was conducted according to the Helsinki Declaration. Study endpoints The primary endpoint was all-cause mortality at 30 days. Secondary endpoint was all-cause mortality at one-year. Survival status was ascertained using hospital medical records or municipal civil registry. One-year follow-up was complete for 100% of the patients. Socio-demographic characteristics comprised age and gender. Clinical characteristics comprised cardiac history (previous myocardial infarction, previous stroke, previous coronary artery bypass surgery (CABG) or PCI), and cardiovascular risk factors (hypercholesterolemia, smoking, diabetes mellitus, hypertension, family history of coronary artery disease, and body mass index (BMI)). Clinical parameters at admission included blood pressure, heart rate, hemoglobin (mmol/L), SaO2 (Oxygen Saturation, %), pH, temperature (degrees Celsius), CK (U/L), CKMB (g/L), hsTnT (ng/L), lactate (mmol/L), time to ROSC, Cardiogenic shock). Cardiogenic shock was defined as a systolic blood pressure of <90 mmHg longer than 30 min or use of inotropic medication. Statistical data analysis Continuous variables are presented as mean ± standard deviation (SD) and categorical variables are expressed as percentages. Continuous variables were compared using Student’s t-test or oneway ANOVA. Pearson’s Chi-Square test was used for categorical variables. Patients were stratified into 2 groups; patients that underwent cardiac catheterization ≤3 h, and patients not undergoing cardiac catheterization within 3 h. The incidence of mortality over time was studied with the use of the Kaplan-Meier method, whereas the log-rank test was applied to evaluate differences between the treatment groups. Cox
proportional-hazards regression analyses were applied to adjust for potential confounders. Variables with p < 0.10 in the univariate analyses were entered in the multivariable Cox proportional hazards models. Control of potential confounders was attempted by constructing a propensity score using logistic regression. The propensity score was the probability that a patient would undergo an early invasive strategy, and was computed using an extensive, non-parsimonious, logistic regression model including the following variables: age, sex, body-mass index (BMI), smoking, previous myocardial infarction, previous CABG, time of OHCA, time until return of spontaneous circulation (ROSC), ST- segment elevation on the electrocardiogram, hemoglobin level at admission, saturation, mean arterial pressure at admission, temperature, lactate level at admission and pH at admission. The selection of the variables was made so as to get the best discriminating model as assessed by the C-statistics. Final results are presented as adjusted hazard ratios with 95% confidence interval. Statistical analyses were performed using SPSS (version 21.0). All statistical tests are 2-tailed. Sensitivity analyses were performed in order to test the heterogeneity of the treatment effect in patients presenting with STE, No-STE and shock as well as a definition of early invasive being 2 h and 6 h. Results This retrospective cohort consists of 612 patients presenting with an OHCA. Analyses were performed on those presenting with no obvious extracardiac cause of OHCA (n = 507) (Fig. 1). Of the 507 patients, 291 underwent cardiac catheterization ≤3 h (early invasive group) and 216 patients did not undergo cardiac catheterization ≤3 h (non-early invasive group. In the non-early invasive group, 100 patients underwent in-hospital cardiac catheterization later than 3 h after hospital admission at an average of 4120 ± 7116 min (corresponding to 69 ± 119 h). A total of 116 patients did not undergo coronary angiography. Timing of angiography Table 1 presents the differences between patients that underwent early invasive or non-early invasive treatment. In brief, patients in the early invasive group were younger and presented more often with ST-segment elevation and/or cardiogenic shock, had a lower MAP and temperature and higher cardiac enzymes at admission however, they also had a higher mean Hb and SaO2 at admission. Coronary artery disease was present in 84% of the patients in the early invasive group vs. 79% in the patients that underwent in-hospital angiography >3 h (n = 100) in the non-early invasive group. PCI was performed in 72% of the patients in the early invasive group versus 23% of the non-early group. All-cause 30-day mortality was 28.9% in the early invasive group and 36.6% in the non-early group (log-rank p-value 0.071) (Fig. 2). All-cause 1-year mortality was 32.3% in the early invasive group and 40.7% in the non-early group (p = 0.055). Propensity adjusted cox multivariable regression analyses demonstrated age (HR 1.04/year; 95% CI 1.02 −1.07) and presentation with cardiogenic shock (HR 5.1; 95% CI 1.8–14.0) to be the sole independent predictors of 30-day mortality while catheterization within 3 h was not associated with 30-day mortality (HR 0.69; 95% CI 0.35–1.37) (Table 2). Sensitivity analyses ST-segment elevation (STE) at presentation was present in 220 patients (43%) while ST-segment elevation was absent (No-STE) in the remaining 287 patients (57%). Cumulative 30-day all-cause mortality was 32.8% in patients presenting with No-STE vs. 31.4%
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OHCA n=612
Possible ACS n=507
No possible ACS (n=105) Non ischemic CMP
n=27
Primary arrhythmia
n=19
Asphyxia
n=12
Pulmonary embolism n=10
Early invasive (≤3 hours) n=291
Non-early invasive (>3 hours) n=216
Intoxication
n=9
AV block
n=7
Stroke
n=6
Other
n=15
Fig. 1. Selection and stratification of patients.
in STE patients (p = 0.869), increasing to 35.5% for STE patients and 36.2% for No-STE patients at 1-year (p = 0.965). All-cause 30-day mortality in STE patients was 28.7% in the early invasive group and 43.6% in the non-early group (log-rank p-value 0.033) (Fig. 3). All-cause 1-year mortality was 33.1% in the early invasive group and 46.2% in the non-early group (p = 0.058). In STE patients propensity adjusted Cox multivariable regression analyses demonstrated age (HR 1.05; 95% CI 1.02–1.08), Hb at admission (HR 0.61; 95% CI 0.41–0.90) and presentation with cardiogenic shock (HR 7.2; 95% CI 1.9–27.7) to be the sole independent predictors of 30-day mortality. An early invasive strategy was not associated with 30-day mortality (HR 0.90; 95% CI 0.34–2.37). All-cause 30-day mortality in No-STE patients was 29.1% in the early invasive group and 35.0% in the non-early group (log-rank p-value 0.348) (Fig. 4). All-cause 1-year mortality was 30.9% in the early invasive group and 39.5% in the non-early group (p = 0.19). In No-STE patients age (HR 1.04; 95% CI 1.01–1.07), lactate at admission (HR 1.15; 95% CI 1.0–1.3) and presentation with cardiogenic shock (HR 3.2; 95% CI 1.1–9.5) appeared to be the sole independent predictors of 30-day mortality while an early invasive strategy was not associated with 30-day mortality rates (HR 0.74; 95% CI 0.47–1.16). Also in patients presenting with cardiogenic shock (n = 275), an early invasive strategy did not significantly impact 30-day mortality rate (adjusted HR 0.83; 95 CI 0.47–1.47; p = 0.53). Final sensitivity analyses did not show a significant difference in the treatment effect when an early invasive strategy was defined as either 2 h (adjusted HR 0.69, 95% CI 0.32–1.48) or 6 h (adjusted HR 0.64, 95% CI 0.32–1.29).
Causes of death In the present study a total of 207 died. Only 9 patients (4.3%) died of a clear non-cardiac cause and 57 patients (27.5%) died of a direct cardiac cause. The largest contributor to mortality however appeared to be a poor neurological prognosis (88 patients, 42.5%) resulting in holding of from further treatment.
Discussion The principle outcome of this study was that early coronary angiography (<3 h), as compared to a non-early invasive strategy, was not associated with reduced 30-day mortality in patients hospitalized after OHCA, irrespective of the presence of ST segment elevation or cardiogenic shock at presentation. Defining the exact etiology of an OHCA is complex. Electrocardiographic findings in post CPR patients are most often abnormal, bundle branch block is frequently observed and ST segment elevation has proven to be a poor predictor of an actual STEMI. While an acute obstructive lesion is absent in up to 20% of patients presenting with STE, it can be found in nearly 25% of patients without STE [2,7–9]. The latter is demonstrated also by the present work in which coronary artery disease was absent in almost 20% of the cases referred for coronary angiography and PCI was not performed in 34% of the cases demonstrating that an invasive approach only could have led to an improvement in outcome in 66% of the cases, irrespective of the timing of angiography. Thereby the use of contrast, on top of the bolus of approximately 100cc used for excluding secondary causes of OHCA in the emergency department in a substantial number of patients undergoing CTA, significantly increases the risk of acute kidney injury [10]. To the best of our knowledge, there are currently no results available of dedicated randomized-controlled trials assessing the potential benefit of an early invasive strategy in patients presenting with OHCA. While the results of randomized prospective trials like COACT, PEARL and ARREST are still to be awaited, current guidelines [11] are mostly based on the result of relatively small retrospective studies, suggesting a potential benefit of an early invasive strategy. Spaulding et al, in 1997, concluded that immediate coronary angiography (CAG) in survivors of OHCA seemed to improve survival, based on the fact that successful PCI was performed in 28 out of 84 patients [2]. Also in the more recent PROCAT registry, including 435 survivors of OHCA without obvious extracardiac causes, successful immediate revascularization was associated with improved hospital survival, while the post resuscitation ECG pattern was not [3]. In the present however, we could not demonstrate a benefit of an early invasive strategy. A finding
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4 Table 1 Baseline characteristics for all ACS patients (n = 507).
Early invasive (n = 291)
Non-early invasive (n = 216)
p-value (early invasive vs. non-early invasive)
Gender, male Mean age (±SD)
82% (238/291) 63 (12)
75% (161/216) 67 (13)
0.049 0.001
Dyslipidemia Smoking Diabetes Mellitus Hypertension Family history for CAD
23% (67/288) 38% (83/221) 16% (47/289) 32% (92/289) 14% (39/289)
22% (47/213) 28% (42/150) 20% (43/213) 36% (76/213) 15% (31/213)
0.752 0.056 0.257 0.367 0.735
Prior infarction Prior stroke Prior PCI Prior CABG
22% (63/289) 6% (18/289) 12% (33/288) 5% (13/289)
29% (63/214) 11% (23/214) 13% (28/213) 12% (26/214)
0.051 0.067 0.568 0.002
BMI (±SD) ST elevation MAP at admission Heart rate at admission Hb at admission SaO2 at admission pH at admission Temperature at admission
28 (5) 62% (181/291) 87 (21) 91 (26) 8.8 (1.0) 94 (11) 7.2 (0.1) 35.4 (1.1)
27 (5) 18% (39/216) 93 (26) 93 (27) 8.4 (1.1) 90 (17) 7.2 (0.2) 35.7 (0.9)
0.545 <0.001 0.003 0.594 <0.001 0.005 0.677 0.037
CK admission ULN CK max ULN CKMB admission ULN CKMB max ULN hsTnT admission ULN hsTnT max ULN Lactate at admission
2.5 (4.3) 20.6 (24.5) 3.5 (12.9) 39.0 (49.9) 14.2 (28.6) 270.5 (612.6) 6.4 (3.5)
1.4 (2.4) 10.3 (13.3) 1.2 (2.0) 14.8 (30.1) 6.9 (9.8) 110.7 (270.6) 6.5 (3.8)
0.003 <0.001 0.012 <0.001 0.002 0.001 0.845
Shock Time to ROSC
60% (173/291) 18 (11)
47% (102/216) 16 (14)
0.006 0.119
ROSC > 30 min pH < 7.2 Lactate > 7 Age > 85
7% (20/291) 36% (105/291) 32% (93/291) 3% (9/291)
6% (12/216) 32% (70/216) 29% (62/216) 7% (16/216)
0.546 0.389 0.431 0.026
CAG during admission Time to Cathlab, (minutes ± SD); min-max CAG findings -1 vesseldisease -2 vesseldisease -3 vesseldisease -no CAD Invasive strategy - PCI - CABG - Conservative after CAG - No CAG
100% (291/291) 68 (37); 4–176
44% (100/226) 4120 (7116); 185 − 31878
30% (85/286) 25% (72/286) 29% (82/286) 16% (47/286)
41% (40/98) 20% (20/98) 17% (17/98) 21% (21/98)
0.043 0.340 0.027 0.264
72% (208/291) 1% (4/291) 27% (79/291) 0% (0/291)
23% (49/216) 2% (4/216) 22% (47/216) 54% (116/216)
<0.001 0.670 0.165 <0.001
Continuous variables are presented as mean ± standard deviation (SD) and categorical variables are expressed as percentages.
Adjusted HR 0.69; 95% CI 0.35-1.37; p=0.29
40
40.7% 36.6%
Early invasive
Death (%)
30 20
32.3%
28.9%
10 0 30
100
200
300
365
Time in days Early invasive
207
200
197
197
197
Fig. 2. Kaplan survival curve in patients with ACS stratified according to treatment strategy.
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Table 2 Univariate and multivariate analysis of the total study population by Cox proportional hazards model. Variable
Unadjusted HR (95% CI)
Propensity score adjusted HR (95% CI)
Age Gender Hypertension Diabetes Mellitus Dyslipidemia Smoking Family history of CAD Prior PCI Prior CABG Prior MI Prior stroke Shock BMI MAP Heart rate at admission Hemoglobin at admission Saturation pH at admission Temperature at admission Lactate at admission Time until ROSC Early invasive strategy
1.04 (1.03–1.06) 1.27 (0.89– 1.81) 1.23 (0.89–1.69) 1.52 (1.05–2.18) 0.83 (0.56–1.22) 0.84 (0.55–1.29) 0.32 (0.17–0.64) 0.82 (0.53–1.27) 1.11 (0.64–1.93) 1.39 (0.99–1.94) 1.99 (1.26–3.15) 7.77 (4.91–12.30) 1.00 (0.96–1.05) 0.99 (0.98–1.00) 1.00 (0.99–1.00) 0.66 (0.57–0.76) 0.97 (0.97–0.98) 0.01 (<0.01–0.03) 0.78 (0.63–0.96) 1.18 (1.13–1.22) 1.04 (1.03–1.05) 0.76 (0.56–1.03
1.04 (1.02–1.07)
1.23 (0.63–2.39)
0.19 (0.03–1.43)
1.41 (0.76–2.63) 1.10 (0.49–2.49) 5.05 (1.82–14.04) 0.99 (0.98–1.01) 0.85 (0.65–1.11) 1.01 (0.99–1.03) 0.26 (0.02–4.33) 1.06 (0.82–1.39) 1.07 (0.96–1.20) 1.02 (1.00–1.04) 0.69 (0.35–1.37)
that might have a multifactorial explanation. Significant differences exist in the definition of what is called “an early invasive approach” [2,5,12,13]. For the present study we used a cut-off of 3 h whereas in other studies the cut-off ranged from 2 h to 24 h [5,14]. Furthermore, when scrutinizing the results of previous work, significant differences emerge in the patients included and the capacities of sites involved. Callaway and colleagues advocated an early invasive strategy in survivors of OHCA, however, only 19% of 3981 all-comer survivors were referred for early coronary angiography (<24 h) in 151 sites [5]. Besides the fact that patients with obvious extracardiac causes were included, huge heterogeneity existed in the capacities and volumes of the sites – some referred 0% of their patients for early coronary angiography. Additionally, patients presenting with STE were not referred for coronary angiography within 24 h in 24% of the cases as compared to 6% in the present study. Furthermore, a significant number of studies were focused on patients already selected for an immediate invasive strategy and actually looked at the benefit of PCI, precluding any statements on when and if a patient should be referred for coronary angiography [2–4]. Instead, in the present work we aimed to assess the potential benefit of an early invasive strategy in patients presenting with an OHCA without obvious extracardiac causes in a high volume institution with PCI capabilities. The importance of the latter is
illustrated by the fact that overall 30-day survival rate for the total studied population in the present study was 67.9% as compared to results as low as 33.1% in previous work [5]. Unfortunately, the only question to be answered at admission, irrespective of the presence of STE, is whether or not to proceed for immediate or early coronary angiography. The question to perform a PCI or a delayed angiography, can only be answered at a later stage. In the present work, an attempt to perform a PCI within 3 h was made in 286/507 patients (56%) which is higher than in the vast majority of previous studies in which an acute CAG was performed in 41% of the cases [12]. Nevertheless, no significant survival benefit could be found when correcting for independent predictors of 30 day mortality. Multivariable analyses in the present study demonstrated that shock and a higher age at presentation were the only predictors of 30-day mortality, whereas STE and an early invasive approach were not. Additional sensitivity analyses demonstrated a consistency of these findings in patients presenting with STE, no-STE or shock, in which an early invasive treatment strategy did not appear to improve 30-day mortality rates. Extensive regression analyses revealed several multivariable predictors of 30 day mortality. Hb level at admission was an independent predictor of 30-day mortality among STE patients. This
Adjusted HR 0.90; 95% CI 0.34-2.37
40
46.2% 43.6%
Early invasive
Death (%)
30 33.1% 28.7%
20 10 0
0 30
100
200
300
365
Time in days Early invasive
129
123
121
121
121
Fig. 3. Kaplan survival curve in patients with STE stratified according to treatment strategy.
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Adjusted HR 0.74; 95% CI 0.47-1.16
40
39.5% 35.0%
Early invasive
Death (%)
30 30.9%
29.1%
20 10 0
0 30
100
200
300
365
Time in days Early inv asiv e
78
78
76
76
76
Fig. 4. Kaplan survival curve in patients with NSTE stratified according to treatment strategy.
finding is in line with several previous studies suggesting a potential detrimental outcome in patients with lower Hb levels at admission [15,16]. Lactate level at admission was shown to be an independent predictor of 30 days mortality in patients presenting with NSTE. Higher lactate levels at admission have been associated with higher mortality in OHCA patients while higher lactate clearance proved to be protective [17–20]. Furthermore, lower post-resuscitation lactate levels have even been associated with better neurological outcome among OHCA patients [17,18,20]. Finally, in our study, higher age and cardiogenic shock at presentation proved to be strong independent predictors of 30 day mortality, in line with previous work suggesting in detrimental outcome patients at higher age or those presenting in shock [3,21–24]. Finally, severe ischemic brain injury with severe neurologic deficit was the leading cause of mortality in 42.5% of the patients dying in the present study, and even accounted for 54% of the causes of death within 30 days. It is likely that the latter might have mitigated to potential effect of an early revascularization strategy in survivors of OHCA with a suspected ACS. The results of our study might have been biased by several limitations. As in all previous non-randomized studies, selection bias might have played an important role. Although it is impossible to correct for all variables clinicians take into account when selecting patients for early invasive or non-early invasive treatment we used propensity score adjusted analyses in order to account for the likelihood that a patients was referred for an early invasive strategy. Nevertheless, the results of the present study question the need for an early invasive approach in patients with an OHCA without obvious extracardiac causes and warrant further research to determine which patients will benefit from an early invasive strategy. If confirmed, these findings might have important implications for resource management and cost given the fact that the vast majority of OHCA patients arrive outside working hours. Conclusion In this retrospective study, early coronary angiography (<3 h), as compared to a −non-early invasive strategy, was not associated with reduced 30-day mortality in patients hospitalized after OHCA, irrespective of the presence of ST segment elevation or cardiogenic shock at presentation. Funding sources No external funding.
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Please cite this article in press as: Staudacher II, et al. Timing of coronary angiography in survivors of out-of-hospital cardiac arrest without obvious extracardiac causes. Resuscitation (2017), https://doi.org/10.1016/j.resuscitation.2017.11.046