TIMELY REPERFUSION THERAPY

ORIGINAL CONTRIBUTION System Delay and Mortality Among atients With STEMI Treated With rimary ercutaneous Coronary Intervention Christian Juhl Terkelsen, MD, hd Jacob Thorsted Sørensen, MD Michael Maeng, MD, hd Lisette Okkels Jensen, MD, DmSc Hans-Henrik Tilsted, MD Sven Trautner, MD Werner Vach, hd Søren aaske Johnsen, MD, hd Leif Thuesen, MD, DmSc Jens Flensted Lassen, MD, hd TIMELY REERFUSION THERAY with either fibrinolysis or primary percutaneous coronary intervention (CI) is recommended for patients with ST-segment elevation myocardial infarction (STEMI). 1 However, agreeing on the definition of timely is difficult, because the benefit achieved by earlier initiation of reperfusion therapy is controversial. The only unbiased studies that have evaluated the effects of earlier reperfusion therapy on outcome are randomized controlled studies that compared prehospital and in-hospital fibrinolysis. In those studies, prehospital fibrinolysis was associated with earlier initiation (1 hour) of reperfusion therapy, resulting in an extra 15 to 21 lives saved per 1000 treated patients. 2-4 The time-dependent benefit of primary CI has been evaluated from observational data only, and the nearly neutral relationship observed between treatment delay and mortality may lead Context Timely reperfusion therapy is recommended for patients with ST-segment elevation myocardial infarction (STEMI), and door-to-balloon delay has been proposed as a performance measure in triaging patients for primary percutaneous coronary intervention (CI). However, focusing on the time from first contact with the health care system to the initiation of reperfusion therapy (system delay) may be more relevant, because it constitutes the total time to reperfusion modifiable by the health care system. No previous studies have focused on the association between system delay and outcome in patients with STEMI treated with primary CI. Objective To evaluate the associations between system, treatment, patient, and doorto-balloon delays and mortality in patients with STEMI. Design, Setting, and atients Historical follow-up study based on populationbased Danish medical registries of patients with STEMI transported by the emergency medical service and treated with primary CI from January 1, 2002, to December 31, 2008, at 3 high-volume CI centers in Western Denmark. atients (N=6209) underwent primary CI within 12 hours of symptom onset. The median follow-up time was 3.4 (interquartile range, 1.8-5.2) years. Main Outcome Measures Crude and adjusted hazard ratios of mortality obtained by Cox proportional regression analysis. Results A system delay of 0 through 60 minutes (n=347) corresponded to a long-term mortality rate of 15.4% (n=43); a delay of 61 through 120 minutes (n=2643) to a rate of 23.3% (n=380); a delay of 121 through 180 minutes (n=2092) to a rate of 28.1% (n=378); and a delay of 181 through 360 minutes (n=1127) to a rate of 30.8% (n=275) (.001). In multivariable analysis adjusted for other predictors of mortality, system delay was independently associated with mortality (adjusted hazard ratio, 1.10 [95% confidence interval, 1.04-1.16] per 1-hour delay), as was its components, prehospital system delay and door-toballoon delay. Conclusion System delay was associated with mortality in patients with STEMI treated with primary CI. JAMA. 2010;304(7):763-771 www.jama.com Author Affiliations: Departments of Cardiology (Drs Terkelsen, Sørensen, Maeng, Thuesen, and Lassen) and Clinical Epidemiology (Dr Johnsen), Aarhus University Hospital, Aarhus, Denmark; Department of Cardiology, Odense University Hospital, Odense, Denmark (Dr Jensen); Department of Cardiology, Aalborg University Hospital, Aalborg, Denmark (Dr Tilsted); Falck Emergency Medical Service, The Falck House, Copenhagen, Denmark (Dr Trautner); and Department of Clinical Epidemiology, University Medical Centre, Freiburg, Germany (Dr Vach). Corresponding Author: Christian Juhl Terkelsen, MD, hd, Department of Cardiology, Aarhus University Hospital, DK-8200 Aarhus N, Denmark (christian_juhl_terkelsen@hotmail.com). 2010 American Medical Association. All rights reserved. (Reprinted) JAMA, August 18, 2010 Vol 304, No. 7 763

to the perception that the effect of primary CI is less time-dependent than the effect of fibrinolysis. 5-7 However, patients presenting early have a high mortality without reperfusion therapy and receive a large benefit from primary CI. Conversely, those presenting late are typically lowrisk patients who have already survived the prehospital phase and benefit less from reperfusion therapy. 8,9 This difference in patient characteristics may explain the lack of a clear association between treatment or patient delay and mortality, because early presenting high-risk patients who receive optimal reperfusion therapy ultimately have nearly the same mortality as those presenting late. 10,11 Moreover, determination of treatment and patient delay is based on information regarding symptom onset, which may be uncertain because of recall bias and because the onset of acute myocardial infarction (AMI) may have been preceded by hours of unstable angina. Thus, it is impossible to establish the exact time of onset of the AMI. To study the effect of delayed primary CI therapy on mortality, it may be more relevant to focus on a parameter not hampered by recall bias and less prone to selection bias, information bias, and confounding. Several studies have focused on the association between door-to-balloon delay and outcome, whereas the total health care system delay, defined as the time from first contact with the health care system to initiation of reperfusion therapy, has received only limited attention (FIGURE 1). 12 The present study assessed the associations between treatment, patient, system, and door-to-balloon delays and mortality in a large population-based cohort of patients with STEMI treated with primary CI. METHODS Setting and Design This study was based on public medical databases that cover the entire population of Western Denmark (approximately 3 million, corresponding to 55% of the Danish population). The Danish National Health Service provides tax-supported health care for all inhabitants, guaranteeing access to treatment at general practitioners and hospitals, along with emergency medical service (EMS) transportation. The EMS system in Denmark includes 5 different EMS agencies. In Western Denmark, one agency (Falck a/s) covers approximately 95% of the study region, and other EMS agencies working in Western Denmark were covered by the dispatch center operated by Falck a/s, guaranteeing access to prehospital data from these agencies also. The EMS system is organized as a partially 1-tier and partially 2-tier system with initial dispatcher triage. All emergencies deemed in need of an ambulance result in the dispatch of a primary unit manned with 2 EMS personnel trained in basic life support and the use of a defibrillator in automated external defibrillator mode. Subject to availability and determined by either dispatcher triage or evaluation by the Figure 1. Delays From Symptom Onset to rimary ercutaneous Coronary Intervention in atients With ST-Segment Elevation Myocardial Infarction Transported by the Emergency Medical Service Field-triaged to a CI center Symptom onset EMS call Arrival at CI center rimary CI atient delay Transportation delay Door-to-balloon delay rehospital system delay Treatment delay System delay Transferred from local hospitals Symptom onset EMS call Arrival at local hospital Departure from local hospital Arrival at CI center rimary CI atient delay Transportation delay Local hospital delay Interhospital delay Door-to-balloon delay rehospital system delay (before arrival at CI center) System delay Treatment delay Stratified according to prehospital triage. EMS indicates emergency medical service; CI, percutaneous coronary intervention. 764 JAMA, August 18, 2010 Vol 304, No. 7 (Reprinted) 2010 American Medical Association. All rights reserved.

primary unit, a physician-manned ambulance or a unit manned with a paramedic or nurse anesthetist also attend the scene. Equipment for telecommunication was gradually implemented beginning in 1999, and in 2006 all ambulances had equipment for acquisition and transmission of electrocardiographic data. The use of field triage for primary CI gradually increased during the study period. Throughout the study period, the catheterization laboratory was notified when the diagnosis of STEMI was established, whether in the prehospital phase or at the local hospital, and patients were admitted directly to the catheterization laboratory. Unambiguous individual-level linkage between the databases used in this study was possible using the civil registration number, a unique 10-digit personal identification number assigned to every Danish citizen at birth. 13,14 The study was approved by the Danish Data rotection Agency (J.No. 2008-41- 2299). atients and rocedures The study population consisted of 6209 patients with STEMI or bundlebranch block myocardial infarction admitted for primary CI between January 1, 2002, and December 31, 2008, at the 3 Western Denmark highvolume CI centers: Aarhus University Hospital, Skejby; Odense University Hospital, Odense; and Aalborg University Hospital, Aalborg. atients were identified in the Western Denmark Heart Registry (WDHR), which collects baseline characteristics and patient- and procedure-specific information on all angiographies and coronary interventions performed in Western Denmark. Self-presenters and patients without EMS data were excluded. rimary CI has been the recommended treatment for STEMI in Denmark since the publication of the Danish Trial of Acute Myocardial Infarction 2 (DANAMI-2) in 2003. 15 atients must meet the following criteria to be eligible for primary CI: symptom duration of 12 hours or less and STsegment elevation of 0.1 mv or greater in at least 2 contiguous leads ( 0.2 mv in V 1 -V 3 ) or presumed new-onset left bundle-branch block. retreatment with fibrinolysis was used in 118 patients (2.0%). Treatment, atient, System, and Door-to-Balloon Delay The estimates of various delays to the initiation of reperfusion therapy were based on prehospital data registered by the EMS provider (Falck a/s, Copenhagen, Denmark) and data registered Table 1. Characteristics of atients With ST-Segment Elevation Myocardial Infarction Transported by the Emergency Medical Service and Treated With rimary ercutaneous Coronary Intervention (N = 6209) Characteristic Field-Triaged Directly to CI Center (n = 2183) No. (%) Admitted at Local Hospital and Transferred to CI Center (n = 4026) Cases No. (%) Cases Value Demographics Age, median (IQR), y 64 (55-74) 2183 65 (56-74) 4026.37 Women 548 (25) 2183 1106 (28) 4026.04 Comorbid conditions Treated hypertension 481 (32) 1521 924 (30) 3053.36 Diabetes 151 (9.7) 1564 332 (11) 3161.39 revious myocardial infarction 136 (9.1) 1502 337 (11) 3008.03 revious CI 94 (6.3) 1500 185 (6.2) 3006.90 revious congestive heart failure 59 (2.9) 2014 134 (3.5) 3779.22 Active or previous smoker 1160 (79) 1462 2316 (79) 2916.97 Delays and transportation Delay, median (IQR), min a Treatment 172 (117-261) 2183 240 (175-340) 4026.001 atient 74 (34-160) 1945 106 (49-210) 3548.001 System 97 (78-124) 2183 139 (103-180) 4026.001 rehospital system 50 (37-67) 1638 89 (49-134) 3014.001 Door-to-balloon 39 (24-70) 1618 29 (21-72) 3008.001 Transportation, median (IQR), km 25 (7-46) 2183 71 (42-104) 4026.001 Clinical characteristics Body mass index, median (IQR) b 26 (24-29) 1157 26 (24-29) 1903.62 Blood pressure, median (IQR), mm Hg Systolic 130 (115-150) 1286 126 (110-143) 2252.001 Diastolic 78 (65-85) 1279 75 (65-80) 2242.001 Killip class 2181 4023 I 1976 (91) 3653 (91) II 108 (5.0) 189 (4.7) III 46 (2.1) 94 (2.3) IV 51 (2.3) 87 (2.2) Anterior STEMI or BBBMI 909 (45) 2009 1658 (46) 3624.72 Culprit vessel 2107 3902 Left main artery 39 (1.9) 60 (1.5) Left anterior descending artery 911 (43) 1684 (43) Circumflex artery 299 (14) 550 (14) Right coronary artery 858 (41) 1608 (41) Multivessel disease 917 (46) 1998 1780 (48) 3717.16 Abbreviations: BBBMI, bundle-branch block myocardial infarction; IQR, interquartile range; CI, percutaneous coronary intervention; STEMI, ST-segment elevation myocardial infarction. a Door-to-balloon delay indicates time from arrival at CI center to primary CI; patient delay, time from symptom onset to contact with the health care system; prehospital system delay, time from contact with the health care system to arrival at the CI center; system delay, time from contact with the health care system to primary CI. b Calculated as weight in kilograms divided by height in meters squared..87.82 2010 American Medical Association. All rights reserved. (Reprinted) JAMA, August 18, 2010 Vol 304, No. 7 765

Figure 2. Flow of atient Inclusion Into Study 13 439 atients admitted for primary CI 562 Excluded (previous index primary CI) 12 877 Had first index STEMI during study period 6209 Included in analysis 6668 Excluded 3291 rimary CI not performed 1552 Treatment delay >12 h 44 Missing treatment delay data 1433 EMS data not available 223 System delay >6 h 125 Mortality data not available 120 Foreign citizen 5 Emigrated System delay indicates time from contact with the health care system to time of primary percutaneous coronary intervention (CI); treatment delay, time from symptom onset to time of primary CI. EMS indicates emergency medical service; STEMI, STsegment elevation myocardial infarction. in the WDHR. Time of ambulance call was registered by a time stamp at the dispatch center, whereas time of arrival on scene, departure from scene, arrival at the local hospital, departure from the local hospital, and arrival at the CI center were registered electronically in the ambulance by the EMS personnel by pressing a radio button. Symptom onset and time of first guiding-catheter insertion were registered in the WDHR. Treatment delay was defined as the time from symptom onset to guidingcatheter insertion during primary CI; patient delay as the time from symptom onset to contact with the EMS; system delay as the time from contact with the EMS to guiding-catheter insertion during primary CI; prehospital system delay as the time from contact with the EMS to arrival at the CI center; and door-to-balloon delay as the time from arrival at the CI center to guiding-catheter insertion during primary CI (Figure 1). The use of guiding-catheter insertion as a surrogate for time of intervention was chosen because time of balloon inflation was only available in a minority of patients, only a few minutes elapse from guiding-catheter insertion to first intervention, and the majority of patients achieve reperfusion before balloon inflation. 16 Mortality and Covariates Data on mortality were obtained from The Danish Civil Registration System, which has recorded changes in vital status of the entire Danish population since 1968. 17 Vital status is updated daily. Baseline characteristics and other covariates (TABLE 1) were derived from the Danish Civil Registration System, the WDHR, and the National Registry of atients. Statistical Analysis Dichotomous data are presented as percentages. Continuous variables are presented as medians (interquartile ranges). The Fisher exact test, 2 test, Mann-Whitney test, and Kruskal- Wallis test were used for comparisons of categorical and continuous variables, as appropriate. Follow-up began on the date of primary CI and ended on the date of death, emigration, or September 24, 2009, whichever came first. We computed Kaplan-Meier cumulative mortality curves, stratified according to intervals of system delay, and made comparisons between groups with log-rank statistics. Cox proportional hazards regression analysis was used to examine the association between the covariates and the intervals of delay to reperfusion described above and mortality. The proportional hazards assumption was checked for each categorical variable by visual inspection and by the method described by Grambsch and Therneau, 18 using the scaled Schoenfeld residuals. For continuous variables, the linearity assumption was checked graphically using the Martingale residuals. Cox-Snell residuals were used to assess the overall model fit. Systolic and diastolic blood pressure levels were converted to categorical values, because they did not fulfill the linearity assumption. Crude and mutually adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) were computed. Variables associated with time to death in the univariable Cox regression analyses (Wald test.05) were included in multivariable Cox regression models. Missing values among covariates were replaced with their conditional means, obtained as predictions from a regression model using all nonmissing covariates for each patient. 19,20 This method for assigning missing values was also used for categorical variables without rounding the binary outcome, as previously proposed by Allison 21 when proportions are not close to0or1. 21,22 Because of colinearity between infarct location and culprit vessel, only infarct location was entered in the multivariable models; because of colinearity between systolic and diastolic blood pressure, only systolic blood pressure was entered in the models. Separate models were performed considering only nonoverlapping intervals of time to reperfusion: model 1 considered treatment delay, model 2 considered patient and system delay, and model 3 considered patient, prehospital system, and door-to-balloon delay. All statistical analyses were performed using Stata 10.0 (StataCorp, College Station, Texas). RESULTS A total of 13 439 patients with suspected STEMI or bundle-branch block myocardial infarction were transferred to or admitted directly to 1 of the 3 CI centers. The first index STEMI during the study period (n=12 877 patients) was included for further analyses. atients were excluded if primary CI was not performed (n=3291 patients) or if they had a treatment delay greater than 12 hours (n=1552), missing treatment delay data (n=44), or a system delay greater than 6 hours (n=223). Mortality data were not available for patients who were foreign citizens (n=120) or had emigrated (n=5). In 1433 patients considered selfpresenters, EMS data were not 766 JAMA, August 18, 2010 Vol 304, No. 7 (Reprinted) 2010 American Medical Association. All rights reserved.

available. Thus, the study cohort consisted of 6209 patients (FIGURE 2), of whom 2183 (35%) were field-triaged directly to a CI center, bypassing the local hospital. The proportion of patients field-triaged directly to the CI centers increased from 386 of 1414 (27%) in the first 2 years of the study period to 873 of 1864 (47%) in the last 2 years (.001). When stratifying according to whether patients were field-triaged directly to the CI center or transferred from other hospitals, there were significant differences in several baseline characteristics and in the door-toballoon and system delays (Table 1). For field-triaged, transferred, and all EMS-transported patients, the proportion treated with a system delay of 120 minutes or less was 72% (n=1566), 35% (n=1424), and 48% (n=2990), respectively, and among patients with available door-to-balloon time (n=4626) the proportion treated with a door-to-balloon delay of 90 minutes or less was 86% (n=1399), 80% (n=2407), and 82% (n=3806). The median time from guiding-catheter insertion to balloon inflation was 4 (interquartile range, 1-8) minutes in patients in whom time of balloon inflation was registered (n=1836). The median follow-up time was 3.4 (interquartile range, 1.8-5.2) years, with a cumulative 1-year mortality of 9.3% (n=579). The majority of covariates were associated with mortality at follow-up in the univariable analysis (TABLE 2). According to Wald statistics, system delay had the strongest association with mortality among the covariates modifiable in the acute phase, with an HR of 1.22 (95% CI, 1.15-1.29;.001) per 1-hour increase in system delay (Table 2). When stratifying according to intervals of system delay, long-term cumulative mortality was 15.4% (n=43) in patients with system delays of 0 through 60 minutes (n=347), 23.3% (n=380) in those with delays of 61 through 120 minutes (n=2643), 28.1% (n=378) in those with delays of 121 through 180 minutes (n=2092), and 30.8% (n=275) in those with delays of 181 through 360 minutes (n=1127) (.001). Kaplan-Meier mortality curves are presented in FIGURE 3. For the different intervals of system delay, no differences were observed in infarct location, culprit vessel, or Killip class, whereas significant differences were observed in the majority of remaining covariates (TABLE 3). In the multivariable analyses, after adjusting for other covariates, treatment delay and patient delay were not associated with mortality (TABLE 4), whereas system delay remained independently associ- Table 2. Crude Hazard Ratios of Covariates Associated With Long-term Mortality in Univariable Cox Regression Analysis (N = 6209). Characteristics Cases Deaths a HR (95% CI) Wald Test Value b Demographics Age, per 1-year increase 6209 1.074 (1.069-1.080) 666.001 Women 6209 364 1.46 (1.29-1.66) 35.001 Comorbid conditions Treated hypertension 4574 280 1.45 (1.25-1.69) 25.001 Diabetes 4725 146 2.29 (1.91-2.73) 82.001 revious myocardial infarction 4510 122 1.55 (1.28-1.89) 20.001 revious CI 4506 53 1.19 (0.90-1.58) 1.5.22 revious congestive heart failure 5793 102 4.22 (3.43-5.17) 189.001 Active or previous smoker 4378 505 0.78 (0.66-0.93) 7.6.006 Delays and transportation Delay, per 1-h increase c Treatment 6209 1.054 (1.029-1.080) 19.001 atient 5493 1.042 (1.014-1.071) 8.8.003 System 6209 1.22 (1.15-1.29) 51.001 rehospital system 4652 1.19 (1.11-1.27) 26.001 Door-to-balloon 4626 1.13 (1.048-1.22) 10.002 Transportation distance, per 1-km increase Clinical characteristics Body mass index, per 1-unit increase Systolic blood pressure, mm Hg 3537 550 6209 1.00 (0.999-1.002) 0.45.50 3060 0.94 (0.91-0.96) 25.001 110 641 170 1 [Reference] 78.001 110-129 1111 161 0.49 (0.40-0.61) 42.001 130-144 873 101 0.40 (0.31-0.51) 54.001 145 912 118 0.45 (0.35-0.56) 46.001 Diastolic blood pressure, mm Hg 3521 546 65 812 191 1 [Reference] 69.001 65-74 819 119 0.55 (0.44-0.69) 26.001 75-84 1092 157 0.53 (0.43-0.65) 35.001 85 798 79 0.37 (0.29-0.48) 55.001 Killip class 6204 1073 I 5629 811 1 [Reference] 545.001 II 297 97 2.63 (2.13-3.24) 81.001 III 140 76 5.09 (4.02-6.44) 184.001 IV 138 89 8.65 (6.94-10.8) 370.001 Anterior infarct location 5633 467 1.35 (1.19-1.54) 21.001 Culprit vessel LM/LAD 6009 520 1.28 (1.14-1.45) 16.001 Multivessel disease 5715 640 2.19 (1.92-2.49) 138.001 Abbreviations: CI, confidence interval; HR, hazard ratio; LAD, left anterior descending artery; LM, left main artery, CI, percutaneous coronary intervention. a Total deaths=1076. b By univariable Cox regression. c Door-to-balloon delay indicates time from arrival at the CI center to primary CI; patient delay, time from symptom onset to contact with the health care system; prehospital system delay, time from contact with the health care system to arrival at the CI center; system delay, time from contact with the health care system to primary CI; treatment delay, time from symptom onset to primary CI. 2010 American Medical Association. All rights reserved. (Reprinted) JAMA, August 18, 2010 Vol 304, No. 7 767

Figure 3. Kaplan-Meier Cumulative Mortality Estimates for atients With ST-Segment Elevation Myocardial Infarction Treated With rimary ercutaneous Coronary Intervention (N=6209) Mortality, % ated with mortality, with an adjusted HR of 1.10 (95% CI, 1.04-1.16; =.002) per 1-hour delay (Table 4). The main components of system delay were also associated with mortality: prehospital system delay had an adjusted HR of 1.10 (95% CI, 1.02-1.18; =.02), and doorto-balloon delay had an adjusted HR of 1.14 (95% CI, 1.05-1.24; =.001) per 1-hour delay (Table 4). COMMENT To our knowledge, this study is the first to evaluate the association between system delay and outcome in an unselected cohort of patients with STEMI transported by an EMS and treated with primary CI. In contrast to treatment and patient delay, system delay was independently associated with mortality. Moreover, it was the highest ranking among the covariates studied that can be modified in the acute phase, and it comprises the total delay that is modifiable by the health care system. The mortality benefit obtained by earlier initiation of reperfusion therapy is difficult to assess in observational studies. revious studies have plotted mortality according to treatment delay and reported a nearly horizontal association between time to 30 20 10 0 0 No. at risk System delay, min 0-60 347 61-120 2643 121-180 2092 181-360 1127 System delay, min 0-60 61-120 121-180 181-360 1 311 2339 1836 923 2 3 4 Follow-up, y 278 1906 1503 765 230 1420 1183 647 Log-rank <.001 192 1006 842 491 Stratified according to intervals of system delay (time from contact with the health care system to the time of primary CI). CI indicates percutaneous coronary intervention; STEMI, ST-segment elevation myocardial infarction. 5 138 667 533 332 reperfusion and mortality. 6,23 However, confounding and selection bias may hamper such analyses. High-risk patients tend to present early, whereas those presenting late have already survived the early hours, ie, the period in which they are at highest risk of death. This so-called survivor-cohort effect is supported by Löwel et al. 8 In the prefibrinolytic era, they reported that 88% of patients with AMI who contacted the health care system within 1 hour of symptom onset died during the prehospital phase or in the hospital. In comparison, among patients who contacted the health care system from 1 to 24 hours after symptom onset, 43% died during the prehospital phase or in the hospital. 8,24 This finding is consistent with those reported by Aquaro et al and Nallamothu et al, who demonstrated that early presenters had the highest risk scores 11 and the largest ST-segment elevations. 25 Without reperfusion therapy, patients presenting early have the highest mortality, but with optimal reperfusion therapy, they may attain nearly the same mortality as those presenting late. 10 This phenomenon may explain the neutral association previously observed between treatment delay and mortality. 6,23,26 aradoxically, the 6 87 375 278 172 7 phenomenon also supports a timedependent benefit of primary CI, because it implies that the benefit of primary CI is more pronounced in the early hours after symptom onset and confirms that the reduction in mortality achieved by earlier reperfusion therapy is underestimated when evaluated from observational data. 10 We were able to adjust for major risk factors in the analysis of the effect of treatment delay and patient delay and hence able to reduce the effect of confounding. Nevertheless, we found no association with mortality. This may be explained by the selection bias, which is still present. It also may be related to the fact that patient delay and treatment delay depend on the time from onset of symptoms and are affected by substantial measurement error, because patients have to recall this onset. Moreover, the biologically relevant point is the time of onset of infarction, which may not to be identical to the time of first symptoms. Door-to-balloon delay is suggested by the D2B Alliance as A key indicator of quality of care in STEMI patients treated with [primary] CI. 27 Undoubtedly, this parameter is associated with mortality, 7,28,29 as is also documented in the present study. It is useful for monitoring primary CI performance at CI centers, and various initiatives have successfully reduced door-to-balloon delay. 30 However, door-to-balloon delay comprises only a minor part of the health care system delay. A strategy of prehospital diagnosis and rerouting patients directly to a catheterization laboratory may shorten system delay by as much as 1 hour, 31 although such a strategy may be associated with longer doorto-balloon delay, because shorter notice gives the catheterization laboratory less time to prepare for the arrival of field-triaged patients. 31 Therefore, doorto-balloon delay should be used as a performance measure at the CI centers to ensure a focus on optimal center performance, but it may not be an ideal general health care system performance measure in patients with STEMI. 768 JAMA, August 18, 2010 Vol 304, No. 7 (Reprinted) 2010 American Medical Association. All rights reserved.

The effects of different primary CI delays on mortality cannot be subject to randomized assessments. Given that confounding, selection bias, and recall bias may hamper patient and treatment delays, it seems reasonable that the optimal way to evaluate the association between delayed initiation of reperfusion therapy and mortality in a nonrandomized study is to focus on system delay. Even though patient and treatment delays are theoretically applicable to all patients, data on these delays are available only in the selected cohort of patients surviving until making contact with the health care system and only if the patient is able to recall the exact time of symptom onset. Moreover, it is questionable if the exact onset of AMI can be determined, because it is based on subjective information and the AMI may have been preceded by hours of unstable angina. Accordingly, the lack of an association between patient delay and mortality may be explained by confounding, selection bias, recall bias, and measure- Table 3. Characteristics of atients With ST-Segment Elevation Myocardial Infarction Transported by the Emergency Medical Service and Treated With rimary ercutaneous Coronary Intervention, Stratified According to System Delay (N = 6209) System Delay, min 0-60 (n = 347) 61-120 (n = 2643) 121-180 (n = 2092) 181-360 (n = 1127) Variables No. (%) Cases No. (%) Cases No. (%) Cases No. (%) Cases Value a Demographics Age, median (IQR), y 62 (54-72) 347 63 (55-73) 2643 65 (56-75) 2092 67 (58-77) 1127.001 Women 91 (26) 347 645 (24) 2643 584 (28) 2092 334 (30) 1127.003 Comorbid conditions Treated hypertension 81 (27) 297 615 (31) 2008 449 (30) 1494 260 (34) 775.18 Diabetes 33 (11) 300 194 (9.4) 2074 158 (10) 1537 98 (12) 814.18 revious myocardial infarction 16 (5.7) 283 197 (9.9) 1982 133 (9.1) 1458 127 (16) 787.001 revious CI 18 (6.4) 280 121 (6.1) 1979 77 (5.3) 1456 63 (8.0) 791.10 revious congestive heart failure 7 (2.1) 327 74 (3.0) 2453 59 (3.0) 1959 53 (5.0) 1054.007 Active or previous smoker 231 (81) 287 1585 (82) 1944 1105 (78) 1414 555 (76) 733.005 Delays, transportation, and triage Delay, median (IQR), min b Treatment 170 (99-265) 347 180 (125-277) 2643 221 (173-315) 2092 299 (243-378) 1127.001 atient 131 (60-226) 337 99 (45-199) 2435 92 (41-188) 1827 86 (39-173) 894.001 rehospital system 29 (23-35) 201 55 (41-71) 1920 101 (50-123) 1598 159 (55-193) 933.001 Door-to-balloon 19 (15-23) 199 28 (20-46) 1901 37 (24-92) 1593 55 (26-154) 933.001 Transportation, median (IQR), km 7 (4-37) 347 38 (13-59) 2643 74 (33-106) 2092 90 (47-133) 1127.001 Field-triaged to CI center 153 (44) 347 1413 (54) 2643 495 (24) 2092 122 (11) 1127.001 Clinical characteristics Body mass index, median (IQR) c 26 (24-29) 165 26 (24-29) 1446 26 (24-29) 963 26 (24-29) 486.97 Blood pressure, median (IQR), mm Hg Systolic 130 (115-149) 189 130 (115-147) 1598 125 (110-140) 1141 125 (110-140) 609.001 Diastolic 78 (67-85) 189 79 (68-85) 1592 75 (65-80) 1135 72 (60-80) 605.001 Killip class 347 2641 2090 1126 I 316 (91) 2418 (92) 1899 (91) 996 (89) II 16 (4.6) 117 (4.4) 100 (4.8) 64 (5.7) III 7 (2.0) 60 (2.3) 45 (2.2) 28 (2.5) IV 8 (2.3) 46 (1.7) 6 (2.2) 38 (3.4) Anterior STEMI or BBBMI 148 (47) 312 1085 (44) 2441 868 (46) 1895 466 (47) 985.40 Culprit vessel 327 2557 2039 1086 Left main artery 3 (0.9) 39 (1.5) 31 (1.5) 26 (2.4) Left anterior descending artery 158 (48) 1091 (43) 888 (44) 458 (42) Circumflex artery 37 (11) 359 (14) 274 (13) 179 (17) Right coronary artery 129 (39) 1068 (42) 846 (42) 423 (39) Multivessel disease 140 (44) 319 1084 (45) 2419 929 (48) 1936 544 (52) 1041.001 Abbreviations: BBBMI, bundle-branch block myocardial infarction; IQR, interquartile range; CI, percutaneous coronary intervention; STEMI, ST-segment elevation myocardial infarction. a By Kruskal-Wallis test. b Door-to-balloon delay indicates time from arrival at CI center to primary CI; patient delay, time from symptom onset to contact with the health care system; prehospital system delay, time from contact with the health care system to arrival at the CI center; system delay, time from contact with the health care system to primary CI. c Calculated as weight in kilograms divided by height in meters squared..15.06 2010 American Medical Association. All rights reserved. (Reprinted) JAMA, August 18, 2010 Vol 304, No. 7 769

ment bias, but neither this observation nor the lack of any long-lasting effect of media campaigns on patient or treatment delays should deter encouraging patients to seek medical help as soon as possible after the onset of symptoms. 32,33 In comparison, system delay is by definition only defined in patients surviving until contact with the health care system; hence, studying the effect of system delay is not affected by selection bias from survival. It can be studied in all patients contacting the health care system, and it is an objective parameter not prone to recall bias. Most importantly, however, system delay and its components appear to be the only risk factors that can be modified in the acute phase, by optimizing prehospital and in-hospital triage. 31,34 This study has a number of limitations. System delay may have been underestimated, because data were not available on contacts with general practitioners in the acute phase. In reviewing a sample of 130 hospital records, we found that 6% of the EMS-transported patients were not in the EMS registry, resulting in a minor underestimation of the number of patients transported by the EMS. Usually, the time of the first balloon inflation is used as the time of reperfusion, but reperfusion often takes place before balloon inflation (eg, during wiring or thrombectomy). Therefore, the time of first wiring of the vessel might be a better parameter for representing the time of reperfusion. 16 However, data on first wiring were not available, and because insertion of the guiding catheter is followed within a few minutes by the first coronary intervention, we decided to use the time of guiding-catheter insertion as the time of first intervention. Acknowledging the widespread acceptance of the door-to-balloon delay as a performance measure, we decided to use the door-to-balloon delay synonymously with the time from arrival at the CI center to the first insertion of the guiding catheter. We conclude that health care system delay is valuable as a performance measure when patients with STEMI are treated with primary CI, because it is associated with mortality, it consti- Table 4. Multivariable Cox Regression Analysis of Covariates Associated With Long-term Mortality in atients With ST-Segment Elevation Myocardial Infarction Treated With rimary ercutaneous Coronary Intervention (N = 6209) a Model 1 Model 2 Model 3 Covariates Remaining Significant in Models b HR (95% CI) Value c HR (95% CI) Value c HR (95% CI) Value c Demographics Age, per 1-y increase 1.067 (1.060-1.074).001 1.066 (1.060-1.073).001 1.066 (1.060-1.073).001 Comorbid conditions Diabetes 1.97 (1.64-2.37).001 1.94 (1.61-2.33).001 1.95 (1.63-2.35).001 revious congestive heart failure 1.73 (1.39-2.16).001 1.78 (1.43-2.22).001 1.78 (1.43-2.22).001 revious or current smoking 1.24 (1.05-1.48).01 1.25 (1.05-1.48).01 1.26 (1.06-1.50).008 Delays, per 1-h increase d Treatment 1.00 (0.98-1.03).54 atient 1.00 (0.98-1.03).63 1.00 (0.98-1.03).64 System 1.10 (1.04-1.16).002 rehospital system 1.10 (1.02-1.18).02 Door-to-balloon 1.14 (1.05-1.24).001 Clinical characteristics Systolic blood pressure, mm Hg 110 1 [Reference] 1 [Reference] 1 [Reference] 110-129 0.76 (0.63-0.92).004 0.74 (0.61-0.90).004 0.74 (0.61-0.89).001 130-144 0.66 (0.55-0.81).001 0.68 (0.56-0.82).001 0.66 (0.55-0.80).001 145 0.52 (0.40-0.66).001 0.53 (0.41-0.67).001 0.52 (0.41-0.67).001 Killip class I 1 [Reference] 1 [Reference] 1 [Reference] II 1.61 (1.29-2.01).001 1.65 (1.33-2.06).001 1.63 (1.31-2.03).001 III 2.47 (1.92-3.18).001 2.55 (1.98-3.28).001 2.51 (1.95-3.23).001 IV 4.73 (3.69-6.06).001 4.71 (3.67-6.05).001 4.57 (3.56-5.87).001 Anterior STEMI or BBBMI 1.30 (1.14-1.48).001 1.29 (1.13-1.47).001 1.29 (1.13-1.47).001 Multivessel disease 1.53 (1.34-1.76).001 1.51 (1.32-1.73).001 1.51 (1.31-1.73).001 Abbreviations: BBBMI, bundle-branch block myocardial infarction; CI, confidence interval; HR, hazard ratio; STEMI, ST-segment elevation myocardial infarction. a Adjusted for sex, body mass index, history of previous myocardial infarction, and treatment for hypertension. b Nonoverlapping intervals of treatment delay were considered for inclusion in the multivariable models: model 1 considered treatment delay, model 2 considered patient and system delay, and model 3 considered patient, prehospital system, and door-to-balloon delay. c By multivariable Cox regression. d Door-to-balloon delay indicates time from arrival at the CI center to primary percutaneous coronary intervention (CI); patient delay, time from symptom onset to contact with the health care system; prehospital system delay, time from contact with the health care system to arrival at the CI center; system delay, time from contact with the health care system to primary CI. 770 JAMA, August 18, 2010 Vol 304, No. 7 (Reprinted) 2010 American Medical Association. All rights reserved.

tutes the part of treatment delay modifiable by the health care system in the acute phase, and it applies to patients field-triaged directly to the CI center as well as to patients transferred from local hospitals. Increased focus on the total health care system delay may optimize triage of patients with STEMI and may be the key to further improving survival of these patients. Author Contributions: Dr Terkelsen had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Terkelsen, Maeng, Trautner, Thuesen, Lassen. Acquisition of data: Terkelsen, Sørensen, Jensen, Tilsted, Trautner, Lassen. Analysis and interpretation of data: Terkelsen, Sørensen, Maeng, Trautner, Vach, Johnsen, Lassen. Drafting of the manuscript: Terkelsen, Sørensen, Jensen, Thuesen, Lassen. Critical revision of the manuscript for important intellectual content: Terkelsen, Sørensen, Maeng, Jensen, Tilsted, Trautner, Vach, Johnsen, Lassen. Statistical analysis: Terkelsen. Obtained funding: Terkelsen, Sørensen, Lassen. Administrative, technical, or material support: Terkelsen, Sørensen, Jensen, Trautner, Lassen. Study supervision: Maeng, Jensen, Tilsted, Johnsen, Thuesen, Lassen. Financial Disclosures: Dr Sørensen reported receiving an unrestricted grant from Falck EMS, Denmark, to perform studies unrelated to the present study. No other authors reported disclosures. Funding/Support: This study was supported by grants from the Helga and eter Kornings Foundation, Aarhus, Denmark ( J.No. 40-134918) and the Health Research Fund of Central Denmark Region, Aarhus, Denmark ( J.No. 1-45-72-1-08). Role of the Sponsors: The funders had no role in the design and conduct of the study, in the collection, management, analysis, and interpretation of the data, or in the preparation of the manuscript. Additional Contributions: We thank Tim Lash, DSc, MH, Department of Epidemiology, Aarhus University, Aarhus, Denmark, for his advice during the revision of the manuscript. Dr Lash received no compensation for his contributions. REFERENCES 1. Antman EM, Hand M, Armstrong W, et al; Canadian Cardiovascular Society; American Academy of Family hysicians; American College of Cardiology; American Heart Association. 2007 Focused Update of the ACC/AHA 2004 Guidelines for the Management of atients With ST-Elevation Myocardial Infarction: a report of the American College of Cardiology/American Heart Association Task Force on ractice Guidelines. J Am Coll Cardiol. 2008;51(2):210-247. 2. 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