In patients with ST-segment elevation myocardial infarction. Original Research

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1 IMPROVING PATIENT CARE Original Research Health Care System Delay and Heart Failure in Patients With ST-Segment Elevation Myocardial Infarction Treated With Primary Percutaneous Coronary Intervention: Follow-up of Population-Based Medical Registry Data Christian Juhl Terkelsen, MD, PhD; Lisette Okkels Jensen, MD, DmSc, PhD; Hans-Henrik Tilsted, MD; Sven Trautner, MD; Søren Paaske Johnsen, MD, PhD; Werner Vach, PhD; Hans Erik Bøtker, MD, DmSc; Leif Thuesen, MD, DmSc; and Jens Flensted Lassen, MD, PhD Background: In patients with ST-segment elevation myocardial infarction (STEMI), delay between contact with the health care system and initiation of reperfusion therapy (system delay) is associated with mortality, but data on the associated risk for congestive heart failure (CHF) among survivors are limited. Objective: To evaluate the association between system delay and the risk for readmissions or outpatient contacts due to CHF after primary percutaneous coronary intervention (PPCI) in patients with STEMI. Design: Historical follow-up study using population-based medical registries. Setting: Western Denmark. Patients: Patients with STEMI who were transported by emergency medical service from 1 January 1999 to 7 February 2010 and treated with PPCI within 12 hours of symptom onset and who had a system delay of 6 hours or less (n 7952). The median duration of follow-up was 3.1 years. Measurements: Cumulative incidence of readmissions or outpatient contacts due to CHF was determined by using competing-risk regression analysis, with death as the competing risk. Crude and adjusted cause-specific hazard ratios for readmissions or outpatient contacts due to CHF were determined for system delay and other covariates. Results: System delays of 60 minutes or less (n 451), 61 to 120 minutes (n 3457), 121 to 180 minutes (n 2655), and 181 to 360 minutes (n 1389) corresponded with long-term risks for readmissions or outpatient contacts due to CHF of 10.1%, 10.6%, 12.3%, and 14.1%, respectively (P 0.001). In multivariable analysis, system delay was an independent predictor of readmissions or outpatient contacts due to CHF (adjusted hazard ratio per hour increase in delay, 1.10 [95% CI, 1.02 to 1.17]). Limitation: In any nonrandomized study, there are risks for selection bias and residual confounding. Conclusion: In patients with STEMI, shorter delay to PPCI is associated with lower risk for readmissions or outpatient contacts due to CHF during follow-up. Primary Funding Source: The Karl G. Andersen Foundation, the Helga and Peter Korning Foundation, the Health Research Fund of Central Denmark Region, the Research Foundation at Skejby University Hospital, the Riisfort Foundation, and the Arvid Nilsson Foundation. Ann Intern Med. 2011;155: For author affiliations, see end of text. In patients with ST-segment elevation myocardial infarction (STEMI), timely reperfusion therapy with fibrinolysis or primary percutaneous coronary intervention (PPCI) is associated with reduced mortality (1 3). Accordingly, guidelines recommend that the health care system delay that is, the delay from the call to emergency medical services (EMS), from the arrival of EMS, or from the first medical contact to reperfusion therapy is less than 90 to 120 minutes (1, 4). We have previously documented that health care system delay is associated with mortality in patients with STEMI (3). Because coronary heart disease is the initiating cause in 70% of cases of congestive heart failure (CHF), it is also of interest to determine whether system delay affects the incidence of CHF in patients surviving STEMI. The present study sought to evaluate the association between system delay and readmissions or outpatient contacts due to CHF in a large population-based cohort of patients with STEMI who were treated with PPCI. METHODS Setting and Design We conducted a historical follow-up study using public administrative health care databases covering the entire population of western Denmark (approximately 3.0 million inhabitants, corresponding to 55% of the Danish population). The Danish National Health Service provides taxsupported health care for all inhabitants, guaranteeing free access to general practitioners and hospitals. Unambiguous individual-level linkage between the databases used in this See also: Print Editors Notes Web-Only Conversion of graphics into slides 2011 American College of Physicians 361

2 Original Research Health Care System Delay and Heart Failure in Patients With STEMI Treated With PPCI Context Patients with ST-segment elevation myocardial infarction are more likely to die when there are delays in reperfusion with fibrinolysis or primary percutaneous coronary intervention. Contribution This study found that delays are also associated with increased numbers of hospital readmissions and outpatient visits for congestive heart failure. Caution It is difficult to establish cause and effect in observational studies, such as this one, because selection bias and residual confounding are possible. Implication Reducing the number and length of reperfusion delays may prevent some patients from developing heart failure. The Editors study was possible with the civil registration number, a unique 10-digit personal identification number assigned to every Danish citizen at birth (5, 6). The study was approved by the National Data Protection Agency (J.Nr ). Patients and Procedures The study sample comprised patients with STEMI or presumed new-onset bundle branch block myocardial infarction, admitted for PPCI at the 3 PCI centers in western Denmark (Skejby, Odense, and Aalborg) from 1 January 1999 to 7 February Patients were identified from the Western Denmark Heart Registry (7). This registry prospectively collects baseline characteristics, as well as patient- and procedure-specific information on all angiographies and coronary interventions performed in western Denmark. Primary percutaneous coronary intervention for STEMI has been the recommended treatment in Denmark since publication of the results of DANAMI-2 (DANish trial in Acute Myocardial Infarction-2) in 2003 (8). To be eligible for PPCI, patients must meet the following criteria: 1) symptom duration less than 12 hours and 2) STsegment elevation of 0.1 mv or greater in at least 2 contiguous electrocardiography leads ( 0.2 mv in leads V1 to V3) or presumed new-onset left bundle branch block. Treatment Delay, Patient Delay, and System Delay The estimation of various delays from symptom onset to PPCI was based on prehospital data registered by the EMS provider (Falck A/S, Copenhagen, Denmark), and time of symptom onset and first catheterization during PCI were registered in the Western Denmark Heart Registry. Patient delay was calculated as the time from symptom onset to EMS call, system delay was calculated as the time from EMS call to first catheterization during PCI, and treatment delay was calculated as time from symptom onset to PPCI. Mortality, Readmissions, and Outpatient Contacts Due to CHF The Danish Civil Registration System has kept daily updated electronic records on sex, date of birth, change of address, date of emigration, and changes in vital status on the entire Danish population since 1968 (9). Data on mortality status were obtained on 18 March The Danish National Registry of Patients holds data on all hospitalizations from all Danish nonpsychiatric hospitals since 1997 and all outpatient contacts since 1996, including dates of admission and discharge, date of outpatient contact, surgical procedures performed, and up to 20 discharge diagnoses assigned by the treating physician and coded according to the International Classification of Diseases (8th revision until the end of 1993 and 10th revision thereafter) (10). We searched the National Registry of Patients from 1977 to 18 March 2010 to identify previous admissions or outpatient contacts with a diagnosis of CHF (International Classification of Diseases diagnosis codes J819, I110, I130, I132, I255, I420, I426, I427, I428, I429, I500, I501, and I509) (before the index STEMI) and readmissions or outpatient contacts with a diagnosis of CHF (after the index STEMI). Covariates Baseline characteristics and other covariates used in the analyses (Table 1) were derived from the Danish Civil Registration System and the Western Denmark Heart Registry. Statistical Analysis Dichotomous data are presented as numbers (percentages). Continuous variables are presented as medians (interquartile range) or means (variance). The Fisher exact test, chi-square test, and Mann Whitney test were used to compare categorical and continuous variables as appropriate. Follow-up began on the date of PPCI and ended on the date of readmission or outpatient contact due to CHF; death by 18 March 2010; or after 7 years of follow-up (to ensure that at least 10% of the study sample remained at risk), whichever came first. Missing values among covariates were replaced by using multiple imputation of chained equations by the Stata ICE command (11). Logistic regression modeling was used for binary covariates, ordinal logistic regression modeling was used for Killip class, and linear regression modeling was used for continuous covariates. We imputed 10 data sets. All covariates in Table 1 were considered in the multiple imputation, together with the indicator for censoring, death or CHF, and the time until event transformed to a baseline hazard (the Nelson Aalen estimate) as recommended by White and Royston (12). Competing-risk regression analysis was performed (13) to examine the association between various covariates and events defined as readmission or outpatient contact due to September 2011 Annals of Internal Medicine Volume 155 Number 6

3 Health Care System Delay and Heart Failure in Patients With STEMI Treated With PPCI Original Research Table 1. Characteristics of Patients With STEMI Who Were Transported by Emergency Medical Service and Treated With Primary Percutaneous Coronary Intervention, Stratified by Readmissions or Outpatient Contacts Due to CHF (n 7952) Characteristic No Readmission or Outpatient Contact Due to CHF (n 7167) Readmission or Outpatient Contact Due to CHF (n 785) P Value Patients Valid Cases, n Patients Valid Cases, n Demographic Median age (IQR), y 64 (55 74) (59 76) Women, n (%) 1912 (27) (26) Comorbid conditions, n (%) Treated hypertension 1978 (31) (33) Diabetes 743 (11) (12) Previous MI 626 (9.8) (18) Previous PCI 360 (5.6) (9.9) Previous CHF 187 (2.6) (7.9) Active or previous smoker 4750 (77) (77) Delays and transportation Median treatment delay (IQR), h* 3.57 ( ) ( ) Median patient delay (IQR), h* 1.55 ( ) ( ) Median system delay (IQR), h* 2.02 ( ) ( ) Median transportation distance (IQR), km 52 (19 91) (19 95) Clinical Median body mass index (IQR), kg/m 2 26 (24 29) (24 29) Median blood pressure (IQR), mm Hg Systolic 128 ( ) ( ) Diastolic 75 (65 80) (64 82) Killip class I, n (%) 6298 (91) (82) Anterior STEMI or bundle branch block MI, n (%) 2650 (38) (69) Culprit vessel, n (%) Left main artery 109 (1.6) 13 (1.7) Left anterior descending artery 2877 (41) 505 (66) Circumflex artery 977 (14) 87 (11) Right coronary artery 2994 (43) 158 (21) Multivessel disease, n (%) 3040 (44) (56) CHF congestive heart failure; IQR interquartile range; MI myocardial infarction; PCI percutaneous coronary intervention; STEMI ST-segment elevation myocardial infarction. * Treatment delay is the time from symptom onset to PCI; patient delay is the time from symptom onset to contact with the health care system; system delay is the time from contact with the health care system to PCI. CHF after the index STEMI. Death was considered as the competing risk. Cumulated incidence curves were stratified according to intervals of system delay. Comparisons between groups were performed by including system delay as a categorical variable in the competingrisk regression analysis. Crude and mutually adjusted subhazard ratios (subsequently called hazard ratios ) were calculated, and 95% CIs are presented. The proportional hazard assumption was checked by evaluating whether the hazard ratios for each covariate were timevarying. Variables associated with time to readmissions or outpatient contacts due to CHF in the univariable competing-risk regression analyses (Wald test; P 0.10) were included in multivariable competing-risk regression models. Because of collinearity between infarct location and culprit vessel, only infarct location was entered in the multivariable models; as a result of collinearity between systolic and diastolic blood pressures, only systolic blood pressure was entered in the models. Separate models that involved nonoverlapping intervals of delay to reperfusion were performed: Model 1 implemented treatment delay, and model 2 implemented patient delay and system delay. All variables associated with readmission or outpatient contact due to CHF in the multivariable model, as well as year of admission with STEMI, were analyzed separately for a potential modification of the effect of system delay on readmission or outpatient contact due to CHF by inclusion of corresponding interaction terms. All statistical analyses were performed by using Stata software, version 11.0 (StataCorp LP, College Station, Texas). Role of the Funding Source The study was supported by the Karl G. Anderson Foundation, the Helga and Peter Korning Foundation, the Health Research Fund of Central Denmark Region, the Research Foundation at Skejby University Hospital, the Riisfort Foundation, and the Arvid Nilsson Founda September 2011 Annals of Internal Medicine Volume 155 Number 6 363

4 Original Research Health Care System Delay and Heart Failure in Patients With STEMI Treated With PPCI Table 2. Univariable Competing-Risk Regression Analyses of the Association Between Covariates and the Risk for Readmission or Outpatient Contact Due to CHF* Characteristic Hazard Ratio (95% CI) P Value Demographic Age, per 10-y increase 1.17 ( ) Male sex 1.05 ( ) 0.59 Comorbid conditions Treated hypertension 1.23 ( ) Diabetes 1.19 ( ) 0.11 Previous myocardial infarction 1.75 ( ) Previous PCI 1.71 ( ) Previous CHF 2.88 ( ) Active or previous smoker ( ) 0.98 Delays and transportation Treatment delay, per 1-h increase 1.05 ( ) Patient delay, per 1-h increase 1.00 ( ) 1.00 System delay, per 1-h increase 1.14 ( ) Transportation distance, per 1-km increase 1.00 ( ) 0.64 Clinical Body mass index ( ) 0.65 Systolic blood pressure mm Hg 1.00 (reference) mm Hg 0.76 ( ) mm Hg 0.74 ( ) mm Hg 0.77 ( ) Diastolic blood pressure mm Hg 1.00 (reference) mm Hg 0.85 ( ) mm Hg 0.84 ( ) mm Hg 0.88 ( ) 0.29 Killip class I 1.00 (reference) II 2.19 ( ) III 2.93 ( ) IV 1.32 ( ) 0.21 Anterior infarct location 3.08 ( ) Culprit vessel: left main/left anterior 2.65 ( ) descending artery Multivessel disease 1.52 ( ) CHF congestive heart failure; PCI percutaneous coronary intervention. * Death was the competing risk. Complete-case analysis was based on imputed values (n 7952). Treatment delay is the time from symptom onset to PCI; patient delay is the time from symptom onset to contact with the health care system; system delay is the time from contact with the health care system to PCI. tion. The funding sources had no role in the study design; collection, analysis, or interpretation of data; the writing of the manuscript; or the decision to submit the manuscript for publication. RESULTS A total of patients suspected of having STEMI or bundle branch block myocardial infarction were transferred to or admitted directly to 1 of the 3 PCI centers. The first index contact during the study period (n patients) was included in further analyses. Primary percutaneous coronary intervention was performed in patients. Foreign citizens and patients who emigrated were excluded (n 218), as were patients with a treatment delay greater than 12 hours, those with missing data on treatment delay (n 2374), those with no EMS data (n 1674), and those with a system delay greater than 6 hours or missing data on system delay (n 353). The remaining 7952 patients made up the study sample. The overall mean treatment delay was 4.2 hours (variance, 5.9 hours), with a mean patient delay of 2.3 hours (variance, 5.2 hours) and a mean system delay of 2.2 hours (variance, 1.0 hour). The median duration of follow-up was 3.1 years (interquartile range, 0.9 to 5.4 years). At 1 year, the mortality rate was 9.2% (n 733) and the proportion of patients with readmission or outpatient contact due to CHF was 7.4% (n 587); readmission was the initial contact in 3.0% of patients (n 237), and an outpatient visit was the initial contact in 4.4% (n 350). The total proportion of patients dying during follow-up was 17.5% (n 1394), and the proportion with readmission or outpatient contact due to CHF was 9.9% (n 785); readmission was the initial contact in 4.4% of patients (n 346), and an outpatient visit was the initial contact in 5.5% (n 439). When we stratified the results according to presence or absence of readmissions or outpatient contacts due to CHF, most baseline characteristics differed significantly, including delays to reperfusion (Table 1). Most covariates were associated with readmissions or outpatient contacts due to CHF during follow-up (Table 2). In patients with a system delay of 60 minutes or less (n 451), 61 to 120 minutes (n 3457), 121 to 180 minutes (n 2655), and 181 to 360 minutes (n 1389), the corresponding long-term cumulative incidence rates of readmissions or outpatient contacts due to CHF were 10.1%, 10.6%, 12.3%, and 14.1%, respectively (P 0.001) (Figure). Treatment delay remained independently associated with readmissions or outpatient contacts due to CHF in multivariable analysis (adjusted hazard ratio, 1.04 per hour increase in delay [95% CI, to 1.06]; P 0.012). When we separated treatment delay into its 2 components, patient delay and system delay, only system delay remained independently associated with readmissions or outpatient contacts due to CHF in multivariable analysis (adjusted hazard ratio per hour increase in delay, 1.10 [CI, 1.02 to 1.17]; P 0.01), in contrast to patient delay (adjusted hazard ratio, 1.00 [CI, to 1.003]; P 0.62) (Table 3). When we restricted analyses to patients without previous CHF (n 7703), the adjusted hazard ratio for the cumulative incidence of CHF was 1.09 per hour increase in system delay (CI, 1.02 to 1.18). The other covariates associated with readmission or outpatient contact due to CHF in multivariable analysis (Table 3), as well as those associated with year of admission with STEMI, did not significantly modify the effect of system delay on readmission or outpatient contact due to CHF September 2011 Annals of Internal Medicine Volume 155 Number 6

5 Health Care System Delay and Heart Failure in Patients With STEMI Treated With PPCI Original Research DISCUSSION Our main finding is that shorter health care system delay is associated with lower risk for readmissions or outpatient contacts due to CHF in patients with STEMI treated with PPCI. Previous studies have mainly focused on the effect of rapid reperfusion therapy on mortality (3, 14). Among patients surviving STEMI, it is important to clarify whether prompt reperfusion therapy also reduces the risk for CHF, because CHF has a major impact on quality of life, sick leave, and early retirement from work. For ethical reasons, we cannot perform randomized studies to evaluate the influence of delayed reperfusion on development of CHF. Accordingly, analyses must rely on observational data. In studies of the association between time to reperfusion and development of CHF, it may not be optimal to focus on cumulated treatment delay, patient delay, or door-to-balloon delay because such measures are hampered by bias. Both patient delay and treatment delay are defined by symptom onset and thus are influenced by recall bias (that is, the patient must recall the exact time of symptom onset). Moreover, these delays are inaccurate because of measurement error; the observed onset of symptoms is not necessarily the same as the exact onset of acute myocardial infarction, which may have been preceded by hours of unstable angina and spontaneous opening and closure of the artery. This imprecision results in uncertainty about the estimate of patient delay and influences the estimate of treatment delay. This is also supported by empirical results Figure. Cumulative incidence of readmissions or outpatient contacts due to congestive heart failure in patients with ST-segment elevation myocardial infarction treated with primary percutaneous coronary intervention. Cumulative Incidence System delay 0 60 min System delay min System delay min System delay min Follow-up, y Competing-risk regression analysis was used, with death as the competing risk. Data were stratified according to intervals of system delay (time from emergency medical service call to primary percutaneous coronary intervention) (n 7952). from the present study, in which the variance of the estimate of patient delay was 5 times larger than the variance of the estimate of system delay, even though mean patient delay and system delay were similar. This discrepancy is hard to explain solely by the true difference in the population variation; thus, it probably also reflects measurement error. Finally, patient delay and treatment delay are ham- Table 3. Multivariable Competing-Risk Regression Analysis of Covariates Associated With Long-Term Risk for Readmission or Outpatient Contact Due to Congestive Heart Failure After Primary Percutaneous Coronary Intervention in Patients With STEMI* Covariates Implemented in the Models Model 1 Model 2 Hazard Ratio (95% CI) P Value Hazard Ratio (95% CI) P Value Age per 10-y increase 1.07 ( ) ( ) History of MI 1.40 ( ) ( ) History of congestive heart failure 1.96 ( ) ( ) History of previous PCI 1.30 ( ) ( ) Treatment for hypertension 1.07 ( ) ( ) 0.81 Treatment delay, per 1-h increase 1.04 ( ) Patient delay, per 1-h increase 1.00 ( ) 0.62 System delay, per 1-h increase 1.10 ( ) 0.01 Systolic blood pressure 110 mm Hg 1.00 (reference) 1.00 (reference) mm Hg 0.77 ( ) ( ) mm Hg 0.76 ( ) ( ) mm Hg 0.75 ( ) ( ) Killip class I 1.00 (reference) 1.00 (reference) II 1.65 ( ) ( ) III 1.92 ( ) ( ) IV 0.76 ( ( ) 0.25 Anterior STEMI or bundle branch block MI 2.88 ( ) ( ) Multivessel disease 1.38 ( ) ( ) MI myocardial infarction; PCI percutaneous coronary intervention; STEMI ST-segment elevation myocardial infarction. * Death was the competing risk. Complete-case analysis was based on imputed values (n 7952). Analyses were adjusted for history of previous percutaneous coronary intervention. Implements treatment delay (time from symptom onset to PCI). Implements patient delay (time from symptom onset to emergency medical services call) and system delay (time from emergency medical services call to PCI) September 2011 Annals of Internal Medicine Volume 155 Number 6 365

6 Original Research Health Care System Delay and Heart Failure in Patients With STEMI Treated With PPCI pered by the survivor cohort effect: Late presenters are survivors of the prehospital phase (3, 15). Overall, these factors may explain why patient delay was not associated with readmission or outpatient contact due to CHF in our study. This finding only indicates that in observational studies, any lack of an association between patient delay and the risk for readmission with CHF can be explained by bias and indicates that patient delay is an imprecise measure of delay to reperfusion. In reality, delay to reperfusion must have the same effect on the risk for readmission due to CHF, regardless of whether the delay is before or after contact with the health care system. Recently, we proposed the cumulated health care system delay as the ideal performance measure in triaging patients with STEMI for PPCI (16). This variable is objective, is not prone to recall bias, applies to all patients surviving until contact with the health care system (even if they die in the prehospital phase before answering the question about symptom onset), and is useful for both transferred patients and those triaged in the field. Moreover, the uncertainty of the estimate of system delay is considerably smaller than the uncertainty of the estimate of patient delay. We previously demonstrated that overall health care system delay is associated with mortality in patients with STEMI treated with PPCI (3). The present study extends these findings and demonstrates that health care system delay is also associated with the risk for readmissions or outpatient contacts due to CHF after STEMI. This seems logical because delayed reperfusion is associated with more extensive myocardial necrosis and lower left ventricular ejection fraction. Our study documents that in treating patients with STEMI, the earliest hours may have a huge influence not only on mortality but also on morbidity. Lambert and colleagues (17) recently found that timely reperfusion therapy with PPCI was associated with a tendency toward lower risk for readmission due to CHF. In their cohort of 1440 patients with STEMI, a system delay of 90 minutes or more was associated with an odds ratio of 2.02 (CI, 0.92 to 4.40) for readmission due to CHF within 1 year when compared with patients with a system delay of 90 minutes or less (17). In the present study, the risk for readmission due to CHF at 1 year was similar to Lambert and colleagues findings; however, our study cohort was considerably larger, with a longer followup. Furthermore, we also included visits in the outpatient clinic as a proxy for development of CHF. Overall, the present study is, to our knowledge, the largest so far evaluating the association between system delay and the risk for CHF in patients with STEMI. Because coronary heart disease is the initiating cause in 70% of CHF cases in Europe, CHF is responsible for 5% of all hospital admissions, 4% of the population has CHF, and 2% of the national expenditure on health is used on CHF, we should focus on any initiatives that may reduce CHF (18). The present findings, that each hour of extra system delay is associated with a hazard ratio of 1.10 for readmission or outpatient visit due to heart failure, further support the need for optimal health care system performance in the acute phase in patients with STEMI. Thus, a 1-hour reduction in system delay achieved via prehospital diagnosis and field-triage of patients with STEMI to PCI centers (19) may have a considerable effect not only on mortality but also on morbidity among those surviving STEMI. Most important, among the risk factors studied, only system delay can be modified in the acute phase of STEMI. Future studies are needed to clarify whether the benefit of earlier reperfusion therapy on development of CHF also translates into reduced sick leave and later retirement from work. In any observational study, there will always be risks for selection bias and residual confounding. The National Registry of Health was used to identify patients with readmissions or outpatient contacts due to a diagnosis of CHF, which was considered a proxy for development of CHF. However, patients exclusively treated by their general practitioner or patients with a misdiagnosis were not included, and we may have underestimated the true proportion of patients developing CHF after STEMI. Nonetheless, there is no reason to believe that this underestimation depends on system delay, and thus there is no reason to believe that this limitation affects our overall study conclusion. From Aarhus University Hospital, Aarhus, Denmark; Odense University Hospital, Odense, Denmark; Aalborg University Hospital, Aalborg, Denmark; Falck Emergency Medical Service, Copenhagen, Denmark; and University Medical Centre, Freiburg, Germany. Grant Support: By grants from the Karl G. Andersen Foundation, the Helga and Peter Korning Foundation, the Health Research Fund of Central Denmark Region, the Research Foundation at Skejby University Hospital, the Riisfort Foundation, and the Arvid Nilsson Foundation. Potential Conflicts of Interest: Disclosures can be viewed at M Reproducible Research Statement: Study protocol and statistical code: Available from Dr. Terkelsen ( , Christian_Juhl_Terkelsen@hotmail.com). Data set: Available from Dr. Terkelsen; however, signed agreement regarding the purpose and an approval from the Danish Data Protection Agency are required. Requests for Single Reprints: Christian Juhl Terkelsen, MD, PhD, Department of Cardiology B, Aarhus University Hospital, DK-8200 Aarhus, Denmark; , Christian_Juhl_Terkelsen@hotmail.com. Current author addresses and author contributions are available at References 1. Antman EM, Hand M, Armstrong PW, Bates ER, Green LA, Halasyamani LK, et al; Canadian Cardiovascular Society focused update of the ACC/ September 2011 Annals of Internal Medicine Volume 155 Number 6

7 Health Care System Delay and Heart Failure in Patients With STEMI Treated With PPCI Original Research AHA 2004 guidelines for the management of patients with ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2008; 51: [PMID: ] 2. Boersma E; Primary Coronary Angioplasty vs. Thrombolysis Group. Does time matter? A pooled analysis of randomized clinical trials comparing primary percutaneous coronary intervention and in-hospital fibrinolysis in acute myocardial infarction patients. Eur Heart J. 2006;27: [PMID: ]. 3. Terkelsen CJ, Sørensen JT, Maeng M, Jensen LO, Tilsted HH, Trautner S, et al. System delay and mortality among patients with STEMI treated with primary percutaneous coronary intervention. JAMA. 2010;304: [PMID: ] 4. Van de Werf F, Bax J, Betriu A, Blomstrom-Lundqvist C, Crea F, Falk V, et al; ESC Committee for Practice Guidelines CPG. Management of acute myocardial infarction in patients presenting with persistent ST-segment elevation: the Task Force on the Management of ST-Segment Elevation Acute Myocardial Infarction of the European Society of Cardiology. Eur Heart J. 2008;29: [PMID: ] 5. Frank L. Epidemiology. When an entire country is a cohort. Science. 2000; 287: [PMID: ] 6. Sorensen HT. Regional administrative health registries as a resource in clinical epidemiology. A study of options, strengths, limitations and data quality provided with examples of use. International Journal of Risk and Safety in Medicine. 1997;10: Schmidt M, Maeng M, Jakobsen CJ, Madsen M, Thuesen L, Nielsen PH, et al. Existing data sources for clinical epidemiology: The Western Denmark Heart Registry. Clin Epidemiol. 2010;2: [PMID: ] 8. Andersen HR, Nielsen TT, Rasmussen K, Thuesen L, Kelbaek H, Thayssen P, et al; DANAMI-2 Investigators. A comparison of coronary angioplasty with fibrinolytic therapy in acute myocardial infarction. N Engl J Med. 2003;349: [PMID: ] 9. Pedersen CB, Gøtzsche H, Møller JO, Mortensen PB. The Danish Civil Registration System. A cohort of eight million persons. Dan Med Bull. 2006;53: [PMID: ] 10. Andersen TF, Madsen M, Jørgensen J, Mellemkjoer L, Olsen JH. The Danish National Hospital Register. A valuable source of data for modern health sciences. Dan Med Bull. 1999;46: [PMID: ] 11. White IR, Royston P, Wood AM. Multiple imputation using chained equations: issues and guidance for practice. Stat Med. 2011;30: [PMID: ] 12. White IR, Royston P. Imputing missing covariate values for the Cox model. Stat Med. 2009;28: [PMID: ] 13. Putter H, Fiocco M, Geskus RB. Tutorial in biostatistics: competing risks and multi-state models. Stat Med. 2007;26: [PMID: ] 14. Boersma E, Maas AC, Deckers JW, Simoons ML. Early thrombolytic treatment in acute myocardial infarction: reappraisal of the golden hour. Lancet. 1996;348: [PMID: ] 15. Aquaro GD, Pingitore A, Strata E, Di Bella G, Palmieri C, Rovai D, et al. Relation of pain-to-balloon time and myocardial infarct size in patients transferred for primary percutaneous coronary intervention. Am J Cardiol. 2007;100: [PMID: ] 16. Terkelsen CJ, Christiansen EH, Sørensen JT, Kristensen SD, Lassen JF, Thuesen L, et al. Primary PCI as the preferred reperfusion therapy in STEMI: It is a matter of time. Heart. 2009;95: [PMID: ] 17. Lambert L, Brown K, Segal E, Brophy J, Rodes-Cabau J, Bogaty P. Association between timeliness of reperfusion therapy and clinical outcomes in STelevation myocardial infarction. JAMA. 2010;303: [PMID: ] 18. Dickstein K, Cohen-Solal A, Filippatos G, McMurray JJ, Ponikowski P, Poole-Wilson PA, et al; Task Force for Diagnosis and Treatment of Acute and Chronic Heart Failure 2008 of European Society of Cardiology. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2008: the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2008 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association of the ESC HFA and endorsed by the European Society of Intensive Care Medicine ESICM. Eur Heart J. 2008;29: [PMID: ] 19. Terkelsen CJ, Lassen JF, Nørgaard BL, Gerdes JC, Poulsen SH, Bendix K, et al. Reduction of treatment delay in patients with ST-elevation myocardial infarction: impact of pre-hospital diagnosis and direct referral to primary percutanous coronary intervention. Eur Heart J. 2005;26: [PMID: ] INFORMATION FOR AUTHORS The Annals Information for Authors section is available at All manuscripts must be submitted electronically using the manuscript submission option at September 2011 Annals of Internal Medicine Volume 155 Number 6 367

8 IMPROVING PATIENT CARE Current Author Addresses: Dr. Terkelsen: Department of Cardiology B, Aarhus University Hospital, Skejby, Brendstrupgaardsvej 100, DK Aarhus, Denmark. Dr. Jensen: Department of Cardiology, Odense University Hospital, Sdr. Boulevard 29, DK-5000 Odense, Denmark. Dr. Tilsted: Department of Cardiology, Aalborg University Hospital, Hobrovej 18-22, DK-9100 Aalborg, Denmark. Dr. Trautner: Falck Emergency Medical Service, The Falck House, Polititorvet, DK-1780 Copenhagen, Denmark. Dr. Johnsen: Department of Clinical Epidemiology, Aarhus University Hospital, Oluf Palmes Alle 43-45, DK-8200 Aarhus, Denmark. Dr. Vach: Department of Clinical Epidemiology, University Medical Centre, Stefan-Meier-Strasse 26, Freiburg, Germany. Drs. Bøtker, Thuesen, and Lassen: Department of Cardiology, Aarhus University Hospital, Skejby, Brendstrupgaardsvej 100, DK-8200 Aarhus, Denmark. Author Contributions: Conception and design: C.J. Terkelsen. Analysis and interpretation of the data: C.J. Terkelsen, S.P. Johnsen, W. Vach. Drafting of the article: C.J. Terkelsen, H.E. Bøtker. Critical revision of the article for important intellectual content: C.J. Terkelsen, L.O. Jensen, H. Tilsted, S. Trautner, S.P. Johnsen, W. Vach, H.E. Bøtker, L. Thuesen, J.F. Lassen. Final approval of the article: C.J. Terkelsen, L.O. Jensen, H. Tilsted, S. Trautner, S.P. Johnsen, W. Vach, H.E. Bøtker, L. Thuesen, J.F. Lassen. Statistical expertise: C.J. Terkelsen, S.P. Johnsen. Administrative, technical, or logistic support: C.J. Terkelsen, S. Trautner, H.E. Bøtker. Collection and assembly of data: C.J. Terkelsen, L.O. Jensen, H. Tilsted, S. Trautner, S.P. Johnsen. W September 2011 Annals of Internal Medicine Volume 155 Number 6