System Delay and Mortality Among Patients With STEMI Treated With Primary Percutaneous Coronary Intervention FREE

Timely reperfusion therapy with either fibrinolysis or primary percutaneous coronary intervention (PCI) 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 PCI has been evaluated from observational data only, and the nearly neutral relationship observed between treatment delay and mortality may lead to the perception that the effect of primary PCI 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 PCI. Conversely, those presenting late are typically low-risk 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 PCI 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 PCI.

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 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 PCI 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 Protection Agency (J.No. 2008-41-2299).

The study population consisted of 6209 patients with STEMI or bundle-branch block myocardial infarction admitted for primary PCI between January 1, 2002, and December 31, 2008, at the 3 Western Denmark high-volume PCI centers: Aarhus University Hospital, Skejby; Odense University Hospital, Odense; and Aalborg University Hospital, Aalborg. Patients 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.

Primary PCI 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 Patients must meet the following criteria to be eligible for primary PCI: symptom duration of 12 hours or less and ST-segment elevation of 0.1 mV or greater in at least 2 contiguous leads (≥0.2 mV in V₁-V₃) or presumed new-onset left bundle-branch block. Pretreatment with fibrinolysis was used in 118 patients (2.0%).

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 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 PCI 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 guiding-catheter insertion during primary PCI; 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 PCI; prehospital system delay as the time from contact with the EMS to arrival at the PCI center; and door-to-balloon delay as the time from arrival at the PCI center to guiding-catheter insertion during primary PCI (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

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 Patients.

Dichotomous data are presented as percentages. Continuous variables are presented as medians (interquartile ranges). The Fisher exact test, χ² 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 PCI 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 P < .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 Allison²¹ when proportions are not close to 0 or 1.^{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).

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 PCI centers. The first index STEMI during the study period (n = 12 877 patients) was included for further analyses. Patients were excluded if primary PCI 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 self-presenters, EMS data were not available. Thus, the study cohort consisted of 6209 patients (Figure 2), of whom 2183 (35%) were field-triaged directly to a PCI center, bypassing the local hospital. The proportion of patients field-triaged directly to the PCI 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 (P < .001).

When stratifying according to whether patients were field-triaged directly to the PCI center or transferred from other hospitals, there were significant differences in several baseline characteristics and in the door-to-balloon 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; P < .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) (P < .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 associated with mortality, with an adjusted HR of 1.10 (95% CI, 1.04-1.16; P = .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; P = .02), and door-to-balloon delay had an adjusted HR of 1.14 (95% CI, 1.05-1.24; P = .001) per 1-hour delay (Table 4).

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 PCI. 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. Previous studies have plotted mortality according to treatment delay and reported a nearly horizontal association between time to 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 scores¹¹ 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} Paradoxically, the phenomenon also supports a time-dependent benefit of primary PCI, because it implies that the benefit of primary PCI 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] PCI.”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 PCI performance at PCI 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 door-to-balloon delay, because shorter notice gives the catheterization laboratory less time to prepare for the arrival of field-triaged patients.³¹ Therefore, door-to-balloon delay should be used as a performance measure at the PCI 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.

The effects of different primary PCI 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 measurement 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 PCI 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 PCI, because it is associated with mortality, it constitutes 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 PCI 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.