Regional Systems of Care to Optimize Timeliness of Reperfusion Therapy for ST-Elevation Myocardial Infarction
The Mayo Clinic STEMI Protocol
Background— Quality improvement efforts have focused on strategies to improve the timeliness of reperfusion therapy in ST-elevation myocardial infarction patients who present to hospitals with and without percutaneous coronary intervention (PCI) capability. We implemented and evaluated a protocol to optimize the timeliness of reperfusion therapy and to coordinate systems of care for a PCI center and 28 regional hospitals located up to 150 miles away across 3 states.
Methods and Results— The present study focused on a prospective, observational cohort of 597 patients who presented with ST-segment elevation and within 12 hours of symptom onset to Saint Marys Hospital and 28 regional hospitals up to 150 miles away between May 2004 and December 2006. The Mayo Clinic ST-elevation myocardial infarction protocol implemented strategies to improve timeliness of reperfusion therapy and to coordinate systems of care for transfer between hospitals. The study sample consisted of 258 patients who presented to Saint Marys Hospital and were treated with primary PCI (group A), 105 patients who presented to a regional hospital with symptom onset >3 hours and then were transferred for primary PCI (group B), and 131 patients who presented to a regional hospital with symptom onset <3 hours and were treated with full-dose fibrinolytic therapy (group C). For groups A and B, median door-to-balloon times were 71 and 116 minutes, respectively. Door-to-balloon time <90 minutes was achieved in 75% of group A and 12% of group B. Median door-to-needle time was 25 minutes for group C, and 70% had door-to-needle time <30 minutes.
Conclusions— The Mayo Clinic ST-elevation myocardial infarction protocol demonstrates the feasibility of implementing strategies to optimize the timeliness of reperfusion therapy and the times that can be achieved through coordinated systems of care for ST-elevation myocardial infarction patients presenting to a PCI center (Saint Marys Hospital) and 28 regional hospitals without PCI capability located up to 150 miles away across 3 states.
Received March 2, 2007; accepted May 29, 2007.
Rapid initiation of reperfusion therapy for ST-elevation myocardial infarction (STEMI) with either full-dose fibrinolytic therapy or primary percutaneous coronary intervention (PCI) limits infarct size and improves survival.1 Fibrinolytic agents have survival benefits that have been shown in randomized trials involving >100 000 patients2 but are most effective when administered within 2 to 3 hours from symptom onset and are associated with a 1% to 2% risk of stroke or intracranial hemorrhage.3–7 Primary PCI has been shown to improve survival and to lower recurrent myocardial infarction (MI) and stroke compared with fibrinolytic therapy in recent trials and pooled analyses.8–11
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Current guidelines recommend a door-to-balloon time <90 minutes for STEMI patients undergoing primary PCI,1 but there are significant hospital delays for primary PCI because <40% of nontransferred and 5% of transferred STEMI patients achieve this goal.12,13 Bradley and colleagues14 determined that 6 strategies were associated with significant reductions in door-to-balloon time for STEMI patients presenting to PCI-capable hospitals. There also is interest in developing regional systems of care to improve the timeliness of reperfusion therapy and to increase access to primary PCI for STEMI patients who present to hospitals without PCI capability.15–17
We implemented a protocol to optimize timeliness of reperfusion therapy and to coordinate systems of care for a PCI center and 28 regional hospitals located up to 150 miles away across 3 states. At the PCI center, our protocol implemented 4 of the 6 strategies determined by Bradley et al14 and at the 28 regional hospitals, our protocol used novel strategies and systems of care to improve time to reperfusion. We evaluated the effect of our protocol and regional system of care on door-to-balloon and door-to-needle times for STEMI patients presenting to the PCI center and 28 regional hospitals.
The Mayo Clinic STEMI Protocol
Patients who presented to Saint Marys Hospital in Rochester (Minn) underwent primary PCI as the reperfusion strategy. The protocol was implemented in May 2004 and included the following strategies: (1) prioritizing 12-lead ECG acquisition and physician interpretation within 10 minutes of hospital arrival for all patients with suspected acute coronary syndrome; (2) emergency department activation of the cardiac catheterization laboratory without review or approval by cardiology; (3) single-call system to activate the entire cardiac catheterization team; (4) catheterization laboratory fully operational within 30 minutes after activation; and (5) data collected prospectively with a computerized, Web-based database with feedback provided to staff within 24 to 48 hours. Strategies 2 through 5 represent 4 of the 6 strategies described by Bradley and colleagues.14 Before May 2004, these strategies were not used routinely at Saint Marys Hospital.
The regional STEMI protocol was implemented in December 2004 at 28 regional hospitals located in Minnesota, Wisconsin, and Iowa and up to 150 miles away from Saint Marys Hospital (Figure 1). Twelve regional hospitals were part of the Mayo Health System, and 16 regional hospitals were independent facilities. Regional hospitals were selected to participate if the total transfer time from the regional hospital to Saint Marys Hospital could be achieved reliably within 30 to 90 minutes (median, 57 minutes) and if Saint Marys Hospital was the closest facility providing PCI 24 hours a day, 7 days a week. We intentionally did not enroll regional hospitals located closer to another PCI facility with this 24×7 capability. The regional STEMI protocol included previous strategies adopted at Saint Marys Hospital and the following new strategies: (1) standard order set and protocol used to select fibrinolytic therapy (for symptom onset <3 hours) or PCI (for symptom onset >3 hours) as the primary reperfusion strategy and adjunctive medications; (2) single-phone-call system for the receiving cardiologist and regional physician to discuss case, to activate air ambulance transfer, and to activate the cardiac catheterization team; (3) a central communication center selected the fastest mode of transfer from 3 helicopters; (4) helicopter “hot load” protocol with engine left running to minimize ground time to ≤10 minutes; and (5) bypassing of Saint Marys Hospital emergency department evaluation.
Before December 2004, these strategies were not used routinely, and reperfusion choice and transfer were decided by individual physician preferences. This new system of care was discussed by all coronary care unit and interventional staff at Mayo Clinic to achieve consensus. After consensus was achieved, a Mayo Clinic cardiologist and nurse coordinator made site visits to each of the 28 regional hospitals to educate and train the regional hospital staff. The 28 regional hospitals were sequentially enrolled over the course of 6 months from December 2004 to May 2005. The protocol provided feedback within 24 to 48 hours to all physicians involved in a specific patient’s care, the program director (H.H.T.), and nurse coordinator (C.M.B.); the only protocol deviations occurred when inclement weather prevented air ambulance transfer for primary PCI.
Regional STEMI patients were treated with full-dose fibrinolytic therapy if the onset of symptoms was <3 hours and there were no contraindications to such therapy. The protocol mandated immediate patient transfer after fibrinolytic drug administration to Saint Marys Hospital, and patients were evaluated by a cardiologist on arrival at Saint Marys Hospital. Patients underwent immediate rescue PCI for suspected failure to reperfuse or routine elective catheterization at 24 to 48 hours if it was thought that reperfusion had been achieved successfully with fibrinolytic therapy. Failed reperfusion after fibrinolytic therapy was defined as persistent chest discomfort or <70% resolution of ST elevation 60 to 90 minutes after fibrinolytic drug administration. We did not use a facilitated PCI strategy, defined as half- or full-dose fibrinolysis followed by immediate catheterization. Regional patients treated with fibrinolytic therapy received reteplase or weight-based tenecteplase at the discretion of the regional hospital. All patients received unfractionated heparin at a loading dose of 60 U/kg (maximum, 4000 U) and continuous infusion at 12 U · kg−1 · h−1 (maximum, 1000 U/h). Low-molecular-weight heparin was not used. All patients received clopidogrel (75 mg) at the time of fibrinolytic therapy administration.
Regional STEMI patients were transferred for primary PCI if symptom duration was >3 hours and immediate transport was available. Inclement weather prohibited helicopter and ground transport <5% of the time. Patients who were at high clinical risk (such as cardiogenic shock or persistent ventricular arrhythmias) or had contraindications to fibrinolytic therapy and patients for whom there was clinical suspicion for other diagnoses such as pericarditis or myocarditis were transferred for a primary PCI strategy regardless of duration of symptoms. All regional patients transferred for primary PCI received unfractionated heparin at a loading dose of 60 U/kg (maximum, 4000 U) and continuous infusion at 12 U · kg−1 · h−1 (maximum, 1000 U/h); low-molecular-weight heparin and clopidogrel were not used. Eptifibatide was administered in 61 patients (58%) in the helicopter during transport with a loading dose of 180 μg/kg twice (10 minutes apart) and continuous infusion at 2 μg · kg−1 · min−1 (glomerular filtration rate ≥50 mL/min) or 1 μg · kg−1 · min−1 (glomerular filtration rate <50 mL/min). The remaining 44 patients (42%) had eptifibatide withheld as a result of a contraindication or at the discretion of the receiving cardiologist because of bleeding risk. Eptifibatide was administered in the helicopter to avoid any transfer delays at the regional hospital and was chosen instead of abciximab because the latter required refrigeration and filtration, making storage and administration more difficult in the helicopter.
The Mayo Clinic STEMI protocol was developed and approved by the cardiac catheterization laboratory, coronary care unit, and emergency medicine department at Mayo Clinic, as well as by the clinical practice committees at each regional hospital. This study was approved by the Institutional Review Board at Mayo Clinic.
From May 2004 to December 2006, 597 patients presented within 12 hours of the onset of symptoms suggestive of myocardial ischemia and new or presumed-new ST-elevation or left bundle-branch block. In accordance with Minnesota statute, 40 patients (6.7%) who did not grant authorization to use their records for research were excluded from this analysis. An additional 63 patients (10.6%) were subsequently determined to have a diagnosis other than acute MI to account for the ECG abnormalities, including myocarditis, pericarditis, apical ballooning syndrome, and left ventricular aneurysm or hypertrophy. Thus, the final study population comprised 494 patients and was divided into 3 reperfusion strategy groups: 258 patients who presented to the Saint Marys Hospital emergency department in Rochester and were treated with primary PCI (group A), 105 patients who presented to a regional hospital with symptom onset >3 hours and then were transferred for primary PCI (group B), and 131 patients who presented to a regional hospital with symptom onset <3 hours and were treated with full-dose fibrinolytic therapy followed by immediate rescue PCI for failed reperfusion or routine elective catheterization at 24 to 48 hours after successful reperfusion (group C). Before implementation of the Mayo Clinic STEMI protocol, we prospectively collected door-to-balloon times for 48 STEMI patients undergoing primary PCI who presented to Saint Marys Hospital in 2003.
Time to Treatment
Time to treatment for PCI was measured with door-to-balloon time. This interval was defined as the time from first hospital arrival to the time of first balloon inflation or use of another therapeutic interventional device such as a stent or a thrombectomy catheter. Time to treatment for fibrinolytic therapy was measured using door-to-needle time, with needle time defined as the time of fibrinolytic therapy administration.
Cardiogenic shock, at or immediately after admission to the hospital, was defined as a persistent systolic blood pressure ≤85 mm Hg that was unresponsive to fluid administration and required vasopressors or placement of an intra-aortic balloon pump. Biomarkers for myocardial injury were drawn at first hospital arrival, every 8 hours for 24 hours, and then at 48 and 72 hours. Additional samples were obtained for any clinical events suspicious for myocardial ischemia. Recurrent MI within 24 hours of qualifying STEMI required typical chest discomfort ≥20 minutes and new or recurrent ST elevation ≥0.10 mV in ≥2 contiguous leads or new left bundle-branch block. Recurrent MI after 24 hours of qualifying STEMI required typical chest discomfort ≥20 minutes with one of the following criteria: new or recurrent ST elevation ≥0.10 mV in ≥2 contiguous leads or new left bundle-branch block, or both an increase in creatine kinase-MB isoenzymes of at least 50% over previous value and documentation that creatine kinase-MB had been decreasing before the suspected recurrent MI.
Continuous variables are summarized as mean±SD. Discrete variables are presented as frequency (percentage). Group differences were tested using 1-way ANOVA and Pearson χ2 test. Not all patients intended for primary PCI actually underwent PCI. In those patients, door-to-balloon time was considered a right-censored measurement recorded as the time to the last checkpoint (eg, arrival at catheterization laboratory or at Saint Marys Hospital from a regional hospital). Kaplan-Meier estimation was used for time to event–type variables such as time to treatment and follow-up mortality. The probabilities of time to treatment for those with and without in-hospital death were estimated with a Kaplan-Meier estimator. Bayes rule was applied to these conditional probabilities to estimate the risk of in-hospital death according to time to treatment. Statistical analyses were performed with SAS version 9.1 (SAS, Inc, Cary, NC).
The authors had full access to and take full responsibility for the integrity of the data. All authors have read and agree to the manuscript as written.
Baseline patient characteristics for Saint Marys Hospital PCI (group A), regional hospital PCI (group B), and regional hospital fibrinolytic therapy (group C) are shown in Table 1. Groups A, B, and C had similar ages (range, 27 to 96 years) and similar percentages of men, hypertension, diabetes, body mass index, congestive heart failure on presentation, and anterior wall infarctions. Group A had a higher prevalence of cardiogenic shock at presentation (11%) compared with group B (7%) and group C (2%).
Aspirin was administered during the index hospitalization for groups A, B, and C in 98%, 95%, and 99%, respectively. A β-blocker was administered during the index hospitalization for groups A, B, and C in 71%, 74%, and 77%, respectively, and β-blocker use was contraindicated and documented for groups A, B, and C in 24%, 17%, and 18%, respectively.
Time to Treatment
Door-to-balloon time and door-to-needle time cumulative distribution curves for groups A, B, and C are shown in Figure 2. The median door-to-balloon time was 71 minutes (interquartile range, 56 to 90 minutes) for group A, with a door-to-balloon time of <90 minutes achieved in 75% of patients, as shown in Table 2. Before implementation of the Mayo Clinic STEMI protocol, 48 historical control patients presented with STEMI to Saint Marys Hospital in 2003; their median door-to-balloon time was 90 minutes (interquartile range, 72 to 121 minutes), and 50% of patients were treated with a door-to-balloon time <90 minutes. Figure 3 shows the door-to-balloon time cumulative distribution curves for group A compared with the Saint Marys Hospital historical control patients from the year 2003 (P=0.004).
The median door-to-balloon time was 116 minutes (interquartile range, 102 to 137 minutes) for group B, and a door-to-balloon time of <90 minutes was achieved in 12% of patients. The median door-to-needle time was 25 minutes (interquartile range, 16 to 33 minutes) for group C, and 70% of patients were treated with a door-to-needle time of <30 minutes. Among STEMI patients who presented to a regional hospital with symptom onset <3 hours, 49 patients were transferred for primary PCI rather than treated with fibrinolytic therapy because these patients either had a contraindication to fibrinolytic therapy or were considered at high clinical risk. These patients had a median door-to-balloon time of 116 minutes (interquartile range, 105 to 141 minutes). We did not have historical control data for regional hospital patients with STEMI for comparison of times.
Suspected failure to reperfuse with fibrinolytic therapy occurred in 48 patients (36.6%), and all these patients underwent immediate catheterization and early rescue PCI. Reperfusion with fibrinolytic therapy was thought to be successful in the remaining 83 patients (63.4%). Among the 83 patients, 2 refused subsequent catheterization, and 81 underwent routine elective catheterization at 24 to 48 hours after fibrinolysis, with 53 of 81 patients undergoing elective PCI during the index hospitalization.
Because of inclement weather, air ambulance transport was not possible for 5 patients (1.0%) during the study period. Four patients were transported by ground ambulance to Saint Marys Hospital for primary PCI and had door-to-balloon times of 103, 107, 122, and 153 minutes. One patient was treated with fibrinolytic therapy with a door-to-needle time of 25 minutes and subsequently transported by ground ambulance to Saint Marys Hospital. Among the 258 STEMI patients in group A, 16 patients were treated medically after catheterization, and 11 underwent urgent bypass surgery. Among the 105 STEMI patients in group B, 10 patients were treated medically after catheterization, and 1 underwent urgent bypass surgery.
The median time from symptom onset to treatment was shortest for group C at 103 minutes compared with 188 and 278 minutes for groups A and B, respectively (Table 2). This observed difference is expected because regional hospital patients with STEMI who presented early (<3 hours from symptom onset) were treated preferentially per our protocol with fibrinolytic therapy.
In-Hospital and Follow-Up Outcomes
In-hospital and follow-up outcomes for groups A, B, and C are shown in Table 3. In-hospital death rates were similar in all 3 groups and occurred in 17 patients in group A (6.6%; 95% CI, 3.9 to 10.3), in 6 patients in group B (5.7%; 95% CI, 2.1 to 12.0), and in 4 patients in group C (3.1%; 95% CI, 0.8 to 7.6). No patients in groups B and C died at the regional hospital before or during transfer to Saint Marys Hospital. In-hospital mortality as a function of door-to-balloon time (Figure 4A) or door-to-needle time (Figure 4B) is shown. Longer time to treatment as measured by door-to-balloon or door-to-needle time was associated with trends for higher in-hospital mortality rates.
Frequency rates of any in-hospital stroke among groups A, B, and C were 0.8% (95% CI, 0.1 to 2.8), 1.0% (95% CI, 0.0 to 5.2), and 3.1% (95% CI, 0.8 to 7.6), respectively. However, hemorrhagic stroke occurred in 3 patients (2.3%; 95% CI, 0.5 to 6.5) from group C who had received fibrinolytic therapy; 2 of these patients died in hospital, and 1 patient made a full neurological recovery (Table 4). Median follow-up time for assessment of outcomes was 184 days. Mortality rates at intermediate follow-up were 10.5% (95% CI, 6.3 to 14.6), 8.8% (95% CI, 2.3 to 14.8), and 6.9% (95% CI, 1.1 to 12.3) and similar for groups A, B, and C, respectively.
The Mayo Clinic STEMI protocol implemented strategies to optimize the timeliness of reperfusion therapy, to improve door-to-balloon and door-to-needle times, and to coordinate systems of care for STEMI patients presenting to a PCI center (Saint Marys Hospital) and 28 regional hospitals without PCI- capability located up to 150 miles away across 3 states. Our system of care achieved a median door-to-balloon time of 71 minutes for patients who presented to Saint Marys Hospital, a median door-to-balloon time of 116 minutes for patients transferred from a regional hospital, and a median door-to-needle time of 25 minutes for regional hospital patients treated with fibrinolysis. In our system of care in a large, diverse geographic area, we achieved median door-to-balloon times of ≈2 hours for patients who required transfer to a PCI center. Whether this is preferable to immediate fibrinolytic therapy remains an unanswered question because half of the patients exceeded 2 hours and fibrinolytic therapy was associated with hemorrhagic stroke at rates similar to previous trials. From a cost perspective, we added an incremental half-time database coordinator and half-time nurse coordinator to implement this system of care, and there were additional variable costs to transport and provide clinical care for every STEMI patient. There were no other fixed costs because the 3 helicopters, equipment, and allied and physician staff were preexisting components in our system.
Reperfusion Strategy at Hospitals With PCI Capability
Our study confirmed that systematically implementing 4 of 6 strategies described by Bradley and colleagues14 was associated with a significantly reduced door-to-balloon time for the PCI-capable hospital. These 4 strategies (emergency medicine physicians activate catheterization laboratory; single phone call activates catheterization laboratory; catheterization laboratory staff arrives to hospital within 20 minutes after activation; and real-time data feedback is given to emergency medicine and cardiology staff) are currently being promoted by the American College of Cardiology D2B Alliance to reduce hospital delays on a national scale. We did not use the other 2 strategies from Bradley et al, namely integrating prehospital ECGs to activate the catheterization laboratory while the patient is en route and having an attending cardiologist always on site, because of complexity and cost.
It is imperative to achieve door-to-balloon time <90 minutes in PCI-capable hospitals because the full advantage of primary PCI compared with fibrinolysis may not be realized for patients who experience prolonged delays.18–20 Nallamothu and colleagues21 showed that there was no mortality advantage for primary PCI versus fibrinolytic therapy when door-to-balloon time exceeded door-to-needle time by 62 minutes. Pinto and colleagues22 extended these findings and demonstrated that patient-specific variables, including age >65 years, duration of symptoms >2 hours, and anterior wall infarction, derived greater benefit from primary PCI, and a door-to-balloon time minus door-to-needle time of up to 114 minutes may be reasonable in these scenarios.
Reperfusion Strategy at Hospitals Without PCI Capability
Our study advances the existing research in reperfusion strategy for STEMI patients presenting to hospitals without PCI capability by using duration of symptoms <3 hours versus ≥3 hours as a decision node to select reperfusion strategy (fibrinolytic therapy versus primary PCI, respectively), using immediate rescue PCI for failed reperfusion with fibrinolytic therapy and routine elective catheterization at 24 to 48 hours after successful reperfusion with fibrinolytic therapy, and implementing novel strategies to streamline and coordinate patient transfer from a regional hospital without PCI capability to a PCI center. To coordinate this real-world practice protocol at 28 regional hospitals, including 12 hospitals from the Mayo Health System and 16 independent hospitals across 3 states, we first had to achieve consensus among cardiologists at the PCI center (Saint Marys Hospital) to minimize variability in care processes and to uniformly adopt a standard order set and protocol. Second, we engaged nursing and air transport staff and a central communication center to support this system of care. Third, we developed an integrated network with the 28 regional hospitals by making initial site visits to enroll and train staff and routine follow-up visits 2 to 4 times per year. The nurse coordinator and physician program director were available by e-mail or telephone to receive feedback and input.
The use of a decision node of 3 hours from onset of symptoms to select reperfusion strategy is consistent with current guidelines.1 Among patients who present within 2 to 3 hours from onset of symptoms and when door-to-balloon time <90 minutes cannot be reliably achieved, a pharmacoinvasive approach of fibrinolysis followed by rescue PCI or routine elective PCI (at 24 to 48 hours after fibrinolysis) has been proposed.23 The Which Early ST-Elevation Myocardial Infarction Therapy (WEST) study found that 30-day mortality was 4% with fibrinolysis and usual care versus 1% with fibrinolysis and a pharmacoinvasive approach.5 Indeed, the timing of routine elective PCI after fibrinolytic therapy has important relevance to subsequent risk of mortality and bleeding. In the Assessment of the Safety and Efficacy of a New Treatment Strategy With Percutaneous Coronary Intervention (ASSENT-4 PCI) trial,24 immediate PCI performed within 1 to 3 hours after fibrinolysis, so-called facilitated PCI, resulted in higher in-hospital mortality, whereas in other trials, routine PCI delayed for up to 13 hours5 or 17 hours4 was not associated with increased mortality. The Mayo Clinic STEMI protocol used a pharmacoinvasive approach for regional hospital patients treated with fibrinolytic therapy; patients underwent immediate rescue PCI for suspected failed reperfusion (36.6%), and the remainder underwent routine elective catheterization (63.4%) at 24 to 48 hours after initially successful reperfusion.
The present observational study was not intended to compare outcomes of different reperfusion strategies or to perform a formal cost-effectiveness analysis. This model of care may not be generalizable to other geographic locations because our system required coordination of air ambulance transport and of 28 regional hospitals with disparate governance and staff.
We implemented the Mayo Clinic STEMI protocol and achieved door-to-balloon and door-to-needle times that were close to or exceeded what is recommended in current guidelines. We demonstrated in a real-world setting that novel and simple strategies and coordination of systems of care make these times achievable with a minimum of risk to patients.
The authors thank Lavon N. Hammes for assistance with data collection.
Source of Funding
The present study was supported by the Division of Cardiovascular Diseases, Mayo Clinic.
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Patients with ST-elevation myocardial infarction (STEMI) should be treated with rapid and appropriate reperfusion therapy to reduce infarct size and adverse outcomes. The guidelines state that STEMI patients who present within 12 hours of symptom onset should be treated with door-to-balloon time <90 minutes and door-to-needle time <30 minutes. The Mayo Clinic STEMI protocol evaluated the impact of implementing 4 strategies recommended by the American College of Cardiology D2B Alliance (emergency medicine physicians activate catheterization laboratory; single phone call activates catheterization laboratory; catheterization laboratory staff arrive at hospital within 20 minutes after activation; and real-time data feedback is given to emergency medicine and cardiology staff) to reduce door-to-balloon time in 258 STEMI patients presenting to a percutaneous coronary intervention center. After these process changes were implemented, median door-to-balloon time decreased from 90 to 71 minutes. We also implemented a regional system of care consisting of 28 community hospitals located up to 150 miles away to coordinate transfer and to optimize timeliness of reperfusion therapy. STEMI patients (n=131) who presented early after symptom onset (<3 hours) were treated with fibrinolytic therapy and achieved a median door-to-needle time of 25 minutes. STEMI patients (n=105) who presented later after symptom onset (>3 hours) and early presenters who were at high risk (cardiogenic shock) or had contraindications to fibrinolytic therapy were transferred for primary percutaneous coronary intervention and achieved a median door-to-balloon time of 116 minutes. We demonstrated in a large, diverse geographic region that novel and simple strategies and coordination of systems of care make these times achievable with a minimum of risk to patients.