How can we optimize the processes of care for acute coronary syndromes to improve outcomes? Lars Wallentin, MD, PhD, a Steen Dalby Kristensen, MD, DMSc, b Jeffrey L. Anderson, MD, c Marco Tubaro, MD, d José Luis Lopez Sendon, MD, e Christopher B. Granger, MD, f Christoph Bode, MD, g Kurt Huber, MD, h Eric R. Bates, MD, i Marco Valgimigli, MD, PhD, j Philippe Gabriel Steg, MD, k and E. Magnus Ohman, MD f Uppsala, Sweden; Aarhus, Denmark; Salt Lake City, UT; Rome, Italy; Madrid, Spain; Durham, NC; Freiburg, Germany; Vienna, Austria; Ann Arbor, MI; Rotterdam, the Netherlands; and Paris, France

Acute coronary syndromes (ACS), either ST-elevation myocardial infarction or non–ST-elevation ACS, are still one of the most common cardiac emergencies with substantial morbidity and mortality. The availability of evidence-based treatments, such as early and intense platelet inhibition and anticoagulation, and timely reperfusion and revascularization, has substantially improved outcomes in patients with ACS. The implementation of streamlined processes of care for patients with ST-elevation myocardial infarction and non–ST-elevation ACS over the last decade including both appropriate tools, especially cardiac troponin, for rapid diagnosis and risk stratification and for decision support, and the widespread availability of modern antithrombotic and interventional treatments, have reduced morbidity and mortality to unprecedented low levels. These changes in the process of care require a synchronized approach, and research using a team-based strategy and effective regional networks has allowed healthcare systems to provide modern treatments for most patients with ACS. There are still areas needing improvement, such as the delivery of care to people in rural areas or with delayed time to treatment. (Am Heart J 2014;168:622-631.e2.)

Despite progress in evidence-based treatments and improved outcomes, the consequences of acute coronary syndromes (ACS) are still serious and underappreciated. Five years postevent, the overall mortality rates for STsegment elevation myocardial infarction (STEMI) and non–ST-segment elevation ACS (NSTE-ACS) patients are approximately 20%, 1 with the highest risk being in the acute phase. 2,3 The risks of complications are strongly related to patient-related risk factors with superb outcomes in younger and lower-risk patients but with a remaining high risk for severe adverse events in older patients or those with high-risk features. 2,3 This review will focus on the processes of care in ACS.

From the aUppsala Clinical Research Center and Department of Medical Sciences, Uppsala University, Uppsala, Sweden, bDepartment of Cardiology, Aarhus University Hospital, Aarhus, Denmark, cUniversity of Utah, Intermountain Healthcare, Salt Lake City, UT, dSan Filippo Neri Hospital, Rome, Italy, eResearch Institute IdiPaz, La Paz University Hospital, Madrid, Spain, fDuke Heart Center, Durham, NC, gUniversity of Freiburg, Freiburg, Germany, h3rd Department of Medicine, Cardiology, Wilhelminen Hospital, Hospital Association, Vienna, Austria, iUniversity of Michigan, Ann Arbor, MI, jThoraxcenter, Erasmus University, Rotterdam, the Netherlands, and kDépartement Hospitalo-Universitaire FIRE, Hôpital Bichat, AP-HP and Université Paris-Diderot, INSERM U-1148, Paris, France. W. Douglas Weaver, MD served as guest editor for this article. Submitted February 7, 2014; accepted July 17, 2014. Reprint requests: E. Magnus Ohman, MD, Duke University Medical Center, Box 3126 DUMC, Durham, NC 27710. E-mail: [email protected] 0002-8703 © 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ahj.2014.07.006

Process of care for the STEMI patient What is the impact of treatment delay on outcome after reperfusion therapy? Current practice guidelines for the management of patients with STEMI recommend primary percutaneous coronary intervention (PPCI) as the preferred reperfusion strategy (Figure 1), provided it is performed in a timely fashion. 5,6 Registry and survey data have shown that adherence to guideline recommendations resulted in improved clinical outcomes, including survival (online Appendix Supplementary Table I). A key underlying principle of reperfusion therapy is that “time is of the essence” because of the progressive increase in myocardial necrosis that occurs as a result of ischemia. A number of studies have examined the impact of time delays on mortality. In one study of 1,791 patients with STEMI treated with PPCI, after adjustment for age, sex, diabetes, and previous revascularization, it was estimated that each 30 minutes of delay until 6 hours was associated with a relative risk for 1-year mortality of 1.075 (95% CI 1.008-1.15). 7 Similarly, prolonged system delay is associated with increased mortality adjusted hazard ratio, 1.10 (95% CI 1.04-1.16) per 1-hour delay up to 6 hours (Figure 2). 8 Prehospital fibrinolysis provides better outcomes than inhospital fibrinolysis, although PPCI is a better choice than both these alternatives. 9 However, a pharmacoinvasive strategy is another option for patients who present to a hospital without cardiac catheterization facilities within 2

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Figure 1 STEMI patient who is a candidate for reperfusion

Initially seen at a PCI-capable hospital

Initially seen at a non-PCI-capable hospital DIDO time ≤30 min

Send to cath lab for primary PCI FMC-device time ≤90 min (Class I, LOE: A)

Transfer for primary PCI FMC-device time as soon as possible and ≤120 min (Class I, LOE: B)

Diagnostic angiogram

Medical therapy only

PCI

CABG

Urgent transfer for PCI for patients with evidence of failed reperfusion or reocclusion (ClassIIa, LOE: B)

Administer fibrinolytic agent within 30 min of arrival when anticipated FMC-device >120 min (Class I, LOE: B)

Transfer for angiography and revascularization within 3-24h for other patients as part of an invasive strategy* (Class I, LOE: A)

Reperfusion therapy algorithm for patients with STEMI. Box arrows and boxes show preferred strategies. *Angiography and revascularization should not be performed within the first 2 to 3 hours after administration of fibrinolytic therapy. CABG, coronary artery bypass graft; DIDO, doorin-door-out; FMC, first medical contact; LOE, level of evidence. 4

to 3 hours after symptom onset. This involves administration of a fibrinolytic agent in an attempt to restore partial flow in the infarct-related artery, followed by immediate transfer to a tertiary care center for angiography and percutaneous coronary intervention (PCI) if required, hopefully resulting in myocardial salvage and improved survival, 10 as suggested in the recent STREAM and TRANSFER-AMI trials, which linked fibrinolysis to a significant reduction in ischemic complications, although intracranial bleeding may be increased. 9,11 Systems of care for STEMI must aim for reduction in all components of the time that encompasses total ischemic time before reperfusion, not just the hospital door-to-balloon time. It is known that systems of care can increase the rate of reperfusion and reduce mortality. 12 Many medical centers in the United States as well as in other parts of the world have now begun to coordinate the care of patients with STEMI beyond the traditional hospital boundaries in order to provide more rapid access to PPCI. The American Heart Association, as part of the Mission: Lifeline ® STEMI systems of care program, recently surveyed existing STEMI systems in order to identify common practices and potential best practices. 12 For the purpose of this survey, a STEMI system was defined as an integrated group of separate entities focused on reperfusion therapy for STEMI within a geographic region that included at least 1 hospital that performs PPCI and at least 1 emergency medical service (EMS) agency. The predominant system characteristics

identified by the survey are summarized in online Appendix Supplementary Table II and provide a benchmark to guide STEMI care. Similar recommendations exist in Europe on how to set up effective national primary angioplasty networks. 13

The prehospital phase The patient delay. Reducing the time from onset of symptoms to activation of the EMS, that is, the “patient delay,” is a key target for improving outcomes in STEMI. The use of EMS by patients with acute chest pain varies by country and region, ranging from as little as 18% to as much as 85%. 13 Not using the EMS results in longer treatment delays and worse outcomes, 14 although recent data showing median symptom onset to first medical contact of only 50 minutes in predominantly urban settings in the United States in the ACTION–Get With The Guidelines Registry is encouraging. Individuals that experience the acute onset of chest discomfort, or other angina equivalents, are advised to call a universal and well-known emergency telephone number immediately. Thereafter, appropriate triage and dispatch are expected, with a properly equipped and staffed ambulance being sent as quickly as possible. Public awareness campaigns have been widely used to inform patients experiencing chest pain about the appropriate actions to take. These have had some small amount of success, and greatest success was achieved if public awareness

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Figure 2

Kaplan-Meier cumulative mortality estimates for patients with STEMI treated with primary PCI. Mortality estimates are stratified according to intervals of system delay (time from contact with the health care system to the time of primary PCI). 8

campaigns were performed repeatedly in relatively short time spans. 15 However, more research on how to influence behavior at the onset of symptoms is greatly needed. The system delay. The other key variable in STEMI management is “system delay,” that is, the time from activation of calling the EMS to reperfusion. A prolonged system delay is associated with increased mortality. 8 The first medical contact for a patient, after alarming the system by an emergency call, is generally the ambulance crew. Currently, a major opportunity exists in STEMI management to optimize the function of ambulance personnel. In some countries, for instance France, the EMS (SAMU) vehicles are staffed by specifically trained emergency physicians that follow a predetermined protocol for triage and treatment for patients with chest pain. Equally, specially trained paramedics have also resulted in excellent outcomes. 15 Direct prehospital referral to a PPCI strategy may reduce door-to-balloon time and mortality. 9 A number of studies have evaluated prehospital care and outcomes in patients with STEMI in different countries (Table I) and show that prehospital triage can reduce revascularization times and improve outcomes (including left ventricular function and survival). Initiating prehospital fibrinolysis coupled with timely coronary angiography has resulted in effective reperfusion in patients who could not undergo timely PPCI within 1 hour after first medical contact. 9,16,18,19 Prehospital electrocardiography. The electrocardiography (ECG) remains the paramount tool used to identify

STEMI and trigger lifesaving treatment. Therefore, early recording and interpretation of an ECG in any suspected ACS is critical, particularly in STEMI, because delays are directly related to outcome. 10 The interpretation must then be coupled with a systematic approach to activating the cardiac catheterization laboratory and with EMS taking the patient directly to a primary PCI center, even if it is modestly further away than a nearer non–PCI-capable hospital. A 15- or 17-lead ECG might help to improve ECG diagnosis of STEMI located in the lateral wall due to occlusion of the circumflex artery or its upper marginal branch. 6 Preliminary experiences have been carried out using smartphones and cloud computing for 12-lead ECG transmission. This system demonstrated reduced PCIrelated delays in AMI. 22

Hospital network systems Currently, there are 2 transfer models for STEMI patients: the hub-and-spoke model and the STEMI recruiting center model. In the first model, patients presenting directly to a non-PCI center are immediately transferred to a PCI center, with or without fibrinolytic treatment, according to the expected time delay. In the second model, diversion protocols enable bypass of the non-PCI center, with patients being directly transported to a 24-h/7-d a week PCI center. The advantages of the second model are that it reduces system delay and door-to-balloon time, thereby increasing timely reperfusion, myocardial salvage, and survival. 8 In the hub-and-spoke model, the decision on reperfusion strategy is made in referring hospitals,

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Table I. Studies of prehospital care and outcomes in patients with STEMI Objective(s) of study To describe the infrastructures and processes of prehospital fibrinolysis programs in Europe and North America and outcomes data from the programs To determine whether prehospital fibrinolysis coupled with timely coronary angiography provides outcomes similar to PPCI

Key findings Prehospital fibrinolysis was used successfully; it was delivered by health care professionals of varying expertise; in-hospital major adverse events were rare. 16

In patients presenting within 3 h of symptom onset who were unable to undergo PPCI within 1 h after first medical contact, prehospital fibrinolysis and antithrombotic cotherapy coupled with timely coronary angiography resulted in effective reperfusion; fibrinolysis was associated with a slight increase in risk of intracranial bleeding. 9,17 To assess the effect of prehospital triage on revascularization time, In patients with STEMI, prehospital (ambulance field) triage decreased door-to-balloon left ventricular function and survival times compared with community hospital and interventional center triages; decreased revascularization time was associated with preserved left ventricular function and improved early survival.18 To evaluate impact of EMS processes of care on revascularization First medical contact-to-balloon times were significantly reduced in patients times in a rural tertiary care medical center who received prehospital ECGs and prehospital cardiac catheterization laboratory activation. 19 To evaluate treatment delays and outcome in real-life patients with In real-life patients with STEMI, prehospital treatment by paramedics prehospital thrombolysis reduced mortality. 20 To assess outcomes of different reperfusion strategies Primary PCI decreased the duration of hospital stay, reinfarction and mortality of unselected STEMI patients compared with prehospital thrombolysis. 21

including when patients present to those centers by private vehicle when there is no opportunity for EMS bypass. Then, the decision of immediate fibrinolysis plus transfer versus transfer alone is based on therapeutic equipoise, that is, the time delay at which PPCI loses its advantages over fibrinolysis. 23 In the hub-and-spoke model, the delay from first medical contact to the STEMI center to PPCI should ideally be ≤90 minutes and even shorter (≤60 minutes) for early presenters with a large myocardial risk area. A further 30-minute delay for transfer patients is considered acceptable (maximum 120 minutes). These timelines are general recommendations because there is good evidence that this equipoise delay is indeed variable according to patient's baseline mortality risk, myocardial infarction (MI) location, and time from the onset of symptoms. 13 Furthermore, these timelines may not be valid in systems where the STEMI center delivers PPCI service as described in model 1. In remote areas or in large cities with very heavy traffic, fibrinolysis may be required, and in such settings, prehospital administration is strongly recommended as well as immediate transportation to a PPCI hospital where coronary angiography will be performed, followed by revascularization, if needed. Air transfers can also be used to reduce the time to hospital. A national policy for the development of a coordinated system of care for patients with STEMI has been called for in many countries and regions. 13,24 Regional STEMI network systems have been established in many different countries worldwide. The reported impact of regional STEMI networks that have been set up in Austria, Brazil, Canada, Denmark, France, Italy, Poland, Scotland, Spain, and the United States is summarized in Table II. Figure 3 illustrates STEMI network maps for Romania (Figure 3A) and Spain (Figure 3B), where quality of care has been significantly improved by implementing hospital network

systems to reduce the time to coronary reperfusion through the Stent for Life Initiative, which has led to a higher number of STEMI patients treated with PCI and lower mortality rates. Some countries, such as Sweden and Denmark, are covered as a whole by regional organizations within national healthcare systems. 34,35 For a recent summary of worldwide STEMI systems of care, their current state, unmet needs, and future developments, see Huber et al. 36

Process of care for the NSTE-ACS patient Current guidelines for the management of patients with NSTE-ACS recommend rapid establishment of a final diagnosis by ECG, ischemia monitoring and repeated determinations of the troponin measurements, 37 and dual antiplatelet and parenteral anticoagulation treatment. Patients with suspected NSTE-ACS and elevated troponin are planned for catheterization and, as appropriate, early revascularization. The optimal timing of invasive procedures depends on the overall risk of the patient, with immediate revascularization in those with ongoing ischemia or hemodynamic compromise, early (within 24 hours) procedures in those at high risk, and catheterization 2 to 5 days in patients at lower risk. 38 All patients with ACS, whether revascularized or not, are recommended for long-term treatment with evidencebased secondary prevention drugs. 37,38 Diagnosis in NSTE-ACS In patients with chest pain without ST-elevation, consideration of the NSTE-ACS diagnosis is based on the pretest probability of the disease in relation to age and baseline characteristics, interpretation of the pain characteristics, and analysis of the occurrence of ST-segment

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Table II. Examples of hospital network systems that have been established in a number of different countries throughout the world for the care of patients with STEMI Location Austria (Vienna) 17 Brazil (Salvador, Bahia)25

Canada (Ottawa, Ontario) 26 Denmark 27

France (Northern Alps) 28 Italy (Emilia Romagna)29 Poland (Malopolska) 30 Scotland (Southeast Scotland)31 Spain 32

United States (Minnesota) 33 United States (North Carolina) 12

Network characteristics

Reported impact on quality of care

5 hospitals: one 24-h PCI center, 4 part-time PCI centers In the first 2 y of the STEMI network (2003-2004), the proportion of patients receiving reperfusion therapy increased from 66% to 87%. Prehospital mobile units, community-based emergency Preliminary results indicate that this STEMI network is effective, units, general hospitals, cardiology reference centers despite “real-world” obstacles faced in a developing country; primary reperfusion rates achieved were comparable with those reported internationally. 5 hospitals: one 24-h PCI center, 4 non-PCI centers This citywide STEMI system, which allows EMS to transport patients directly to a PPCI center, was associated with a significant reduction in all-cause mortality at 180 d. 4 PPCI centers covering the entire country (5.5 million). Thrombolysis is no longer used. EMS transports patients directly to the STEMI centers by ambulance or helicopter. Bypassing regional hospitals and transporting the patients directly to the STEMI center reduced system delay and improved outcome. 7 hospitals Regionalization of care improved access to reperfusion therapy for STEMI patients. 28 centers; 24-h PCI available at 9 of the 28 centers This established STEMI regional network results in rapid reperfusion times and favorable short- and long-term clinical outcomes. 3 PCI centers; 29 non-PCI centers Improved local adherence to guideline-recommended treatment in high-risk ACS patients. 6, including one 24-h PCI center Trends over time show an increasing proportion of patients achieving reperfusion within 90 min of first medical contact. - Organized by communities - System implemented in several communities, including Madrid, Galicia, Catalonia, and others - Selected, predetermined 24-h PCI centers - Selected hospitals with resources to perform good quality PCIs and acute cardiac care service 24 h/d - Unique transfer to closest hospital with catheterization laboratory facilities in b60 min for this patient - Fast track from ambulance to catheterization laboratory 1 PCI center; 30 non-PCI centers Rapid transfer of STEMI patients from community hospitals up to 210 miles from the PCI center is feasible and safe and enabled PCI to be performed in a timely manner. 21 PCI centers; 98 non-PCI centers Extension of the network through the whole state has enabled rapid diagnosis and treatment of STEMI to become an established standard of care independent of geographic location or healthcare setting.

depression and/or T-wave inversion in the ECG at entry or during monitoring. 38 Determination of cardiac troponin and particularly the use of high-sensitivity assays are key steps for ruling in or ruling out the NSTE-MI diagnosis and are important to support treatment decisions. 38 Highsensitivity troponin assays are already available in Europe and are coming soon to the United States. 39 Their primary use may be to distinguish NSTE-ACS from non-cardiac syndromes more rapidly and efficiently than standard assay troponins and to provide the basis for earlier institution of antithrombotic therapy and intervention.39 This increase in sensitivity, especially at early times (ie, at b2-3 hours after symptom onset) may be offset by a decrease in specificity. This occurs because many other cardiovascular and noncardiovascular conditions are associated with slightly elevated troponin levels; indeed, nominal levels can now be measured even in most healthy individuals. 39,40 However, slight troponin elevations predict a worse cardiovascular prognosis even when not associated with ACS (online Appendix Supplementary Table III).

These new assays might lead to new algorithms for decision making, such as the one illustrated in Figure 4 or as suggested in the European Society of Cardiology (ESC) guidelines. 38 They provide the opportunity to reduce the time for diagnosis and triage. 39,40 Current (2012) American College of Cardiology/American Heart Association guidelines suggest that an initially negative troponin assay be repeated after 6 to 8 hours. In the newly proposed algorithm, a 3-hour interval is proposed, and some have suggested a repeat assay in 2 hours or less for determination of a delta troponin. 41 The troponin results are used both for diagnosis and to guide subsequent management. Based on results from randomized trials, troponin elevation interacts with the risk/benefit of both early revascularization and treatment with platelet inhibition and anticoagulation. 37 Risk stratification by patient characteristics and by several other biomarkers provides information on the absolute risk and thereby the absolute benefits of most treatments. However, so far, only troponin seems to have a directional

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Figure 3

A

B

Map of STEMI networks. A, Romanian STEMI Network (December 31, 2012). Small red circles signify catheterization laboratories. B, Spanish STEMI Network in 2013. Blue signifies the areas of the populations covered by the STEMI network, with a total of 10 STEMI networks covering 61.3% of the population.

interaction with the treatment effects. 37 Based on the intense research in the area of risk stratification and new biomarkers, several new algorithms for decision support might appear in the future but will require validation in prospective trials.

Noninvasive imaging in NSTE-ACS The differential diagnosis of chest pain in the setting of possible NSTE-ACS may be assisted by point-of-care echocardiography or advanced imaging. 42 Recent studies have tested coronary computed tomographic (CT) angiography for its diagnostic use in patients with chest pain of uncertain origin and generally support coronary CT angiography as being cost-competitive with standard algorithms (most commonly, using radionuclide perfusion imaging) and decreasing time to discharge. 42 However, the impact on outcomes remains to be established. In addition to detecting anatomic coronary artery disease, emerging CT technology will also provide perfusion information. Positron emission tomographic scanning, which is beginning general application in the United States, represents a further major imaging advance. 42 The view of many noninvasive imagers is that these modalities may surpass our current radionuclide scans in diagnostic accuracy, although radiation and availability/cost of these new techniques may limit their widespread use. Cardiac intensive care units Cardiac intensive care units (CICUs) have experienced a marked evolution in recent years. More complicated patients, with more severe cardiovascular diseases and more comorbidities, are treated in modern CICUs, and new technologies (mechanical ventilation, renal support, mechanical circulatory support, advanced imaging) are

widely applied in the framework of comprehensive cardiovascular critical care, which includes nurse empowerment and advanced nursing care. These characteristics are the basis of the fundamental difference between the CICU model and the chest pain unit model, the latter of which allows patients to refer themselves directly to the chest pain unit for rapid identification of the origin of acute chest pain. 43 The 3 major evidence-based trends in CICU are involvement of dedicated intensivists with advanced expertise in cardiovascular critical care, application of integrated multidisciplinary care, and a focus on CICUrelated complications as determinants of outcome. 43 Dualcertification training (cardiovascular disease and critical care medicine) in the United States and the Core Curriculum for the Cardiac Intensivist from the ESC are effective models that are being developed for training in CICUs.

Improving long-term prognosis after ACS Cardiac rehabilitation and secondary prevention In ACS, cardiac rehabilitation (CR) and secondary preventive measures are important and should be initiated in all patients. 44Direct CR measures are mainly indicated in patients at higher risk, such as those with clinical instability, severe complications, or advanced heart failure. Thus, all patients should have counseling on physical activity and exercise training, weight control, lipid reduction, blood pressure monitoring, smoking cessation, psychosocial adjustment, and compliance with the prescribed medications. The delivery of secondary prevention is usually provided by multidisciplinary staff of health care professionals. 45 The process should already be started before hospital discharge and has 3 phases: in-patient, early outpatient, and long-term out-patient.

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Figure 4 Clinical setting consistent with myocardial ischemia

Baseline ≥14 to

How can we optimize the processes of care for acute coronary syndromes to improve outcomes?

Acute coronary syndromes (ACS), either ST-elevation myocardial infarction or non-ST-elevation ACS, are still one of the most common cardiac emergencie...
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