ACCESS TO CARDIAC CATHERIZATION SERVICES IN A RURAL-URBAN SETTING IN NORTHERN BRITISH COLUMBIA: EXAMINING THE IMPACT OF TIME-DELAY TO PCI ON PATIENT OUTCOMES AND WHETHER THE SICKEST GO THE QUICKEST... by Damanpreet Kandola BHSc. Biomedical Studies, University o f Northern British Columbia, 2011 THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE IN COMMUNITY HEALTH SCIENCE UNIVERSITY OF NORTHERN BRITISH COLUMBIA March 2014 © Damanpreet Kandola, 2014 UMI Number: 1525706 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a complete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. D i!ss0?t& iori P iib list’Mlg UMI 1525706 Published by ProQuest LLC 2014. Copyright in the Dissertation held by the Author. Microform Edition © ProQuest LLC. All rights reserved. This work is protected against unauthorized copying under Title 17, United States Code. ProQuest LLC 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106-1346 Abstract This thesis describes the results of a study exploring patient access to percutaneous coronary intervention (PCI) in a rural-urban setting in northern British Columbia, Canada. It specifically examines: 1) whether longer times to treatment (>120mins) are associated with higher adverse outcomes (death, re-infarction, heart failure, or stroke) in the UA, NSTEMI and STEMI groups within 30-days and 1-year of hospital admission and 2) whether patients most at risk using the Global Registry of Acute Coronary Events (GRACE) risk score receive PCI faster in the UA, NSTEMI and STEMI groups. Data were collected through retrospective medical chart reviews. Times to treatment and adverse outcomes data are provided although quantitative analysis of this association was not performed. It was determined that the only significant predictor of time to PCI was age and patients were not transferred according to their risk status. Thus it can be concluded that this exploratory study provided valuable real-time feedback for cardiac services in this region and is a basis for further longitudinal investigation in this area. Keywords: percutaneous coronary intervention, thrombolysis, unstable angina, segment elevated myocardial infarction, non-segment elevated myocardial infarction, Global Registry of Acute Coronary Events, GRACE, risk score, GRACE risk score Table of Contents Abstract ii Table of Contents iii-v List of Tables vi List of Figures vii Glossary viii-x Acknowledgment xi CHAPTER 1: Introduction Acute coronary syndrome 1-2 Risk factors 2 Geography and the link to cardiovascular disease 3-5 Symptoms 5 Diagnosis and management o f ACS at UHNBC 6-11 Treatment options 12-13 Knowledge gaps 13-14 University Hospital of Northern BC 14-16 Study rationale 17-19 Research objectives 19 Significance of research 19-20 A northern perspective 20-21 Summary 21-22 CHAPTER 2: Literature Review Search strategy 23-24 Percutaneous Coronary Intervention 24-40 Global Registry of Acute Coronary Events (GRACE) risk stratification 40-43 iii Gaps in the literature 43-44 Summary 44 CHAPTER 3: Methods Study design 45-46 Study population 47 Community profile 47 Data extrapolation and source 47-48 Date collection and criterion 48-50 Measures and analytic procedures 50-54 Ethical considerations and confidentiality 55 CHAPTER 4: Results Preliminary data analysis 56 Patient baseline characteristics 57 Classification of patients by body mass index 58 Classification of obese patients 59 Classification of patients by area of residence 60 Classification of patient cases by specific diagnosis 61 Classification of patients given thrombolytics by diagnosis 62 Hospital discharge status 63 Length o f hospital stay 64 Length of stay prior to transfer 65 GRACE risk status by diagnosis 66 Time to PCI 67 GRACE risk status and length o f stay prior to transfer 69-70 iv CHAPTER 5: Discussion & Conclusion Time to PCI and adverse outcomes 71-75 Time to PCI and patient risk status 75-77 Secondary findings 77-78 Study strengths and limitations 79-80 Key findings and contributions 80 Recommendations 80-84 Implications for future research 84 Implications for policy and practice 84-86 Conclusion 86 References 87-98 Appendix A: ICD-9 ACS Codes 99 Appendix B: UHNBC Management of STEMI Protocol 100 Appendix C: UHNBC Management o f NSTEMI/UA Protocol 101 Appendix D: Cardiac Catherization Lab referral form 102 Appendix E: Hospital Transfer Form 103 Appendix F: GRACE risk stratification calculator 104 Appendix G: PCI Studies Summarized 105-114 Appendix H: GRACE Studies Summarized 115-127 Appendix I: UNBC Research Ethics Board Ethics Approval Certificate 128 Appendix J: Northern Health Research Ethics Review Committee Ethics 129 Approval Certificate v List o f Tables Table 1. Body-Mass Index Classifications 52 Table 2. Killip Classification for GRACE 53 Table 3. High-sensitivity troponin-elevation guideline for GRACE 53 Table 4. GRACE risk score tertiles for NSTEMI/UA and corresponding 54 mortality risk Table 5. GRACE risk score tertiles for STEMI and corresponding mortality risk 54 Table 6. Patient Baseline Characteristics 57 Table 7. Multiple linear regression for time to PCI predictors 68 vi List o f Figures Figure 1. Management o f suspected ACS algorithm 10 Figure 2. Location of provincial cardiac catherization labs in British Columbia 11 Figure 3. Areas served by the Northern Health Authority 16 Figure 4. Patient Classification by Body Mass Index (BMI) 58 Figure 5. Patient Classification by Class o f Obesity 59 Figure 6. Patient Area of Residence 60 Figure 7. Classification o f Patient Cases 61 Figure 8. Classification of Patients given thrombolytics by diagnosis 62 Figure 9. Patient Hospital Discharge Status 63 Figure 10. Average length of hospital stay according to diagnosis 64 Figure 11. Average length of hospital stay prior to transfer according 65 to diagnosis Figure 12. Average GRACE risk score by diagnosis 66 Figure 13. Adverse outcomes for 30-day and 1-year post ACS admission 68 vii GLOSSARY Acute coronary syndrome (ACS): umbrella terms for the clinical signs and symptoms of myocardial ischemia; unstable angina (UA), non-segment elevated myocardial ischemia (NSTEMI), and segment elevated myocardial ischemia (STEMI) Acute myocardial infarction: chest pain due to the sudden reduction of blood flow to the heart Atherogenic dyslipidemia: a metabolic risk factor characterized by the serum elevation of triglycerides, apo B and low density lipoproteins (LDL), as well as a decreased level of high density lipoproteins Atherosclerosis: plaque buildup which can lead to the narrowing o f coronary arteries Angioplasty: also known as balloon angioplasty, percutaneous coronary intervention, balloon angiography, coronary angiography Catheter: a small, narrow tube that can be inserted into a body cavity, duct or vessel Congestive heart failure (CHF): condition that occurs when the heart is unable to provide sufficient blood flow to maintain the needs o f the body and vital organs Coronary artery bypass graft (CAGB): a type of open-heart surgery in which a vein is removed from an area such as the leg is stitched to the aorta and coronary artery to create a new path for the flow of oxygenated blood to the heart Coronary heart disease (CHD): a disease of the coronary arteries in which plaque buildup obstructs the supply o f oxygenated blood to the heart Coronary heart disease: narrowing or blockage of the arteries which supply blood to the heart Door-to-balloon time (d2b): the time elapsed between the patient presenting to the emergency department with ACS symptoms to the point o f PCI initiation Fibrinolysis: see thrombolysis Global Registry of Acute Coronary Events (GRACE): a risk stratification tool used to predict both in-hospital and six month mortality post acute coronary syndrome presentation Myocardial infarction: a heart attack Myocardial ischemia: a sudden reduction in blood flow to the heart Non-segment elevated myocardial ischemia (NSTEMI): the partial occlusion of a coronary artery Percutaneous coronary intervention: a non-surgical procedure which uses a catheter to place stent to open blood vessels in the heart which were occluded by plaque Peripheral vascular disease (PVD): the obstruction of arteries (other than coronary) from plaque buildup and thrombus formation among other causes Segment-elevated myocardial ischemia (STEMI): usually indicative of a full occlusion of a coronary artery which can lead to the necrosis o f the myocardium Thrombolysis: the use of pharmacological agents to break up blood clots, often interchangeably used in the literature with the term, fibrinolysis Thrombolysis in Myocardial Infarction (TIMI): a risk stratification tool used to predict mortality post acute coronary syndromes Thrombus: a blood clot University Hospital of Northern British Columbia (UHNBC): the largest regional hospital in Northern British Columbia, located in Prince George, also serves as a clinical teaching centre for the Northern Medical Program offered jointly through the University of British Columbia and the University o f Northern British Columbia ACKNOWLEDGEMENT This study was supported by a research project award from the Office of Research and Graduate Studies at the University of Northern British Columbia. This work would not have been possible without the support of the following individuals and organizations that played a key role in its success. I would like to thank Rusty McColl, triage coordinator at the catherization lab at Vancouver General Hospital and Linda Axen at Northern Health for their guidance at various stages of this work. Thank-you to Northern Health as an organization, the medical records department staff at UHNBC and Cardiac Services BC for their assistance. A special thank-you to the Office of Graduate Studies at UNBC for their support throughout this entire process. I would like to thank Dr. Hadi, for his valuable clinical expertise and advice. I am grateful for the support of my committee members, Dr. Davina Banner-Lukaris and Dr. Luke Harris and thank them for their time and diverse perspectives that have enriched this work. I am grateful for the opportunity to work with my supervisor Dr. Mamdouh Shubair. Thank-you for your time, and mentorship along each stage of this journey. Finally I am grateful for the support of my family and friends. To my sisters and grandma for their unconditional support. To my mum, for being an invaluable source of strength and inspiration. Dedication To my father- J.S.K. I will never outgrow the feeling I get in knowing you are on my side. I know that if I need a little encouragement you will always be there just like when I was little. Thank you for giving me the strength to believe in myself and reach for the stars. T.G.N. And to the patients o f northern British Columbia, who despite the many associated with rural life, call this their home. CHAPTER ONE: INTRODUCTION Cardiovascular disease can be defined as a group of disorders that affect the heart and blood vessels (Public Health Agency o f Canada, 2009). Cardiovascular disease is one of the leading causes o f death for all Canadians (Statistics Canada, 2012). In fact it is estimated that every seven minutes, a Canadian dies due to heart disease or stroke (Heart and Stroke Foundation, 2012). Economically, CVD and stroke cost the Canadian economy over $20.9 billion annually in physician services, hospital costs, lost wages and decreased productivity (Charles River Associates, 2010; Heart and Stroke Foundation, 2012 ). Coronary heart disease (CHD) is the most common form of CVD. CHD can lead to an acute myocardial infarction (AMI), or chest pain due to a sudden reduction in blood flow to the heart muscle. This restriction in blood flow results from a buildup of plaque deposits in the coronary arteries that are responsible for supplying oxygenated blood to the heart. It is estimated that there are nearly 70,000 AMIs a year in Canada 19,000 of which are fatal (Tu et al., 2003; Healthy People, 2010) and a large number o f Canadians suffering from an AMI die before they are able to receive medical care. Acute Myocardial Infarction most commonly presents in the form o f acute coronary syndrome (ACS). Acute coronary syndrome is the umbrella term given for the clinical signs and symptoms of the following conditions associated with myocardial ischemia including: unstable angina (UA), non-ST-segment elevation myocardial infarction (NSTEMI), and ST-segment elevated myocardial infarction (STEMI) (Overbaugh, 2009). These conditions represent a continuum of acuity and increasing 1 intensity from unstable angina to ST-segment myocardial infarction. Unstable angina and non-ST segment elevated myocardial infarction typically arise from a partially occluded coronary artery whereas ST-segment elevated myocardial infarction is indicative of a full occlusion of the artery and typically results in a full thickness infarction (Overbaugh, 2009). Risk factors There are a number of established cardiometabolic risk factors for CVD. These include: smoking, Type 2 diabetes mellitus, alcohol consumption, a lack o f physical activity, elevated levels of serum cholesterol, and high blood pressure (Tanuseputra et al., 2003). According to recent statistics by the Heart and Stroke Foundation (2012) of Canada, at least nine out o f ten Canadians have at least one or more o f these risk factors. In addition to these factors, risk can also be increased due to certain influences such as sex (male), age (45 and over for males, 55 and over for females), family history, prior cardiac history (prior myocardial infarction, congestive heart failure (CHF), prior percutaneous coronary intervention (PCI), prior coronary artery bypass graft (CABG), a history of stroke and/or transient ischemic attack (TLA), atrial fibrillation (AF), and peripheral vascular disease (PVD)) and ethnic background. For example, research has shown that those of South Asian descent have much higher rates o f cardiovascular disease when compared to other ethnic groups (Anand et al., 2000; Gupta et al, 2006; Joshi et al., 2007). 2 Geography and the link to cardiovascular disease Canada is recognized by many around the world for the health care system and related services that it provides its citizens (Romanow, 2002). One of the core principles o f the publically funded Canadian health care system is that o f universal access to medically necessary care. While universal access to health services is perceived as one o f the most important and underlying values o f the system, the fact remains that not all Canadians are true recipients of universal and equal access to these services. In Canada, the vast geography o f the country makes it a challenge to deliver access to health care services and resources on a uniform basis. It is often seen that the larger, more urban centres are often equipped with highly advanced technology and a variety of specialized services and service providers. This is in stark contrast to Canada’s rural and remote regions where health care services are often limited and hard to come by (Smith et al., 2008). In situations like this, patients in rural settings needing more advanced health care services are often faced with the prospect of being transferred to larger centres to receive care. While medically necessary procedures including interventional cardiac services, are covered by provincial health care plans in Canada, the transfer of patients to these centres involves many variables that can affect patient outcomes (Pilote et al., 2004). These include, insufficient staffing levels, a lack o f specialized services, and increased wait times to receive access to services (Ross et al., 2006). One of the main concerns to health care providers is the impact o f wait times on patient health outcomes. This is also true for higher-level life saving cardiac services 3 which are more often readily available in only the larger, more urban centres in Canada (Pilote et al., 2004; Patel et al., 2010). For example, primary percutaneous coronary intervention, is considered the reference treatment for patients suffering from acute coronary syndrome, in particular, STEMI (Zijlstra, 2003). It is considered to be superior to the pharmacological option of thrombolysis with respect to decreasing rates for both patient mortality and morbidity (Antman et al., 2008; Van de W erf et al., 2006; Keeley et al., 2003; Boersma et al., 2006). There are however major barriers to the implementation of widespread use of primary PCI (PPCI). These barriers include, the delay due to the lack of centres capable o f performing PCI and long distances for transport required for access to the procedure (Sorensen et al., 2011). Although not explicitly thought o f as a risk factor, the concept of geography has been identified as a determinant of health. It can also have a profound influence on risk status for cardiovascular disease. Those living in rural areas are considered to be at higher risk for the development of cardiovascular disease. It is also a well-documented fact that those living in rural areas have poorer health status when compared to their urban counterparts (Romanow, 2002; Pong et al., 2009). Rural dwelling individuals have been documented to display a greater incidence o f unhealthy lifestyle behaviors as compared to those in urban settings (DesMeules & Pongo, 2006; Pamplon et al., 2006). This often results in them having higher frequencies of the classical CVD risk factors such as diabetes, physical inactivity, and obesity. In addition to increased levels of risk factors, risk is further exacerbated due to the unique challenges that rural individuals face when accessing health care services for their conditions. For example, it is a well-known fact that rural areas face challenges in the 4 recruitment of physicians and other allied health care professionals such as physiotherapists, and medical diagnostic technicians (Fleet et al., 2013). This often directly impacts the availability of diagnostic services and advanced level care procedures. As a result, rural patients are faced with the prospect o f having to travel for their health care needs. This leads to the added burden o f travel costs, and added wait times among other issues. As well there may be additional risk associated with moving to an urban centre (Sibley & Weiner, 2011). For example, the risk of travelling long distances in less than ideal weather conditions. Furthermore, patient outcomes are generally worse for those living in rural areas as highlighted by the increased mortality rates for cardiovascular disease in rural patient populations (Filate et al., 2003; DesMeules & Pongo, 2006). Symptoms of acute coronary syndrome Acute coronary syndrome, more commonly referred to in layperson’s terms as a heart attack, presents with some common symptoms. These include: chest pain or discomfort, which is often described as involving a sense o f crushing, tightness or pressure, pain or discomfort in one or both arms, neck, jaw, back or stomach, shortness of breath, a feeling of dizziness or lightheadedness, nausea and/or vomiting, and sweating. However, ischemia can also occur without any of these typical signs or symptoms. It is referred to in medical terms as ‘silent ischemia’ (Overbaugh, 2009). Silent ischemia is more common in the elderly (65 years and older), those with diabetes, and the female sex. The outcomes for silent ischemia are often worse as the absence of symptoms results in delays for seeking treatment. This delay in treatment seeking often leads to lower rates of recovery and higher rates o f mortality (Maron & Hochman, 2013). 5 Diagnosis and management of acute coronary syndrome The protocol for ACS diagnosis at hospitals in British Columbia is based on the guidelines established by British Columbia’s provincial government. These provincial guidelines are based on those developed jointly by both the American Heart Association (AHA) and the American College o f Cardiology (ACC). These guidelines split patients into the following categories namely, definite ACS and possible ACS. When a patient presents to the emergency department with symptoms of ACS such as chest pain or difficulty breathing, there is a set o f steps performed to determine whether it is ACS. These steps are established by the BC Medical Association and are presented in Figure 1. (pg. 10). ACS is essentially a working diagnosis and there are a series o f tests and procedures performed to pinpoint the diagnosis and specifically define the type o f ACS. These patients are triaged according to the Canadian Triage Acuity Scale (CTAS). If the patient complains o f typical ACS symptoms, and more specifically chest pain, they are triaged as a 1 (resuscitation required), 2 (emergent care required), or sometimes a 3 (urgent care required). These patients are given high priority and are evaluated on an urgent basis. Diagnostic test for ACS involve two preliminary tests including a blood test, and a 12-lead electrocardiogram (ECG) and also involves evaluation by a physician. Diagnosis of an acute myocardial infarction is based upon the following criteria being met: detection of a rise and/or fall of cardiac biomarkers, specifically troponin. At least one value should be above the 99th percentile, plus at least one of the following: symptoms of ischemia, ECG changes indicating new ischemia; ST elevation; new left 6 bundle branch block, new pathological Q waves in the ECG, and /or imaging showing a new loss of viable myocardium or new regional wall motion abnormality. Myocardial ischemia causes tissue damage and myocardial cell death resulting in the release of cardiac biomarkers in the blood, specifically troponins, TnT and Tnl, and CK-MB). Testing for these biomarkers is perfomed alongside a 12-lead ECG and physician evaluation to diagnose ACS. The cardiac troponins are considered to be more sensitive and more specific in the detection of myocardial damage, and they are measured upon patient presentation and six to eight hours post chest pain onset. A diagnosis of STEMI is made when cardiac biomarkers are elevated and electrocardiography reveals that there is ST-segment elevation or new left-bundle branch block whereas a diagnosis o f NSTEMI is made when cardiac biomarkers are elevated and electrocardiography reveals there is ST-segment depression or T-wave inversion. Unstable angina is diagnosed when cardiac biomarkers are not elevated and electrocardiography findings reveal ST-segment depression or T-wave inversion. Management of STEMI Patients with STEMI are treated with the intent of reperfusing the ischemic muscle. The reference treatment for STEMI is PCI while thrombolysis is now only used in hospitals without PCI capabilities or in instances when PCI cannot be delivered in the target ‘door-to-balloon’ (d2b) times of 90 minutes or less (Levine et al., 2011). The ACC/AHA guidelines recommend that patients who receive thrombolytic therapy are transferred to a PCI capable centre following the treatment. Patients with STEMI presenting to UHNBC are transferred via British Columbia (BC) air ambulance, a flight 7 with duration o f about an hour to one of the five cardiac catherization labs in the province. These include: Vancouver General Hospital (VGH) or St. Paul’s Hospital (SPH) in Vancouver, Royal Jubilee Hospital (RJH) in Victoria, Kelowna General Hospital (KGH) in Kelowna, or Royal Columbian Hospital (RCH) in New Westminster (Figure. 2). This inter-hospital transfer of patients to provincial cardiac catherization labs is overseen by BC Bedline, formerly known as the Patient Transfer Network (PTN). Management of NSTEMI/UA Patients with NSTEMI or UA are treated for acute myocardial ischemia (British Columbia Medical Association, Guidelines and Protocols Advisory Committee, 2008). This treatment involves: bed rest with continuous ECG monitoring, oxygen for patients with respiratory distress or oxygen levels o f less than 90%, sublingual nitrates for those experiencing continuous pain or intravenous nitrates for those with stable blood pressure readings or those unresponsive to sublingual nitrates or beta-blockers (Fitchett et al., 2011; Wright et al., 2011). Percutaneous coronary intervention (PCI) may also used for NSTEMI/UA patients though less frequently than those with STEMI (Fitchett et al., 2011; Wright et al., 2011). An alternative and more frequently used approach for NSTEMI and UA patients is the use o f low molecular weight heparin, aspirin and anti­ platelets agents such as clopidogrel, as well as statins and ace inhibitors. Along with betablockers these have been shown to decrease mortality in these patients (Wong et al., 2003). However, if considered suitable candidates for PCI, patients with NSTEMI or UA are also transferred to provincial cardiac labs like those with STEMI. Although the optimal time frame for maximum therapeutic benefit from PCI for these patients has not 8 been well-defined however early or immediate catherization is recommended (Jneid et al., 2012). 9 Chest M a > 1# adn at raat (possible ACS, no alternative cats Send to Emergency Dept by ambulance for further evaluation Normal ECS and cardiac bcmarfcen Observe and follow-up at > 6 Iws from onset No recurrent pain, negative repeat ECG& cardiac biomarkers M tk lC I do ECGand cardiac bnm riim ECCabnormalities ofher than ST elevation, ongoing pain, positive canfiac taomarkars, or tientodynanuc atmonnafrbes ST elevation/new LB8B Positive canine Manage as Acute M Evaluate far reperfusion Recurrent ischemic paax posSjveECGcr cardnc bnmarfcars Stress test (-*-/- imafyng) it recommended • interniedmfc risk: before discharge ■ kmr risk: written 72 tws as Harm patient of warning symptoms FoSowup at 30 days by Family Physician Recurrent chest psan Re-evahnte as at begmnmg ofafganthnn Figure 1. Management of suspected ACS algorithm (reprinted with permission from the British Columbia Medical Association, Guidelines & Protocols Advisory Committee 2014) 10 British Columbia Provincial Health Authorities Health Authorities ( in te r io r Heath ( F r a s e r Health (V a n c o u v e r Coastal Health ( ’vfcnoouver Island Health Authority (N o r th e rn Health (P ro v in c ia l Health Services Authority f t Hospitals performing invasive cardiac procedures Figure 2. Provincial cardiac catherization labs in British Columbia (reprinted with permission from Cardiac Services BC [CSBC], 2014) 11 Treatment options The current ‘gold standard’ for treatment o f ACS is percutaneous coronary intervention (PCI) with respect to decreasing rates for both patient mortality and morbidity (Antman et al., 2008; Van de W erf et al., 2006; Keeley et al., 2003; Boersma et al., 2006). It is also known as balloon angioplasty, coronary angioplasty, coronary balloon angioplasty, coronary transluminal angioplasty and coronary artery angioplasty. Percutaneous coronary intervention (PCI) is a non-surgical procedure that is used to widen coronary arteries occluded by plaque deposits. It is performed through the use o f a thin catheter. The catheter is inserted through the femoral or radial artery and is used to place a stent in the occluded blood vessel. When the stent tip is in place, a balloon on the end of the stent is inflated. The inflation of the balloon compresses the plaque and expands the stent. When the plaque has been compressed and the stent has fully expanded into place, the balloon is deflated and withdrawn (Heart and Stroke Foundation, 2012). Current ACC/AHA guidelines consider primary PCI (PPCI) to be most effective when delivered in the ‘door to balloon’ time of 90 minutes. In centres where primary PCI is not feasible, a ‘door to balloon’ time of 120 minutes is recommended. Not all hospitals have on-site cardiac catherization labs. In fact some hospitals do not have access to catheriztion labs in their region and require patient transportation across large distances to receive required care. For hospitals not equipped with catherization facilities to perform PCI, pharmacological measures are the next best option. These measures, vary depending on diagnosis of STEMI or NSTEMI/UA. For patients with STEMI, thrombolysis or fibrinolysis, is the preferred treatment and it commonly involves the administration o f tissue plasminogen activators (tPAs) for the 12 purpose of dissolving the artery obstructing clot. According to guidelines developed by the American Heart Association, thrombolytics are most effective when received within the first 90 minutes of presentation and greatly increase the patient’s chances o f survival and recovery if administered within 12 hours o f symptom presentation (Levine et al., 2011 ). Thrombolytics are used only in instances when not countra-indicated. Such countra-indicative factors are usually present in high-risk patients where the risk of administering treatment outweighs the potential for benefit to the patient. Such factors include: recent head trauma, bleeding problems, ulcers, pregnancy, recent surgery, uncontrolled high blood pressure and whether the patient is on blood thinning agents. For patients suffering from NSTEMI or UA, pharmacological options include: low molecular weight heparin, aspirin and anti-platelets agents (eg. clopidogrel) as well as statins and ace inhibitors. Along with beta blockers these have been shown to decrease mortality and the anti-platelet agents and heparin are probably the most important therapies. There is no documented benefit in the literature from thrombolysis in these types of ACS (Levine et al., 2011). However, pretreatment with intensive antithrombotic therapy may diminish thrombus burden and “passivate” unstable plaques, improving the safety of percutaneous revascularization and reducing the risk of peri-procedural ischemic complications (Jneid et al., 2012). Knowledge gaps While recent advances in pharmacology and revascularization procedures have dramatically improved health outcomes for patients with ACS both the incidence and 13 prevalence o f ACS is increasing and is further expected to increase (Grundy et al., 2004). This increase is thought to be in large part due to the exponential increases in obesity and Type 2 diabetes mellitus expected worldwide (Lakka et al., 2002; Malik et al., 2004; Booth et al., 2006; Donahoe, et al., 2007; Fox et al., 2007). This phenomenon is occurring in both, developed and developing countries alike. Rural and northern areas are being the most impacted due to poorer health status and health care resource limitations (Arcury et al., 2005). With the rise in incidence there is an increased stress on the health care system and resources. In such instances it is crucial to find ways to maximize the effectiveness o f these resources and to use them in the most efficient manner possible. To date, there is a scarcity o f research that has been conducted on this topic area. The University Hospital of Northern British Columbia The University Hospital of Northern British Columbia (UHNBC) is located in Prince George, the capital o f northern British Columbia. It is a health care facility with over 200 acute care beds, and is the largest hospital in the entire northern region of the province (Northern Health Community Health Information Portal, 2013). It falls under the jurisdiction of the Northern Health Authority, one o f the six regional health authorities in the province of British Columbia (Figure 3.). The hospital serves as a regional hub for health services and serves a city population of 80,000 and an estimated 300,000 that live in the more rural areas of the north (Rural Coordination Centre of British Columbia, 2013). The UHNBC provides services that are not readily available in smaller community hospitals including: a variety of diagnostic services, radiology, neonatal 14 intensive care, trauma care, as well as clinics for chronic ailments and maternity services. Patients from other areas within the Northern Health Authority boundaries can be sent to UHNBC for evaluation, stabilization or further treatment. Furthermore, some may be transferred from other community hospitals to UHNBC to await transfer to a larger facility in the Lower Mainland for services not available in the north. In addition to providing health care services, the hospital serves as a clinical teaching campus for students in health professions such as physiotherapy, medical laboratory technology and medicine. 15 Burmtato mam *-yg. North*!) HmMi Authority PMP vOWIWJf8VBWM H ttl) Vancouver Vidom Figure 3. Areas served by the Northern Health Authority (reprinted with permission from UBC Faculty o f Medicine, 2014) Rationale for the study This study aims to address the issue of access to cardiac catherization services, specifically PCI for patients in northern British Columbia. It responds to an important health care need in this part of the province. This study aims to explore the issue of access to PCI with a high-risk population with unique geography and health needs. Patients presenting to UHNBC are transferred for care to hospitals equipped with cardiac catherization labs. While most catherization centres recognize the urgency for treatment of patients with ACS, there is lack of a standardized or formal process for assigning patient priority. Instead this is done most often through either a formal or informal triage process. It is a process that often relies highly on physician judgement and can lead to some centres allocating the next ‘available slot’ to patients with ACS requiring the procedure. In fact there is little evidence to support that any centre risk stratifies patients for the urgency of transfer or has a system to ensure appropriate and timely triage of patients with ACS (Patel et al., 2010). The rationale for studying patients presenting to UHNBC with ACS varies. To begin with, ACS is a fairly common presentation at the emergency department at UHNBC. In fact, northern BC has the highest AMI hospitalization rate and highest CVD related mortality rate in all of British Columbia (Cardiac Services British Columbia, 2010 ). Secondly, based on prior estimates of ACS data for UHNBC, it was expected that the sample size would be adequate for this study. It was estimated that there would be 17 approximately 250 patients presenting to UHNBC with ACS for the one year time period o f January 2012 through to December of 2012. Thirdly, the population of northern British Columbia is considered to be a highrisk group for ACS. Higher rates of traditional risk factors, geographical barriers, and limited health care resources all contribute to this heightened risk status. It is therefore important to study this population and it is safe to assume that carrying out this project will help to inform cardiac care for future ACS patients at UHNBC. Fourth, UHNBC currently has no facilities for PCI or angiography, which the literature regards as the ‘gold standard’ treatment for ACS STEMI (D’Souza et al., 2011). Patients with ACS who require this treatment are sent down to the hospitals in the Lower Mainland namely, Vancouver General or St. Paul’s. This is in contradiction to the literature as the literature states that to be the most effective, PCI should be delivered in the ‘door to balloon’ time of 90 minutes (D’Souza et al., 2011). However, it is obvious by just the flight duration from Prince George to Vancouver of over just over an hour that achieving this target time is effectively impossible. Therefore research on this topic will help determine the impact of those wait times and allow for insight into areas o f potential improvement in current practices. Finally, it is important to note that given a Canadian context, the vast geography and population dispersion, we cannot justify the creation o f PCI centres in every hospital. The primary objective here was to see whether when thrombolysed (or not), longer times to treatment for PCI are associated with worse patient outcomes and to determine 18 whether patients are transferred according to their risk status. This will help to provide direction for the future. Research objectives The proposed study has the following research objectives. They include: 1) to determine through multiple linear regression whether longer door-to-balloon times (>120mins) are associated with higher rates of adverse outcomes (death, re-infarction, heart failure, or stroke) in the UA, NSTEMI and STEMI groups within 30-days and oneyear of hospital admission and 2) to determine through multiple linear regression whether the patients most at risk using the GRACE score receive PCI faster in UA, NSTEMI or STEMI groups Significance of the research This research responds to an important health issue of cardiac care in a setting with a high-risk population and limited access to evidence-based treatment. It also has the potential to drive changes in the clinical setting that may aid in improving patient outcomes. There is no doubt that there has been much research into the importance o f rapid access to PCI, as well as the risk stratification of ACS patients using GRACE risk scores. Despite all this research, there remains a gap in the literature when it comes to studying these topics from a rural point of view. In fact the available research is often focused on centres where access to PCI is readily attainable. Furthermore, the study populations in this research are often urban dwelling and have a better overall health status as well as a different set of risk factors than their rural dwelling counterparts. This 19 is o f significance as this limits the generalizability of the findings o f these studies to the rural population. Patients living in rural settings face unique health care challenges. These challenges can be in the form of poorer health status and health outcomes or limitations in access to health care services (Romanow, 2002; DesMeules et al., 2006). Addressing the aforementioned research aims from a rural standpoint will offer a relevant perspective to the issues faced by patient with acute coronary syndrome in a rural health care setting with particular health care needs. A northern perspective Northern British Columbia is a resource rich area o f the province with an abundance of thriving forests, lakes, rivers and wildlife. This region is a major driving force behind the provincial economy. Northern BC is highly industry based with a heavy focus on forestry, mining and fishing. The northern region covers 2/3 o f the northern part of the province, equivalent to area the size o f France (de Leeuw, 2011). It is home to a population of approximately 350,000, most of which live in rural or remote areas. This combination of a vast geographical landscape coupled with an unevenly distributed rural population makes it difficult for efficient health care service delivery. In addition to this, the high-risk lifestyle associated with industry jobs that are dominant in this region can have additional negative impacts on the health status of this subset of the population (Pamplon et al., 2006). The population in northern British Columbia is considered to be at high-risk for ACS. Factors contributing to this increased risk include high rates o f obesity, diabetes, 20 smoking, alcohol consumption and physical inactivity. According to a recent report by Cardiac Services British Columbia (2011), northern British Columbia has the highest diabetes, obesity and smoking rates in the entire province. This region comes second highest for physical inactivity, and third highest for hypertension and heavy alcohol consumption (Cardiac Services British Columbia, 2011). This part o f the province has a large concentration of First Nations people. This is o f significance as heart disease is the leading cause of death among First Nations people (Heart and Stroke Foundation, 2012). Thus this makes it all the more important to study this topic from a northern point of view. In addition to the effects of a northern and rural geography, there are additional factors that can impact the health o f northern dwelling populations (University of Northern British Columbia, 2013). These factors include: physical and emotional isolation, a transient population, and seasonal employment alongside the fluctuation of a resource based economy, and a harsh climate. Additionally, the use of population, which is low and dispersed, can work to further disadvantage this community when it is used determine public investment in services as well as resource allocation, including health care services for this area. This thesis is organized into six chapters. The next section o f this thesis reviews existing literature on the use of PCI and the concept of risk stratifying patients with ACS using the Global Registry of Acute Coronary Events (GRACE) risk score. The approach used to risk stratify patients is described. Findings related to time to PCI and risk status of patients are summarized. The review o f existing literature is followed by a description of the methodological and analytic procedures as well as a presentation of the results of this 21 research. Following this a discussion o f the findings is presented and the thesis concludes with a discussion o f implications, recommendations and directions for future research. 22 CHAPTER TWO: LITERATURE REVIEW A review o f the literature was conducted in relation to the two research questions that will be examined in this study. These include; the importance o f timely access to percutaneous coronary intervention (PCI) for patients with ACS, and value o f performing the risk stratification o f patients with acute coronary syndrome using the Global Registry o f Coronary Events (GRACE) risk scores, (see Appendix G/H for summary tables). It begins with a discussion of the importance o f timely access to primary percutaneous coronary intervention (PPCI) and moves onto discuss options in the event that PPCI is not available or cannot be conducted in the recommended time frame. Finally the GRACE risk score is introduced and its use for ACS patients is discussed. This is followed by a discussion on validation studies conducted on the use of the GRACE risk score for ACS patients and their findings. Search strategy A review o f the literature was conducted through electronic health databases. For both research questions the databases used included: CINHAL, Medline Ovid, PubMed, and Cochrane Reviews. These databases were used as they were found to be most relevant to the research in question and evidence-based medical practice trials. In addition to this, an examination of grey literature available through Google Scholar was conducted to identify any missed relevant literature. Searches were limited to 2002-2013, trials involving humans, and publications in the English language, For the first research question, search words included: percutaneous coronary intervention, coronary 23 intervention, balloon angioplasty, transluminal coronary angioplasty, angioplasty, thrombolysis, fibrinolysis, time to treatment, door to balloon time, primary PCI, facilitated PCI, rescue PCI. Searches were filtered using the restriction o f randomized control trials. For the second research question search terms included: Global Registry of Acute Coronary Events, GRACE, GRACE risk score, risk score, risk stratification, acute coronary syndrome(s). Importance of timely access to percutaneous coronary intervention Percutaneous coronary intervention (PCI) is a non-surgical procedure that helps to restore blood flow to the affected artery. It is essentially used to widen coronary arteries occluded by plaque deposits. It is performed through the use of a thin catheter that is used to place a stent in the occluded blood vessel. When the stent tip is in place, a balloon on the end o f the stent is inflated. The inflation of the balloon compresses the occluding plaque and expands the stent. When the plaque has been compressed and the stent is in place and has fully expanded, the balloon is deflated and withdrawn (Heart and Stroke Foundation, 2012). Current ACC/AHA guidelines consider PCI to be most effective when delivered in the ‘door to balloon’ time of 90 minutes. However, this target time is rarely achieved, especially in hospital settings without on-site cardiac catherization labs (De Luca et al., 2004). Instead facilitated, PCI post thrombolysis, or rescue PCI in the event o f failed thrombolysis, is performed in such cases. ACC/AHA guidelines consider a ‘door to balloon’ time of less than 120 minutes acceptable in such conditions (Levine et al., 2011). Still this recommended target time can be hard to achieve given the real-life context (McNamara et al., 2006; Rathore et al., 2009). Futhermore, the generalizability o f these 24 guidelines may be limited in Canadian context as they are reflective o f the American landscape. The United States has a different geography, a much larger and more distributed population as well as a health care system that is very distinct from the publicly funded system in Canada thus expecting strict adherence to one set o f guidelines for both nations is unfair and unrealistic. Primary PCI has shown to offer more benefits as compared to fibrinolysis for many patients presenting with STEMI (Keeley et al., 2003). These benefits however are only sustained within 2 to 3 hours of door-to-balloon times (Levine et al., 2011). Given the current context, a rural urban setting without PCI capable facilities, the recommended target d2b times o f less than 120 minutes are often a difficult feat to achieve. One of the greatest barriers to achieving target time is the inter-hospital transfer process (Scheller et al., 2003). This process can significantly increase times to treatment. This can be due to certain factors including; unsafe weather conditions for the air ambulance transfer, a lack of beds at the tertiary receiving centre as well a numerous other health care resource limitations which indirectly can affect transfer times. Therefore the current review of the literature will focus specifically on the results o f randomized trials comparing fibrinolysis with transfer to another hospital for PCI and outcomes associated with facilitated or rescue PCI. Facilitated PCI-use with fibrinolytics versus PCI alone A study conducted by Widimisky et al. (2000), referred to as the PRAGUE study (Prim ary Angioplasty in patients transferred from General community hospitals to specialized PTCA Units with or without Emergency thrombolysis) compared three different reperfusion strategies in patients with AMI, presenting within six horns of 25 symptom onset at community hospitals without a catheterization laboratory and related PCI capabilities. Patients were randomized into one o f the three treatment groups namely; group A (thrombolytic therapy in community hospitals (n=99)), group B (thrombolytic therapy during transportation to angioplasty (n=100)), and group C (immediate transportation for primary angioplasty without pre-treatment with thrombolysis (n=101)). The transport distance to the specialized PCTA units varied between 5 and 74 kilometers. There were no complications during transportation in group C. However, complications occurred during transfer for group B involving two instances o f ventricular fibrillation. Median admission-reperfusion time in transported patients was as follows; group B 106 minutes and group C 96 minutes. These times compared favorably with the anticipated 90 minutes time in group A. The combined primary end-point, death or reinfarction and/or stroke at 30 days, was less frequent in group C (8%) compared to both groups B (15%) and A (23%, p < 0.02). The incidence o f reinfarction was markedly reduced by transport to primary angioplasty (1% in group C vs 7% in group B vs 10% in group A, p < 0.03). Therefore, Widimisky and collegues (2000) concluded that transferring patients from community hospitals to a tertiary angioplasty centre, in the acute phase of myocardial infarction, was both feasible and safe. Furthermore this strategy was found to be associated with a significant reduction in the incidence o f reinfarction and the combined clinical end-point of death, reinfarction, and stroke at 30 days (group C 8% and group B 15%) when compared to standard thrombolytic therapy at the community hospital (23%, p < 0. 02). Three years later there was a follow-up study conducted to the PRAGUE trial, entitled the PRAGUE-2 trial by Widimisky et al. (2003). The PRAGUE-2 study involved 26 the randomization o f 850 patients with acute ST elevation myocardial infarction presenting within 12 hours to the nearest community hospital without a catheter laboratory to either thrombolysis in this hospital (TL group, n=421) or immediate transport for primary percutaneous coronary intervention (PCI group, n=429). The primary end-point was defined as 30-day mortality while the two secondary end-points included; death, reinfarction, and /or stroke at 30 days, a combined end-point, and 30-day mortality among patients treated within 0-3 hours and 3-12 hours after symptom onset. The maximum transport distance to catheter laboratories was 120 kilometres. There were five unspecified complications (1.2%) that occurred during patient transport. Randomization-balloon time in the PCI group was between 70 and 124 minutes, and randomization-needle time in the TL group was between 2 to 22 minutes. Mortality at 30 days was 10.0% in the TL group compared to 6.8% mortality in the PCI group (p = 0.12, intention-to-treat analysis). Mortality of 380 patients who actually underwent PCI was 6.0% versus 10.4% mortality in 424 patients who finally received thrombolysis, TL group (p < 0.05). Among the 299 patients randomized more than 3 hours after the onset of symptoms, the mortality of the TL group reached 15.3% compared to 6% in the PCI group (p < 0.02). Patients randomized within 3 hours of symptom onset (n=551) had no difference in mortality whether treated by TL (7.4%) or transferred to PCI (7.3%). A combined end-point occurred in 15.2% of the TL group versus 8.4% o f the PCI group (p < 0.003). Widimisky et al. (2003) thus concluded that long distance transport from a community hospital to a tertiary PCI centre in the acute phase of AMI is safe as this strategy was associated with marked decreases in mortality in patients presenting more than 3 hours after symptom onset. However for patients presenting within 3 hours of 27 symptom onset, TL results were similar to the results in long distance transport for PCI. The Facilitated Intervention with Enhanced Reperfusion Speed to Stop Events (FINESSE) study by Ellis et al. (2004) was a prospective, multicenter, randomized, double-blind, placebo-controlled trials involving 3000-patients. The study compared the efficacy and safety of early administration of reduced-dose reteplase and abciximab combination therapy or abciximab alone followed by PCI with abciximab alone administered just before PCI for AMI. Patients were randomized to one o f these two facilitated PCI treatments, reduced-dose reteplase and abciximab combination therapy or abciximab alone followed by PCI with abciximab alone, or primary PCI in a 1:1:1 fashion. The primary end point was the composite of all-cause mortality or post-MI complications within 90 days of randomization. The primary safety outcome assessment was made through the use of the Thrombolysis In Myocardial Infarction (TIMI) score for the outcome o f major bleeding. One-year mortalities in the three groups, reduced-dose reteplase and abciximab combination therapy or abciximab alone followed by PCI with abciximab alone, or primary PCI, were 6.3%, 7.4%, and 7.0%, respectively (p = NS), representing 1.1%, 1.9%, and 2.5% increments since the 90-day outcome (p = 0.053 for combination treatment vs. primary PCI). A favorable trend with combination treatment was seen for patients with anterior MI (p = 0.09), but no other specified groups were shown to benefit. Independent baseline correlates o f 1-year mortality were systolic blood pressure less than 100 mm Hg, prior myocardial infarction, age, Killip class greater than 1, anterior MI, body mass index less than or equal to 25 kg/m2, heart rate greater than 100 beats/min, and no statin use. Based on the results Ellis et al. (2004) concluded that widespread utilization o f the facilitated approaches tested could not be justified, but that 28 high-risk patient groups such as patients with anterior MI deserve further study. The GRACIA-2 trial (2007) was a randomized controlled trial that evaluated whether lytic-based early routine angioplasty represents a reasonable reperfusion option for victims o f STEMI irrespective of geographic or logistical barriers, more specifically in cases where PPCI was not possible within the recommended guideline times. The trial involved a total o f 212 AMI STEMI patients which were randomized to either the full tenecteplase followed by stenting within 3-12 hours o f randomization (early routine post­ fibrinolysis angioplasty; n=104), or to undergo primary stenting with abciximab within 3 hours of randomization (primary angioplasty; n=108). The primary endpoints were defined as epicardial and myocardial reperfusion, and the extent o f left ventricular myocardial damage, determined by means o f the infarct size and six-week left ventricular function. The secondary endpoints were defined as the acute incidence o f bleeding and the six-month composite incidence o f death, reinfarction, stroke, or revascularization. Results indicated that early routine post-fibrinolysis angioplasty resulted in higher frequency (21 versus 6%, p = 0.003) of complete epicardial and myocardial reperfusion (TIM I3 epicardial flow and TIMI 3 myocardial perfusion and resolution of the initial sum o f ST-segment elevation > or = 70%) following angioplasty. Both groups were similar regarding infarct size (area under the curve of CK-MB: 4613 +/- 3373 versus 4649 +/- 3632 microg/L/h, p= 0.94); 6-week left ventricular function (ejection fraction: 59.0 +/- 11.6 versus 56.2 +/- 13.2%, p= 0.11; end systolic volume index: 27.2 +/- 12.8 versus 29.7 +/-13.6, p = 0.21); major bleeding (1.9 versus 2.8%, p = 0.99) and six month cumulative incidence of the clinical endpoint (10 versus 12%, p = 0.57; relative risk: 0.80; 95% Cl: 0.37-1.74). Thus Fernandez-Aviles et al. (2007) concluded that early 29 routine post-fibrinolysis angioplasty safely results in better myocardial perfusion than primary angioplasty as despite its delayed application, this approach was seen to be equivalent to primary angioplasty in limiting infarct size and preserving left ventricular function. Transfer for PPCI vs. Immediate thrombolysis in AMI The AIR-PAMI study by Grines et al. (2002) involved high-risk AMI patients (aged 70 years or older, anterior MI, Killip class II/III, heart rate greater than 100 beats/min or systolic blood pressure less than 100 mm Hg) who were eligible for thrombolytic therapy. Patients (n= 138) were randomized to either of two treatment arms, transfer for primary PTCA (n=71) or on-site thrombolysis (n=67). The time from arrival to treatment was delayed in the transfer group (155 versus 51 min, p< 0.0001), largely due to the initiation o f transfer (43 min) and transport time (26 min). Patients randomized to transfer had a reduced hospital stay (6.1 +/- 4.3 versus 7.5 +/- 4.3 days, p= 0.015) and less ischemia (12.7% versus 31.8%, p = 0.007). At 30 days, a 38% reduction in major adverse cardiac events was observed for the transfer group however, because of the inability to recruit the necessary sample size, this did not achieve statistical significance (8.4% versus 13.6%, p = 0.331). Grines et al. (2002) concluded that high-risk patients with AMI at hospitals without a catheterization laboratory may have an improved outcome when transferred for primary PTCA versus on-site thrombolysis and suggested that the marked delay in the transfer process suggests a role for triaging patients directly to specialized heart-attack centers. The DANAMI-2 (2003) trial randomly assigned 1572 patients with AMI to treatment with angioplasty or accelerated treatment with intravenous alteplase; 1129 30 patients were enrolled at 24 referral hospitals and 443 patients at five invasive-treatment centers. The primary study end point was a composite of death, clinical evidence of reinfarction, or disabling stroke at 30 days. Among patients who underwent randomization at referral hospitals, the primary end point was reached in 8.5% o f the patients in the angioplasty group, as compared with 14.2% of those in the fibrinolysis group (p=0.002). The results were similar among patients who were enrolled at invasivetreatment centers: 6.7% o f the patients in the angioplasty group reached the primary end point, as compared with 12.3% in the fibrinolysis group (p=0.05). Among all patients, the better outcome after angioplasty was driven primarily by a reduction in the rate of reinfarction (1.6% in the angioplasty group versus. 6.3% in the fibrinolysis group, p<0.001); no significant differences were observed in the rate of death (6.6 % versus 7.8 %, p-0.35) or the rate of stroke (1.1 % versus 2.0 %, p=0.15). Ninety-six % o f patients were transferred from referral hospitals to an invasive-treatment center within two hours. Andersen et al. (2003) concluded that a strategy for reperfusion involving the transfer of patients to an invasive-treatment center for primary angioplasty is superior to on-site fibrinolysis, provided that the transfer takes two hours or less. The ASSENT-4 trial (2006) investigated whether the administration o f full-dose tenecteplase before a delayed PCI could mitigate the negative effect of this delay. ASSENT-4 was a randomized study in which patients with STEMI of less than six hours in duration were (scheduled to undergo primary PCI with an anticipated delay o f 1-3 hours) to standard PCI (n=838) or PCI preceded by administration of full-dose tenecteplase (n=829). All patients received aspirin and a bolus, without an infusion, of unfractionated heparin. The primary endpoint was death or congestive heart failure or 31 shock within 90 days. It is important to note that the initial plan was to enroll 4000 patients, but the premature cessation of enrollment was recommended by the data and safety monitoring board because of a higher in-hospital mortality in the facilitated than in the standard PCI group (6% [43 o f 664] versus 3% [22 of 656], p=0.0105). O f those enrolled, six were lost to follow-up in the facilitated PCI group and seven in the other group. Median time from randomization to first balloon inflation was similar in both groups. The median time from bolus tenecteplase to first balloon inflation was 104 min. The primary endpoint was 19% (151 of 810) of patients assigned facilitated PCI versus 13% (110 o f 819) in those randomized to primary PCI (relative risk (RR): 1.39, 95% Cl 1.11 -1.74; p=0.0045). It was also found that during the hospital stay, significantly more strokes (1.8% (15 o f 829) versus 0, p<0.0001), but not major non-cerebral bleeding complications (6% (46 of 829) versus 4% [37 o f 838], p=0.3118), were reported in patients assigned facilitated rather than standard PCI. Furthermore more ischemic cardiac complications, such as reinfarction (6% (49 o f 805) versus 4% (30 of 820), p=0.0279) or repeat target vessel revascularization (7% (53 o f 805) versus 3% (28 of 818), p=0.0041) within 90 days in this study group. Van der Werf et al. (2006) concluded that the strategy of full-dose tenecteplase with antithrombotic co-therapy, as used in this study and preceding PCI by one to three hours, was associated with more major adverse events than PCI alone in STEMI and cannot be recommended. A follow-up study to the DANAMI-2 trial was conducted by Nielsen et al. in 2010. The study involved the randomization of 1572 patients with STEMI to primary angioplasty or intravenous alteplase; 1129 patients were enrolled at 24 referral hospitals 32 and 443 patients at five angioplasty centres. Ninety-six percent of inter-hospital transfers for angioplasty were completed within two hours and no patients were lost to follow-up. The composite endpoints primarily, death, clinical re-infarction, or disabling stroke, were reduced by angioplasty when compared with fibrinolysis at 3 years (19.6% versus 25.2%, p= 0.006). For patients transferred to angioplasty compared with those receiving on-site fibrinolysis, the composite endpoint occurred in 20.1% versus 26.7% (p= 0.007), death in 13.6 versus 16.4% (p= 0.18), clinical re-infarction in 8.9% versus 12.3% (p= 0.05), and disabling stroke in 3.2% versus 4.7% (p= 0.23). The benefit of transfer for primary angioplasty based on the composite endpoint was sustained after three years. Nielsen et al. (2010) concluded that for patients with characteristics such as those in DANAMI-2, primary angioplasty should be the preferred treatment strategy provided that inter­ hospital transfer can be completed within two hours. The LIPSIA-STEMI (2011) multicenter trial sought to assess the merits of facilitated percutaneous coronary intervention (PCI) versus primary PCI in an STsegment elevation myocardial infarction (STEMI) network with long transfer distances in patients presenting early after symptom onset. Patients with STEMI presenting less than 3 hours after symptom onset, were randomized to either pre-hospital-initiated facilitated PCI using tenecteplase (Group A; n = 81) or primary PCI (Group B; n = 81) plus optimal antithrombotic co-medication. The primary endpoint was infarct size assessed by delayed-enhancement magnetic resonance imaging. Secondary endpoints included micro vascular obstruction and myocardial salvage, early ST-segment resolution, and a composite of death, repeated myocardial infarctions, and congestive heart failure within 30 days. The median time from symptom onset to randomization was 64 min 33 (interquartile range (IQR): 42 to 103 min) in Group A versus 55 min in Group B (IQR: 27 to 91 min; p = 0.26). Despite better pre-interventional TIMI (Thrombolysis In Myocardial Infarction) flow in Group A (71% versus 35% TIMI flow grade 2 or 3; p < 0.001), the infarct size tended to be worse in Group A versus Group B (17.9% o f left ventricle IQR: 8.4% to 35.0%) versus 13.7% IQR: 7.5% to 24.0%); p = 0.10). There was also a strong trend toward more early and late microvascular obstruction, (p = 0.06 and 0.09) and no difference in ST-segment resolution (p = 0.26). The combined clinical endpoint showed a trend toward higher event rates in Group A (19.8% versus 13.6%; p = 0.13, relative risk (RR): 0.52,95% Cl: 0.23 to 1.18). Thiele et al. (2011) concluded that in STEMI patients presenting early after symptom onset with relatively long transfer times, a fibrinolytic-based facilitated PCI approach with optimal antiplatelet co­ medication does not offer a benefit over primary PCI with respect to infarct size and tissue perfusion. Early PCI when PPCI is not feasible The Southwest German Interventional Study in Acute Myocardial Infarction (SIAM-III trial) (2003) investigated potentially beneficial effects o f immediate stenting after thrombolysis as opposed to a more conservative treatment regimen. The SIAM III study was a multicenter, randomized, prospective, controlled trial in patients receiving thrombolysis in AMI (less thanl2 hours). Patients of group I were transferred within six hours after thrombolysis for coronary angiography, including stenting o f the IRA. Group II received elective coronary angiography two weeks after thrombolysis with stenting o f the IRA. A total of 197 patients were randomized, 163 patients fulfilled the secondary (angiographic) inclusion criteria (82 in group I, 81 in group II). Immediate stenting was 34 associated with a significant reduction of the combined end point after six months (ischemic events, death, reinfarction, target lesion revascularization 25.6% versus 50.6%, p = 0.001). Bohmer et al. (2003) concluded that immediate stenting after thrombolysis leads to a significant reduction of cardiac events compared with a more conservative approach including delayed stenting after two weeks. The GRACIA-1 trial (2004) was designed to reassess the benefits of an early post-thrombolysis interventional approach in the era o f stents and new antiplatelet agents. The study involved 500 patients with thrombolysed STEMI, with recombinant tissue plasminogen activator. Patients were randomly assigned to angiography and intervention if indicated within 24 hours of thrombolysis, or to an ischaemia-guided conservative approach. The primary endpoint was the combined rate of death, reinfarction, or revascularisation at 12 months. Invasive treatment included stenting of the culprit artery in 80% (199 of 248) patients, bypass surgery in six (2%), non-culprit artery stenting in three, and no intervention in 40 (16%). Pre-discharge revascularisation was needed in 51 of 252 patients in the conservative group. By comparison with patients receiving conservative treatment, by 1 year, patients in the invasive group had lower frequency of primary endpoint (23 (9%) versus 51 (21%), relative risk 0.44 (95% Cl 0.28-0.70), p=0.0008), and they tended to have reduced rate o f death or reinfarction (7% versus 12%, 0.59 (0.33-1.05), p=0.07). Index time in hospital was shorter in the invasive group, with no differences in major bleeding or vascular complications. At 30 days both groups had a similar incidence of cardiac events. In-hospital incidence of revascularisation induced by spontaneous recurrence o f ischaemia was higher in patients in the conservative group than in those in the invasive group. Fernandez-Aviles et al. (2004) concluded that in 35 patients with STEMI, early post-thrombolysis catheterization and appropriate intervention is safe and might be preferable to a conservative strategy since it reduces the need for unplanned in-hospital revascularization, and improves 1-year clinical outcomes. The CARESS-in-AMI trial (2008) involved the randomization o f patients with STEMI treated by thrombolysis and abciximab at a non-interventional hospital to immediate transfer for PCI, or to standard medical therapy with transfer for rescue angioplasty. 600 patients aged 75 years or younger with one or more high-risk features including; extensive ST-segment elevation, new-onset left bundle branch block, previous myocardial infarction, Killip classification o f greater than two, or left ventricular ejection fraction < or =35%) in various hospitals in France, Italy, and Poland were treated with half-dose reteplase, abciximab, heparin, and aspirin, and randomly assigned to immediate transfer to the nearest interventional centre for PCI, or to management in the local hospital with transfer only in case o f persistent ST-segment elevation or clinical deterioration. The primary endpoint was a composite o f death, reinfarction, or refractory ischaemia at 30 days. O f the 299 patients assigned to immediate PCI, 289 (97.0%) underwent angiography, and 255 (85.6%) received PCI. Rescue PCI was done in 91 patients (30.3%) in the standard care/rescue PCI group. The primary outcome occurred in 13 patients (4.4%) in the immediate PCI group compared with 32 (10.7%) in the standard care/rescue PCI group (hazard ratio 0.40; 95% Cl: 0.21-0.76, p=0.004). Major bleeding was seen in ten patients in the immediate group and seven in the standard care/rescue group (3.4% versus 2.3%, p=0.47). Strokes occurred in two patients in the immediate group and four in the standard care/rescue group (0.7% versus 1.3%, p=0.50). Di Mario et al. (2008) concluded that immediate transfer for PCI improves outcome in high-risk 36 patients with STEMI treated at a non-interventional centre with half-dose reteplase and abciximab. The NORDISTEMI trial (2007) was done to compare a strategy of immediate transfer for percutaneous coronary intervention (PCI) with an ischemia-guided approach after thrombolysis in patients with very long transfer distances to PCI. A total of 266 patients with acute STEMI living in rural areas with more than 90-min transfer delays to PCI were treated with tenecteplase, aspirin, enoxaparin, and clopidogrel and randomized to immediate transfer for PCI or to standard management in the local hospitals with early transfer, only if indicated for rescue or clinical deterioration. The primary endpoint was a composite of death, reinfarction, stroke, or new ischemia at 12 months. The primary endpoint was reached in 28 patients (21%) in the early invasive group compared with 36 (27%) in the conservative group (hazard ratio: 0.72,95% Cl: 0.44 to 1.18, p = 0.19). The composite of death, reinfarction, or stroke at 12 months was significantly reduced in the early invasive compared with the conservative group (6% versus 16%, hazard ratio: 0.36, 95% Cl: 0.16 to 0.81, p = 0.01). No significant differences in bleeding or infarct size were observed. Bohmer et al. (2007) thus concluded that immediate transfer for PCI did not improve the primary outcome significantly, but reduced the rate o f death, reinfarction, or stroke at 12 months in patients with STEMI, treated with thrombolysis and clopidogrel in areas with long transfer distances. The TRANSFER-AMI trial was conducted by Cantor et al. (2009) to determine the role and optimal timing of routine PCI after fibrinolysis. 1059 high-risk patients who had a myocardial infarction with ST-segment elevation and who were receiving fibrinolytic therapy at centers that did not have the capability o f performing PCI were 37 randomly assigned to either standard treatment (including rescue PCI, if required, or delayed angiography) or a strategy of immediate transfer to another hospital and PCI within six hours after fibrinolysis. All patients received aspirin, tenecteplase, and heparin or enoxaparin; and concomitant clopidogrel was recommended. The primary end point was the composite o f death, reinfarction, recurrent ischemia, new or worsening congestive heart failure, or cardiogenic shock within 30 days. Cardiac catheterization was performed in 88.7% o f the patients assigned to standard treatment a median of 32.5 hours after randomization and in 98.5% of the patients assigned to routine early PCI a median o f 2.8 hours after randomization. At 30 days, the primary end point occurred in 11.0% of the patients who were assigned to routine early PCI and in 17.2% of the patients assigned to standard treatment (relative risk with early PCI, 0.64; 95% Cl: 0.47 to 0.87; p=0.004). There were no significant differences between the groups in the incidence o f major bleeding. Among high-risk patients who had a myocardial infarction with ST-segment elevation and who were treated with fibrinolysis, transfer for PCI within six hours after fibrinolysis was associated with significantly fewer ischemic complications than was standard treatment. Thus Cantor et al. (2009) concluded that transfer for PCI among high-risk STEMI patients is most effective provided the transfer occurs within six hours of fibrinolyctic treatment. A real-world perspective Some of the above listed clinical trials have documented that use of “facilitated” percutaneous coronary intervention (PCI) in patients with ST-segment elevation myocardial infarction (STEMI) may be harmful. McKay et al. (2009) examined in­ 38 hospital outcomes in 1,553 consecutive patients with STEMI without cardiogenic shock who underwent PCI at a single tertiary center within six hours of presentation were analyzed. The study group included 767 patients who underwent primary PCI who initially presented to the tertiary center and were triaged for emergent PCI and 786 patients who underwent facilitated PCI who were pretreated at a community hospital with a glycoprotein Ilb/IIIa platelet inhibitor and/or intravenous thrombolytic therapy before transfer for catheter-based therapy. Compared with patients who underwent primary PCI, the facilitated PCI group had longer door-to-balloon times (162 +1-51 versus 113 +/-61 minutes), higher baseline infarct-vessel T IM I3 flow rates (52.8% versus 25.4%; p <0.001), and no increase in major adverse in-hospital outcomes. In patients treated with door-to-balloon times greater than 90 and less than 150 minutes, patients who underwent facilitated PCI had fewer composite major adverse clinical events (combined mortality, recurrent myocardial infarction, emergent repeated PCI, hemorrhagic and nonhemorrhagic stroke, and non-intracranial TIMI major bleeding) compared with patients who underwent primary PCI (RR 0.50, 95% Cl 0.26 to 0.96, p=0.034). McKay etl al. (2009) concluded that facilitated PCI can be safely used to increase pharmacologic reperfusion before catheter-based therapy in patients with STEMI without an increase in clinical hazard and with fewer major adverse clinical events in patients treated with doorto-balloon times greater than 90 and less than 150 minutes. Overall the evidence from the literature suggests that PCI has the potential to significantly reduce morbidity and mortality post ACS provided the access occurs in a timely fashion (Di Mario et al., 2008; McKay et al. 2009). When compared to thrombolysis, primary PCI is considered to be the more effective strategy in reducing 39 rates of re-infarction and stroke (Bohmer et al., 2003). This being said, transfer for primary PCI was seen as an effective intervention provided the transfer time was within 2 hours after thrombolytic therapy (Grines et al., 2002; Andersen et al., 2003; Nielsen et al., 2010). However thrombolysis still remains the treatment o f choice in ST-segment elevation myocardial infarction (STEMI) when primary PCI cannot be performed within 90 to 120 min (Levine et al., 2011). In some cases where primary PCI is not possible, or thrombolysis has failed, rescue or facilitated PCI is the next best option and timely access to these interventions is associated with improved patient outcomes such as lower risk of death, re-infarction, hospital re-admission rates and recurrent ER visits (Bohmer 2003; Fernandez-Aviles et al. 2004; Cantor et al., 2009). GRACE risk stratification tool There are a number of risk stratification tools used in emergency departments around the world for triaging, referring and decision-making purposes when it comes to resource allocation including the TIMI score, NERS, SYNTAX and GRACE score. The Global Registry of Acute Coronary Events (GRACE) score one of the more widely used and well-documented scores in the use of predicting both in-hospital and at discharge to six months mortality for patients who have experienced ACS. The GRACE risk stratification tool was used to determine which STEMI and NSTEMI/UA patients are at highest-risk for mortality upon admission and should be referred for and receive angiography and PCI services the fastest (Appendix F). It was used instead of the more commonly used TIMI score at UHNBC as variables for GRACE score calculation are better documented on patient files and because the GRACE risk score does not require information on the patient’s aspirin use, which can often be misreported or missing from 40 charts. The score can be calculated for all ACS patients using the following information that can be found in their respective medical records including: patient age; heart rate (HR); systolic blood pressure (SBP); creatine levels; CHF (Congestive Heart Failure Classification); cardiac arrest at admission; ST-segment deviation; elevated cardiac enzymes/markers (specifically troponin). Risk stratification of patients using the GRACE risk score The Global Registry of Acute Coronary Event (GRACE) risk score was developed in a large multinational registry to predict in-hospital mortality across the broad spectrum o f acute coronary syndromes (ACS). The GRACE risk score will be used to determine which STEMI and NSTEMI/UA patients are at highest-risk upon admission and therefore should theoretically be referred for and receive angiography and PCI the fastest. While it is one o f many risk stratification tools for ACS available in today’s market, the GRACE risk score has been accepted as a fast and valid method to assess a patient’s cardiovascular risk and can be used in complement to clinical evaluation to help guide patient care due to the simplicity in calculation (Tang et al., 2007; Fox et al., 2006). Current ACC/AHA guidelines promote the use of either TIMI or GRACE risk scores for the risk stratification of ACS patients (Wright et al., 2011). Validation of the use of GRACE to risk-stratify ACS patients The Global Registry of Acute Coronary Events (GRACE) was established in 1999 with the purpose of resolving major uncertainties into what ACS is comprised of, defining the treatment of ACS patients, and to aid in the characterizing o f outcomes for 41 ACS patients (Fox et al., 2010). The GRACE risk models have been derived and validated in large unselected cohorts of patients worldwide. These models have been tested and have shown to be valid for all forms o f ACS, including STEMI, NSTEMI and UA (Alter et al., 2006; de Araujo et al., 2005; Bradshaw et al., 2006; Gale et al., 2009; Tang et al., 2007; Yan et al., 2004; Yan et al., 2007). The use of GRACE risk models is widespread and their usefulness in providing modem day cardiac care is echoed through guidelines put forth by the European Society o f Cardiology (Bassand et al., 2007), NICE (NICE, 2010) and the ACC/AHA (Kushner et al., 2009). GRACE vs. other risk scores Overall, the literature is indicative o f the fact that GRACE risk prediction models are valid and robust predictors of both in-hospital and six month post hospital discharge mortality for all forms o f ACS. Some studies have even demonstrated GRACE as an effective risk prediction model for long-term mortality of ACS patients for up to five years (Kozieradzka et al., 2011). However further studies to validate these findings are warranted. For the purposes of the current study, in-hospital and to six month mortality prediction models are of particular interest as it is this version which has been most widely applied in clinical settings for the purposes of risk estimation for patients with ACS (Fox et al., 2006). Generally speaking, the findings from the literature demonstrate the effectiveness and appropriateness of using the GRACE risk score for risk stratification purposes of patients with unselected ACS. The GRACE risk score has been well documented in the use of predicting mortality rates for patients who have experienced ACS and can be used 42 to determine both in-hospital and six months post hospital discharge ACS mortality rates (Aragam et al. 2009; Elabrouni et al., 2009; Abu-Assi et al., 2010; Stracke et al., 2010;). It has been found to have superior prognostic capacity when compared to the Thrombolysis in Myocardial Infarction (TIMI) score (Correia et al., 2010, Elbarouni et al., 2009, Fox et al., 2006). In addition to this, GRACE risk stratification is seen as being more applicable in hospital settings as it can be used for a wider age range of patients in comparison to the TIMI risk score (Ramsay et al., 2007) and it does not require there to be documentation on a patients use o f aspirin (Fox et al., 2006). Furthermore, risk stratification using either TIMI or GRACE risk scores has been argued to be superior versus electrocardiograms and detection o f troponin markers at presentation in the prediction o f significant coronary events (Ramsay et al., 2007). Gaps in the literature There are certain limitations to consider when interpreting these results. These studies represent randomized-control trials, which occurred in conditions not always reminiscent of the real world. For example, current real world hospital transfer times vary greatly and in most cases can more than two fold of those times eluded to in these trials (Angeja et al., 2002; Nallamothu et al., 2005). After extensive searches of the literature it can be said that there have been no previous studies conducted on this particular topic from a rural northern perspective. It is therefore important to note that this work will serve as a starting point to investigate this area o f cardiac services in the region o f northern British Columbia. Furthermore, current practice guidelines for cardiac care are based on those developed by the ACC/AF1A. While these guidelines are invaluable in both clinical work and research, it is important to note that they may not always reflect the realities o f a Canadian landscape. The structure o f the American health care system coupled with the more dense and disperse American population has resulted in the existence o f more higher-level health care facilities including catherization labs than in Canada. What is possible in terms of access to services and transfer times in the United States can be at times in stark contrast to that Canada due to a number o f differences in the national context. This study will aim to explore these issues from a northern and rural perspective and provide directions for future research as well as recommendations for improvements to current cardiac care for patients presenting with ACS at UHNBC. Summary There has been much research into the importance o f rapid access to PCI, as well as the risk stratification o f ACS patients using GRACE risk scores. Despite all this research, there remains a gap in the literature when it comes to studying these topics from a rural point of view. It is a well acknowledged fact that patients living in rural settings face unique health care challenges. These challenges can be in the form o f poorer health status and health outcomes or limitations in access to health care services. Addressing the aforementioned research aims from a rural standpoint will offer a relevant perspective to the issues faced by those with acute coronary syndrome in a rural health care setting. 44 CHAPTER THREE: METHODS This chapter provides an outline of the methods employed in the study. A retrospective approach was used. A medical records chart review was conducted to obtain patient data o f interest. The use of PowerChart, a computer database for patient medical information, was used to locate any missing data points and validate the data collected from patient charts. Study Design This is a population-based study encompassing a retrospective analysis of all ACS admissions to the UHNBC emergency department was performed. Descriptive statistics on selected patient data were used to determine; patient baseline characteristics, patient residence, classification o f ACS cases, average length o f hospital stay, average length of hospital stay prior to transfer, and classification of patients given thrombolytics by diagnosis. GRACE risk scores for admission to in-hospital and admission to six months probability of death or re-infarction were also calculated. In the current study, rescue or facilitated PCI was of most interest considering that UHNBC lacks a catherization lab to perform PCI and patients requiring the procedure need to be sent to one o f the five provincial catherization labs to receive it. This study was a retrospective review of medical records o f patients presenting to UHNBC with ACS from January through to December of 2012. Medical records were obtained through the medical records department at UHNBC. A medical record can be defined as a document containing patient focused medical information (Worster et al., 2004). There are currently no universally accepted 45 standards for reporting or conducting medical record reviews (Gilbert et al., 1996). Medical records hold information for the purpose o f documenting a patient encounter with the medical system and patient data are typically not collected for research purposes. In fact medical records have certain important limitations when it comes to using them as data collection including; data not being recorded for research purposes, and the possibility o f having missing or incomplete information. Despite these shortcomings medical record review studies are an appropriate method for many situations and can be used for pilot studies, to inform prospective clinical trials, to determine disease patterns throughout extended periods o f time and to investigate questions difficult to answer in prospective trials (Gilbert et al., 1996; Lemer et al., 2002; Worster et al., 2004). Today medical record review studies comprise over 25% of all scientific studies published in peer reviewed emergency medical journals and are used for data collection in 53% o f emergency medical services studies (Worster & Haines, 2004). While there are limitations to using medical records for research purposes the importance and value of medical record reviews in emergency medical research cannot be underestimated. They provide a valuable and rich source o f patient derived medical information which often cannot be found in other environments or captured through typical methods o f data collection in research such as surveys or patient based reporting (Dunn et al., 2006). Furthermore, the information is documented by professionals in the medical field, making the data less prone to patient recall and reporting bias (Worster & Haines, 2004). 46 Study Population The study population consisted o f patients who presented to UHNBC with ACS during January 2012 through to December 2012. A total o f 265 cases were identified. These cases represented 249 people as 16 patients presented to the emergency department more than once throughout the calendar year. Community Profile A community profile for Prince George was extracted from the 2011 census data and the community health information portal through Northern Health (Statistics Canada, 2012; Northern Health Community Health Information Portal, 2013). The profile o f this community is discussed based on demographic characteristics, health status and health facilities in this community. The population for the city o f Prince George was found to be approximately 84,232. The mean age of the population was 39.0 years. The annual number o f births for women of childbearing age was 1,045. The annual death rate was 574. The average life expectancy was 79.3 years, lower than the provincial average of 82 years. Data source and extrapolation Medical records were obtained through the medical records department at UHNBC. A request for access to records was put in to the department requesting access to the records o f those patients presenting to the emergency department of UHNBC with ACS from January 2012 through to December 2012. The patient charts were pulled by the medical records department staff. 47 Patient data was initially entered into an extraction sheet in an Excel workbook by the month of presentation to the emergency department. All variables, including demographic and lab-based values were determined from the patient visit to the emergency department for ACS. For example, there was no looking through past records of patient encounters to determine any variables whether missing or otherwise. This information was located though the initial admission paperwork, ambulance summary, hospital discharge form, hospital transfer summary, cardiac catherization lab referral form, physician notes, nurses notes, PharmaNet medication history, and lab reports. Patients were given a unique identifier different from their personal health number to protect their identity. The variables extracted from the chart included: date and time of admission, area o f residence, mode of arrival, triage code, sex, age, height, weight, heart rate (bpm), blood pressure, creatine, glomerular filtration rate (gif), CHF Killip classification, whether there was a cardiac arrest at admission, whether there was ST-segment elevation, whether there was elevation of cardiac enzymes, whether the patients received thrombolysis, diagnosis, date and time of discharge (whether for transfer or otherwise), facility transfer or discharged to, procedure and previous cardiac history including the presence of risk factors for cardiovascular disease. From these variables there were a number o f data points calculated including: total length of hospital stay regardless of discharge status was calculated, patient body mass index using the documented height and weight of patients who had these data points in their charts and GRACE risk scores. 48 Data collection and criterion Data were collected for patients for the calendar year o f 2012. The rationale for choosing a one year time period from January 2012 to December 2012, was that this reflected the most current and available data as well as provided a longer-term picture of the situation compared to a shorter time period. This was done to minimize the effect of confounding variables that may delay the patient transfer process. Such confounding variables may include: differences in seasonal patterns, and health care service levels. Data were collected through review of medical charts. Any missing data points of interest were located through PowerChart. A total of 344 cases were identified and of these 344 cases, 265 were found to fit the inclusion/exclusion criteria. Patients were included in the dataset if they presented to the UHNBC ED with ACS and were found to have true ACS (UA, NSTEMI or STEMI). They were included: • regardless of their hometown/origin • each time they presented to the UHNBC ED in the year (i.e one time in May of 2012, another in July 2012 and so forth) • if they presented directly to the UHNBC ED without being at another NHA facility • if they were transferred from another NHA facility to UHNBC and the referral for the catherization lab was made at UHNBC • if they were found to have a late-presenting STEMI regardless o f whether they required transfer to the catherization lab 49 Patients were excluded from the dataset if any of the following was true: • patient was admitted in 2011 but was transferred in 2012 (i.e admitted in Dec of 2011 and transferred in Jan 2012) • patient was admitted in 2012 but was transferred in 2013 (i.e admitted in Dec of 2012 and transferred in Jan 2013) • patient presented to the UHNBC ED as an inpatient (inpatient transfers are not captured in the same way as outpatient as vitals and stats are not taken upon presentation) • patients coming to UHNBC from another NHA facility for further evaluation (referral for PCI has already been made and tracking would be done at the respective hospital of origin) • patients coming to UHNBC awaiting transfer to the catherization lab (referral for PCI has already been made and tracking would be done at the respective hospital of origin) • patient presented to ED and was coded as ACS initially but was found to not be true ACS (i.e had elevated blood pressure, exacerbation of COPD) • patient presented to ED with ACS complaint but left against medical advice (AMA) before investigations were completed Measures and analytic procedures Once it was determined that the data collection in the Excel workbook was complete, data were coded for use in IBM SPSS version 21.0. Dichotomous variables for cardiac enzyme elevation, for example, were coded as one for yes and two for no. Males 50 were coded as a one and females as a two. All nominal variables such as age or heart rate were coded as exact values. Baseline characteristics for the study population were determined. They included; age, gender, height, weight, area of residence, and risk factors as documented in their respective medical records (smoking history/status, family history o f CVD, hypertension, diabetes, dyslipidemia, obesity, age, and prior cardiovascular history). Body Mass Indexes (BMIs) for patients were also calculated for those with both height and weight documented in their charts (Table 1.). Study patients were divided into three groups according to the diagnostic and referral methods. Group 1 comprised o f patients presenting with UA. Group 2 consisted o f patients presenting with either NSTEMI. Group 3 consisted o f patients presenting with STEMI. Baseline characteristics were determined through descriptive statistics. Analysis through crosstabs and one-way analysis of variance (ANOVAs) were conducted to determine time to PCI differences between patients presenting with STEMI compared to those with NSTEMI or UA. Data analysis was conducted using multivariate logistical regression through IBM SPSS version 21.0. Risk stratification was performed through the use of the GRACE web-based calculation tool available through the GRACE website at, http://www.outcomesumassmed.org/grace/acs risk/acs risk content.html. Patient data entered included; patient age, heart rate (bpm), systolic blood pressure (mmHg), creatine (umol/L), CHF Killip class as per Parakh et al., 2008 (Table 1.), and whether or not the patient had a cardiac arrest at admission, ST-segment deviation (as per ECG results), and the presence o f elevated cardiac enzymes/markers (as per the pathology report) (Table 2.). Risk scores were determined and a breakdown of probability o f mortality for both admission to in­ 51 hospital and admission to six months for STEMI and NSTEMI/ UA is provided below (Table 3. and Table 4.). Table 1. Body Mass Index Classification Classification Principal Cutoff Points Underweight <18.5 Normal 18.5-24.99 Overweight 25.0-29.99 Obese >30.0 Class I 30.0-34.99 Class II 35.0-39.99 Class III >40.0 (Source: Health Canada. Canadian Guidelines for Body Weight Classification in Adults. Ottawa: Minister of Public Works and Government Services Canada; 2003.) 52 Table 2. Killip Classification fo r GRACE Killip Class Clinical Features I No evidence o f CHF II Crackles in <50% o f lung fields or third heart sound or SBP >90mmHg III Pulmonary oedema and SBP >90mmHg IV Cardiogenic shock with crackles, SBP, <90mmHg and evidence of tissue hypoperfusion CHF; congestive heart failure SBP; systolic blood pressure Table 3. Troponin Elevation Criteria fo r GRACE Value Result <14 Normal 14-50 Borderline >50 Positive >50% from baseline Significant *Note: these criteria are based on the high-sensitivity troponin scale 53 Table 4. GRACE risk categories fo r UAfNSTEMl Risk Category Grace risk score (tertile) In-hospital Grace risk score mortality (%) To 6 month mortality (%) Low <108 <1 <88 <3 Intermediate 109-140 1-3 89-118 3-8 High <140 >3 >118 >8 *Note: scores can range from 2-372 (Abu-Assi et al. 2010 and European Society o f Cardiology, 2012) Table 5. GRACE risk categories fo r STEMI Risk Category Grace risk score (tertile) In-hospital Grace risk score To 6 month mortality (%) mortality (%) Low <25 <1 27-99 <3 Intermediate 126-154 1-3 100-127 3-8 High <155 >3 >128 >8 *Note: scores can range from 2-372 (Abu-Assi et al. 2010 and European Society of Cardiology, 2012) 54 Ethical considerations and confidentiality The study design and procedures for this study were submitted and were approved by both the University o f Northern British Columbia Research Ethics Board (UNBC REB) and the Northern Health Research Ethics Board (NH REB) in May o f 2013. Certificates of ethical approval from both research ethics boards can be found in the appendices (Appendix I. and Appendix J.). Confidentiality of the patient data was strictly maintained throughout all phases of the study. Patients were given a unique identifying number unrelated to their Personal Health Number (PHN) or Northern Health Encounter Number (NH ENC #) to avoid the possibility of patient tracking. All electronic data files were password protected and stored on a password-protected computer and the data collected from patient records did not contain any identifiable information. The electronic files were further placed in a folder that required a username and password for login purposes that only the author of this thesis had access to. It was also ensured that the final deliverable, the thesis, did not include any patient identifiable information. 55 CHAPTER FOUR: RESULTS This chapter presents the results from the data analyzed for this thesis. A descriptive analysis of patient baseline characteristics is provided. Second, statistical differences using crosstabs and one-way ANOVAs between patient area o f residence, classification of cases by diagnosis, and length o f hospital stay are presented. This is followed by statistical analyses using multiple linear regression o f whether longer time to PCI was associated with adverse patient outcomes (death, stroke, reinfarction) and whether patient time to PCI treatment was correlated with GRACE risk status. Preliminary data analysis Preliminary data analyses identified a total of 344 cases. Those not fitting the inclusion criteria such as being diagnosed as not having true ACS (i.e. chronic obstructive pulmonary disease exacerbation or elevated blood pressure) or being inpatients were eliminated. A total of 265 patient cases were identified after the data were cleaned and coded. O f these patients 65.6% (n=174) were male, and 34.4% (n=91) were female. Ages for the patients ranged from 33 years to 94 years old with the average patient age o f 64.1 years. The length o f stay prior to transfer for the catherization lab ranged from 1 day to 47 days with the average length of stay being 4.9 days across all diagnostic categories. 56 Table 5. Patient Baseline Characteristics UA NSTEMI STEMI (n=87) (n=113) (n-65) Median Age (years) 64.0 65.4 61.9 Male (%) 58.6 82.3 80.0 Age (Males 45+, Females 55+) 90.8 90.3 89.2 0.949 Family History 30.0 31.9 29.2 0.381 Smoking 33.3 42.5 52.3 Diabetes mellitus 27.6 29.2 21.5 Hypertension 65.5 65.5 46.2 Dyslipidemia 51.7 48.7 36.9 Obesity 40.6 32.7 16.1 48.3 46.0 38.5 MI 20.7 12.4 16.9 CHF 3.5 6.2 6.2 PCI 19.5 19.5 16.9 CABG 18.4 8.9 4.4 Stroke/TIA 3.5 8.9 4.6 AF 2.3 8.0 3.1 PVD 15.0 11.5 4.4 Risk Factors Prior Cardiovascular History *Note: For obesity UA n=32, NSTEMI n=49 and STEMU n=31 MI, myocardial infarction; CHF, congestive heart failure; PCI, percutaneous coronary intervention; CABG, coronary artery bypass graft; AF, atrial fibrillation; PVD, peripheral vascular disease 57 25 i Underweight n=l Normal n=26 Overweight n=52 BMI Class Obese n=33 Figure 4. Classification of patients by body mass index (BMI) Patients with documented height and weight data in their medical charts (n=l 12) were classified according to their BMI. It was found that 0.4% o f patients (n=l) were underweight (BMI <18.5), 9.8% o f patients (n=26) were within normal range (BMI 18.5- 24.9), 19.6% of patients (n=52) were overweight (BMI 25.0-29.9) and 12.5% of patients (n=33) were obese (BMI > 30.0). Class 2 n=8 Class of obesity Figure 5. Classification of obese patients Patients were classified into classes o f obesity if their BMI was >30.0. There was a total of (n=33) 12.5% of patients which were found to be obese (BMI > 30.0). O f the 12.5%, 7.2% of patients (n=19) were classified as class I obese (BMI 30.0-34.9), 3.0% o f patients (n=8) were classified as class II obese (BMI 35.0-39.9) and 2.3% of patients (n=6) were classified as class III obese (BMI > 40.0). 59 90 81.5 80 70 60 ~5A5 0 I 40 « 0k 30 18.5 20 10 0 Prince George n=21 Other n=49 Area of Residence Figure 6. Classification of patients by area of residence Patients (n=265) were classified according to area of residence. O f the 265 patients 81.5% (n=216) were Prince George residents. O f the remaining 18.5% of patients (n=49) 57.1% o f these patients (n=28) were transferred from other hospitals within the Northern Health Authority including; Kitimat, Fort St. James, Fort St. John, Valemount, Vanderhoof, Bums Lake, Quesnel, Fort Fraser, Mackenzie and Dunster. The remaining 42.9% of patients (n—21) were in Prince George visiting or for work-related purposes from cities including: Surrey, Edmonton, Bumaby, Kelowna, and Hixon. 60 UA n=87 NSTEMI n=l 13 Diagnosis STEMI n=65 Figure 7. Classification o f Patient Cases Classification of patient cases by diagnosis is presented. The most common category of ACS was NSTEMI representing 42.6% o f the total ACS cases (n=l 13). Unstable angina cases came in second with 32.8% of patients (n=87) and STEMI cases comprised the remaining 24.8% of patient cases (n=65). 61 70 60 50 C 40 cs *30 24.4 On 20 14.6 10 0 NSTEMI n=10 Diagnosis STEMI n=25 Figure 8. Classification of Patients given thrombolytics by diagnosis A total of 15.5% of patients (n=41) across all diagnostic categories were administered thrombolytic therapy. O f these 15.5%, 14.6% of patients (n=6) were diagnosed as UA, 24.4 % of patients (n=10) were NSTEMI and 61% of patients (n=25) were STEMI. 62 60 i Facility Figure 9. Patient Discharge Status from UHNBC Roughly 50% (n=124) o f patients presenting to UHNBC with ACS were transferred to St. Paul’s Hospital (SPH). Over a quarter o f patients (n=70) were sent to Vancouver General Hospital (VGH). 14% of patients (n=37) were deemed unsuitable candidates for PCI and were either sent home or to an extended care facility. There were 3.4% (n=9) of patients presenting to UHNBC with ACS that died from the condition, o f which 22.2% (n=2) died while waiting for transfer to the cardiac catherization lab. 63 6.19 « 6 3 >> 5 5w *S 4 3.52 J3 Eo3 fi J JU «CO 2 « 1 ' UA n=87 NSTEMI n=113 STEMI n=65 Diagnosis Figure 10. Average length of hospital stay according to diagnosis The length of hospital stay among all patients with ACS regardless of transfer to a catherization lab was found to be the highest among patients with NSTEMI at an average o f 6.19 days. Unstable angina came in second with an average o f 5.2 days while STEMI patients remained in hospital for an average o f 3.52 days. The two STEMI patients that died from cardiac events while awaiting transfer waited 14-48 hours before death. 64 5.57 5.24 v> ea 3 i 4 3.24 o 53 OH ao V1 OH L « u ^ 1 UA n=68 NSTEMI n=94 Diagnosis STEMI n=56 Figure 11. Average length o f hospital stay prior to transfer according to diagnosis The average length of stay prior to transfer to the catherization lab was 4.91 days. It found to be the highest among patients with unstable angina at an average o f 5.57 days. NSTEMI came in second with an average of 5.24 days while STEMI patients waited an average of 3.54 days prior to transfer. 65 180 -i 155.41 160 133.61 140 - 136.29 124.29 ■ Admission to In Hospital | 120 3.02 102.59 1 100 ‘ g ■ Admission to 6 months 80 - 2 3 60 40 20 - 0 NSTEMI n=113 Diagnosis STEMI n=63 Figure 12. GRACE risk score by diagnosis The GRACE risk score for both admission to in-hospital and admission to six months was the lowest among patients with unstable angina at an average score o f 103.02 and 102.59 respectively. NSTEMI cases had an average GRACE risk score of admission to in-hospital score of 133.61 and an admission to six months score of 124.26. STEMI cases had the highest GRACE risk score of 155.41 and 136.29 for in admission to in-hospital and admission to six months respectively. The largest decrease in risk status from admission to in-hospital to admission to six months was seen among patients with STEMI and the smallest decrease was among those with UA. 66 Adverse outcomes for patients were determined at 30 days and one year of admission. The primary clinical endpoint was a combined measure o f death, re-infarction, heart-failure, or stroke. It was found that a total o f 6.04% of patients (n=16) suffered from adverse outcomes within 30-days o f hospital admission for ACS. O f these patients 37.5% (n=6) belonged to the UA group, 25% (n=4) to the NSTEMI group and the remaining 37.5% o f patients (n=6) were STEMI patients. At the one-year mark, 12.1% o f patients were found to have suffered adverse outcomes. O f these patients 50% (n=16) were from the UA group, and 25% each (n=8) were NSTEMI and (n=8) were STEMI patients. Due to the number of patients suffering from adverse outcomes being less than 50 as required for the statistical significance for the software, IBM SPSS v. 21.0, multiple logistical linear regression analyses for this objective was not possible, however a scatterplot was created to display this data (Figure 13.). 67 Count Count 10.0 20.0 30.0 40.0 S0.0 Figure 13. Adverse outcomes for 30-day (circles) and 1-year (line) post-ACS admission as per length o f hospital stay (x-axis) 68 Table 6. Multiple linear logistical regression analysis of predictors for time to PCI Non-standardized Standardized Coeffiecients Coefficients t Sig. -.790 .432 Model Beta B Std. Error Constant -4.947 6.261 GRACE .044 .045 .546 .977 .331 -.047 .065 -.438 -.724 .471 .157 .077 .347 2.056 .043 -1.531 1.089 -.152 -1.405 .164 .093 .106 .095 .876 .384 1.560 1.117 .160 1.396 .166 -1.031 1.330 -.091 -.775 .440 InHosp GRACE6mos Age Sex BMI Htn Diabetes a. Dependent Variable: PCI b. Predictors: (Constant), Diabetes, Gender, BMI, Age, Hypertension, GRACEInHosp, GRACE6mos 69 Multiple logistical linear regression analysis was used to test if the patients were transferred for and received PCI according to their GRACE risk score o f combined probability of death or reinfarction both from admission to course in hospital and from admission to 6 months. The results of the multiple linear regression indicated that patient age was the only significant predictor of time to PCI. Age explained 5.7 % o f the variance in the outcome of time to PCI (R2=0.131, F(1.772), p <0.43). The other predictors including: diabetes mellitus, gender, BMI, hypertension and GRACE risk score (both admission to in-hospital and admission to six months) were found to be insignificant predictors o f when patients received their PCI treatment. 70 CHAPTER FIVE: DISCUSSION & CONCLUSION The primary objective of the present study was to examine the issue of access to percutaneous coronary intervention (PCI) among patients presenting to the emergency department at the University Hospital in Northern British Columbia in Prince George. Specifically, this study aimed to determine whether the time delay to PCI was associated with more adverse outcomes, namely stroke, death or re-infarction at 30 days and whether the sickest patients, as risk stratified using the GRACE risk score, received care in the least amount of time. The following chapter will interpret the results of the aforementioned research objectives and will discuss strengths and limitations o f the study. Implications for future research, policy and practice will be presented in some detail. Finally, recommendations arising from the findings o f this study will be made alongside concluding remarks. Hypothesis 1: Longer times to treatment for PCI are associated with higher rates of adverse outcomes including stroke, death and re-infarction. The first objective of this study was to explore associations among longer times to PCI treatment and adverse patient health outcomes, including a) stroke, b) death and/or c) re-infarction. Due to statistical software limitations, the sample size for adverse outcomes was insufficient, as was required for SPSS to run multiple linear regression analysis, therefore it was not possible to determine this association quantitatively. However, times to PCI and occurrences o f stroke, death or re-infarction were calculated. 71 The average time to PCI across all diagnostic categories was determined to be 5.9 days. The average time to PCI for each type o f ACS was 6.5, 6.2 and 3.8 days for UA, NSTEMI and STEMI respectively. The shortest length of stay prior to transfer was among the highest-acuity patients with STEMI, however the GRACE scores did not necessarily reflect this as the only significant predictor of patient transfer was age. A plausible explanation to this could be that length o f stay was presented as an average thus may not accurately reflect the range o f days STEMI patients waited for transfer. Furthermore, transfer may be strictly based on symptoms, diagnostic findings and clinical evaluation which depending on time o f patient presentation may not accurately reflect patient risk status. Furthermore, these results reveal an important discrepancy between the current best-practice guidelines and patients in a real-world setting. As previously mentioned in the first chapter, ACC/AHA guidelines recommend PPCI with 90 minutes and rescue or facilitated PCI within 120 minutes. The average times for PCI patients are clearly not meeting these guidelines primarily due to large distance required for transport o f patients for care. Furthermore, the Canadian Cardiovascular Society (CCS) position statement on benchmarks as outlined in the first chapter for access to treatment state that diagnostic catherization and PCI for inpatients should be conducted within five days (Canadian Cardiovascular Society, 2011). Upon examination of the current times to treatment, it is evident that there is clear need for further improvements to reducing this delay in the population studied. Additionally, it is worth noting that two STEMI patients died from cardiac events while awaiting transfer to the cardiac catherization lab. 72 While there were no documented reasons for this delay in patient charts, there are several plausible explanations for this delay as it may result in part in relation to the long­ distance transport required for access to the procedure (Sorenson et al., 2010). First, there are many organizational factors including delayed triage, and evaluation and diagnosis, which can delay a patient’s transfer such as understaffed emergency departments. In addition, patients presenting to rural hospitals may be cared for by physicians other than cardiologists, thus may not receive the latest evidence-based care (Pesut et al., 2013). To the same effect, patients may present with symptoms not typical o f ACS that would require further diagnostics tests to reach a concrete diagnosis which can delay treatment. Second, the receiving hospital with catherization lab capability may also have organizational factors contributing to delay. These include: lack of available beds, their own patient populations within catchment areas, patient transfers from other community hospitals and operational restrictions of a Monday to Friday eight hour time-frame. Third, for patients requiring PCI in the winter months, the harsh northern winter climate can make for unsafe travelling conditions. In such circumstances, there is little that can be done to make conditions more favorable. Fourth, a patient may have one or more comorbid conditions, which can make them less than desirable for immediate transfer thus increasing times to treatment. Fifth, BC Air Ambulance is operational on a 8am-8pm basis which restricts the time frame of patient transfer (BC Ambulance Service, 2013). Furthermore, this may be complicated by a number o f other factors external to the health care environment. For example, there may be presentation delay by patients post­ symptom onset while other patients may be adamant that they wish to receive care at a 73 specific centre based on their prior experience either personally or otherwise (Henry et al., 2014). A recent study by Nallamothu et al. (2006) found that patients with comorbidities, absence o f chest pain, delayed presentation after initial symptom onset, less specific ECG findings or presentation to hospital during off-hours were found to have longer times to treatment. Additional studies have found that patients presenting to rural teaching hospitals also waited longer than those in urban teaching and non-teaching hospitals as well as rural non-teaching hospitals (Aguirre et al., 2008; Sorensen et al., 2011). The increased wait times may be due in part to the effects of working environments seen in rural, often understaffed and resource limited, hospitals that can affect workload and can be further exacerbated due to the additional demands of instruction. Some studies have examined ways to reduce this delay. While the focus of these strategies has been examined at facilities with PCI capabilities a small number of recommendations can also apply to transfer hospitals. Rezaee et al. (2010) found that initiating pre-hospital care including pre-hospital ECGs and pre-cardiac catherization lab activation by EMS led to an average of a 24-minute reduction. A study by Bradley et al. (2006) examined effective strategies to reduce delays in time to treatment for PCI. These strategies included having emergency medicine physicians activate the catheterization laboratory, having a single call to a central page operator activate the laboratory, having the emergency department activate the catheterization laboratory while the patient is en route to the hospital, expecting staff to arrive in the catheterization laboratory within 20 minutes after being paged, having an attending cardiologist always on site, and having 74 staff in the emergency department and the catheterization laboratory use real-time data feedback. Adverse outcomes, namely a combined clinical endpoint resulting in death, re­ infarction, heart failure or stroke, were 7.3% and 14.6% at 30-days and 1-year post­ discharge respectively. Some studies have found that increased times to treatment have little effect on mortality (Brodie et al., 2001) while others have found that increased time to treatment not only increases mortality but infarct size as well (Angeja, 2002; Cannon et al., 2000). Therefore the results mortality due to delayed PCI remain inconclusive however best practice guidelines still stress that PCI should be carried out in a timely fashion. Timely care has been shown to improve overall patient outcomes including morbidity, stroke risk and re-infarction (Antman et al., 2008; Van de et al., 2008; Boersma et al., 2006; Ross et al., 2006; Keeley et al., 2003; Nallamothu et al., 2003). This is of relevance to the current study as results reveal UHNBC is not meeting provincial benchmarks therefore there is an urgent need to reduce this delay to treatment to avoid potential negative impacts on patient health. Hypothesis 2: Patients are not transferred according to their risk status. The second objective of this research was to explore the association between order of patient transfer and patient risk status. Patient time to PCI was not found to be associated with patient risk status. The only significant predictor o f time to treatment is patient age. This finding was consistent with the literature as there has been repeated calls for there to be a formalized system to directly triage patients to cardiac catherization centres in order to reduce this time to treatment (Patel et al., 2010; Grines et al., 2002). 75 Current practice in Canada remains that patients requiring PCI are transferred on a ‘next suitable’ spot basis (Patel et al., 2010). Moreover, a risk-averse strategy seems to be in place when patient priority for transfer is assigned. There are several plausible explanations for this current practice. First, the patient is required to be clinically stabilized before he or she is deemed safe for transfer via air ambulance. This stabilization may or may not correspond with the risk status o f a patient. Additionally while this high-risk unstable patient is being stabilized, an opening at the receiving center may become available thus an already stable, yet lower-risk patient may be transferred first. Second, the current transfer of patients is based largely on ECG findings and clinical evaluation. Third, there tends to be a clinician bias as documented in the literature concerning the hesitation of clinicians to transfer overweight or obese patients due to risk o f bleeding or other post-operative complications. This however is not always a correct assumption as several studies on the ‘obesity paradox’ have demonstrated that overweight or obese patients tend to have a lower incidence of post­ operative complications when compared to their lean counterparts (Hastie et al., 2010; Lancefield et al., 2010; Diercks et al., 2006; Gruberg et al., 2002). Furthermore high BMI has been found to be an insignificant predictor of short and long-term mortality, demonstrated by an inverse relationship between high BMI and patient mortality (Schenkeveld et al., 2012). Regardless of these considerations the GRACE risk score provides a valid alternative to aid in the risk stratification o f patients. It is a readily available tool on mobile devices and can become part o f a clinician’s bedside tool kit to inform the triage and transfer processes (Stracke et al., 2010; Fox et al., 2006). Furthermore it is important 76 to note that while there is a perception that current practice involves the use o f the TIMI risk score at UHNBC to risk stratify patients with ACS, there was little evidence o f its use in patient charts reviewed for this study and use of it was sporadic at best. A potential barrier to this could be that the score requires there to be documentation o f patient aspirin use for risk calculation (Yan et al., 2004). This information may or may not be documented in patient medication history and sometimes may be patient reported. In contrast, the GRACE risk score uses pre-collected basic clinical information which can be located in patient charts and does not require any information o f patient drug use yet provides an equally if not superior risk prediction model (Fox et al., 2006; Ramsay et al., 2007) with a higher degree o f discrimination and predictive accuracy (Correira et al., 2010; Elabarouni et al., 2009; Fox et al., 2006). Secondary findings The examination of demographics and cardiovascular history of the study population led to some important findings. First, the majority of patients presenting to UHNBC with ACS were from Prince George, however there were also patients from smaller community hospitals transferred to UHNBC for care. This finding speaks to the importance of having a regional hospital that is able to provide this level of care not available in the surrounding and more rural community hospitals. The literature also highlights the importance o f thrombolytic therapy in the absence of PPCI availability for patients with STEMI (Mckay et al., 2009; Nallamothu et al., 2003; Zijlstra et al., 2003). In this study, less than quarter of all patients received thrombolytic therapy, while 38.4% were patients with STEMI. A possible explanation to 77 this may be that since thrombolytic therapy is not recommended in high-risk patients, this patient population represents a high-risk group. However, the fact that not all STEMI patients (excluding high-risk, contra-indicated patients) received thrombolysis requires further investigation. Furthermore, thrombolytic therapy was administered to patients with all types of ACS, albeit less frequently then STEMI. This practice, for which there were no documented reasons in patient charts, is in contradiction to the ACC/AHA guidelines which state that there is no benefit from thrombolysis for patients with NSTEMI or UA (Levine et al., 2011). STEMI patients on average were two to three years younger than those with NSTEMI or UA. Furthermore, males were over-represented in each ACS category comprising over half of the patient population. Major risk factors were present in more than half o f the patients and included age, hypertension, dyslipidemia. Other significant risk factors included obesity and prior cardiovascular history. As mentioned in the first chapter, a report by Cardiac Services BC (2011) highlights the presence of traditional risk factors in the northern population. This is also echoed in recent statistics published by Statistics Canada (2012). Traditional risk factors including obesity, diabetes, hypertension, smoking, physical inactivity and dyslipidemia are highly prevalent in northern residing populations. Furthermore, provincial prevalence of cardiovascular disease has remained stable over the last decade, but the NHA is the only health authority to see an increase during this time along with the higher than average provincial mortality rates (Cardiac Services BC, 2011). 78 Study strengths and limitations Research involving patient sensitive data and outcome analysis based on the current practices can be a challenging undertaking. The success o f this research can depend on the acceptance and participation of organizations and professional groups who may be at varying levels o f readiness to explore this area of investigation. Therefore this study strived to be collaborative in nature and sought input from academics, clinicians, organizations and other relevant stakeholders. In addition to this, this study examined patients for a one-year duration. This allowed for a complete analysis of access to PCI for northern patients and accounted for any variability in access times influenced any uncontrollable factors. Factors such as adverse weather conditions affecting transport to the hospitals with catherization centres, or a larger-scale emergency such as a workplace accident or other disaster which can use resources and may take precedence over the immediate transfer of ACS patients. Thirdly this study was the first of its kind to explore this issue for northern patients. It focused on exploring access for rural-dwelling patients, addressing a very important knowledge gap in the research domain as the majority o f literature centered around large urban settings. It focused on the issue of access in both a unique geographical setting as well as on a distinct rural population. There are certain limitations to keep in mind when considering this study. First, this study was limited to patients presenting to UHNBC and therefore may not be fully representative of the smaller, more remote community hospitals in northern BC. Second, the study population was limited to patients presenting directly to the emergency 79 department at UHNBC. This excluded patients who experienced ACS as inpatients as well as patients transferred from smaller community hospitals who had already had their cardiac catherization lab referral process initiated prior to transfer to UHNBC. Third, data was collected from medical records, which typically do not contain data collected for research purposes so there is a possibility of some variation or inaccuracies in the dataset. Key findings and contributions To our knowledge, this study is the first of its kind to be conducted in northern BC on this topic. It uses an exploratory approach to respond to an important and pressing health care issue. It offers insights that cannot be provided through the experience of large-scale randomized control trials that are centered in larger urban centres as the generalizability of these studies is limited in rural settings. It aimed to address this knowledge gap and to identify this population, their risk status and their access to PCI services. Keeping in line with this, a strong effort will be made to disseminate the findings from this study using a knowledge translation (KT) strategy. The KT plan includes: a briefing summary to Northern Health, a webinar, conference presentations and manuscript publications. This will ensure that the results are made available to key decision makers, stakeholders and health care practitioners. Recommendations There are certain recommendations that can be made from the results o f this study. This study was focused on ACS patients presenting to one centre within the Northern Health Authority region. Therefore, a larger scale study covering the entire 80 Northern Health Authority region can be warranted. This would provide a complete picture of access to cardiac services in all o f the north. It would enable a look into access to PCI for all northern patients and provide information concerning risk status, length of patient hospital stay among other factors. It would be beneficial to compare these trends among different areas o f the north to see differences and similarities within the northern context. Furthermore, a larger scale study would allow for meaningful logistical regression analysis to study the relationship between adverse outcomes and length o f stay prior to transfer for PCI. Second, a look into all factors which can influence wait times for PCI is valid. Factors such as the process for transferring patients via BC Air Ambulance, the respective catherization labs procedures and their respective processes, and the referral process for each of the catherization labs. This would allow for the determination of possible areas of improvement as well as the identification o f a standardized process of ‘best practices’ for transfer patients. Alongside this a look into the feasibility o f a dedicated network for patient transfer to reduce transport related delay is also warranted. Third, an exploration of developing a formal triage process for all ACS patients should be explored. This process should be standardized across all provincial cardiac catherization labs to ensure equitable access to treatment. Furthermore, in hospitals without cardiac catherization labs the development o f a provincial patient priority system could potentially ensure that the sickest and highest risk patients would receive their care the fastest. Fourth, it is worthwhile to examine the aspect of having a regional catherization 81 lab in Prince George. There are two reasons to this. Patients receiving PCI typically receive same day discharge from the hospital after their procedure. Therefore having a regional catherization lab for the north could potentially reduce length o f stay for patients resulting in a cost savings for the health authority related to the number of ‘bed days’ used for patients awaiting transfer as well as the cost of an air-ambulance transfer. According to the Canadian Centre for Policy Alternatives (2012) the average cost of treating a patient in hospital ranges from $825-$ 1968 per day and can vary depending on the patient’s individual circumstances including diagnosis, level o f acuity and comorbid conditions. The cost o f an air ambulance for transfer o f patients at UHNBC is as follows. Due to UHNBC not having a rooftop helipad, patients are transferred to the Prince George International Airport, using a ground air ambulance at cost o f $530 per patient (BC Ambulance Service, 2013). From the airport, air ambulance transfer of patients is costed at $2746 per hour o f travel. Furthermore, obese patients may require the use o f a bariatric plane which costs $7 per statue mile (BC Ambulance Service, 2013). Additionally a cardiac catherization lab would be able to perform procedures other than PCI, such as CABG which can result better long-term patient outcomes for certain patients such as those with complex lesions (Mohr et al., 2013). This would not only improve patient outcomes but would enable the triage of patients for medical treatment versus cardiac intervention (PCI or CABG) saving angiography times in the larger centres and resulting in lower costs to the overall health care system. Given the results of this study, a large majority of the patients are high risk with multiple co-morbidities or are elderly which can result in an even larger expenditure related to cost of hospital stay. As well the bed utilization for patients awaiting transfer 82 may also impact services for other patients. According to the BC Medical Association (2008), this can result in the cancellation o f scheduled procedures for other patients. Furthermore, UHNBC does not have a critical care unit (CCU) and high-risk cardiac patients such as those requiring telemetry beds are placed in the intensive care unit (ICU) which can potentially limit the number of beds and consequently level o f care required for non-cardiac but acutely ill patients requiring ICU care. As well, there are also out-of pocket costs for patients associated with travelling for care. For example, the Medical Services Plan (MSP) does not cover travel costs associated with patient travel from the cardiac catherization centre back to Prince George unless the patient is medically unfit and requires repatriation to UHNBC (BC Ambulance Service, 2013). Furthermore, having a catherization lab in Prince George could reduce costs associated with other northern patients. It would potentially save the smaller community hospitals from having to keep their patients in hospital prior to transfer. It may also reduce the burden o f cost associated with patient transfer through BC Ambulance due to shorter travel distances from northern communities to Prince George as compared to the Lower Mainland. This is consistent with research done by Le May et al. (2003) who discovered that in Canadian centers in which facilities and experienced interventionists are available, primary stenting (n=62) was less costly and more effective than thrombolysis (n=61). However this requires the consideration of a number of complex financial and health care service factors given the current context. A detailed analysis o f the literature alongside an examination of the practicality and feasibility o f such a facility is warranted as there is considerable debate concerning the creation o f stand-alone PCI centres. 83 Concerns include the sustainability of the system in terms of staffing levels as they require continuous and/or on-call staffing, infrastructure and patient volumes. This is particularly relevant in rural communities where the recruitment and retention o f health care professionals can be challenging at best. Finally, an examination into patient experiences associated with treatment delay may also provide valuable insight into this issue. This would include an examination of factors associated with patient delays to seeking treatment as well as an exploration of the patient journey in the process including emotional, physical, psychological and financial constraints. The findings from this work could help to inform future initiatives and planning to improve current practices and procedures. Implications for research The findings from this study present several areas for future investigation. To build on the findings from this exploratory study, a longitudinal study encompassing all hospitals within the boundaries of the Northern Health Authority could examine transfer times, and patient health outcomes. In addition to this, a study exploring the organizational barriers both at the transfer and receiving hospitals is needed. Equally as important would be an exploration of the logistics o f current patient transfer via air ambulance through the BC Ambulance Service. Implications for policy and practice For hospitals without on-site cardiac catherization facilities, using transfer strategies there is a need to be cognizant of their own times to transfer. Attention to this can aid in process improvements which in turn can reduce the overall delay from time of 84 presentation to balloon time. This information can also be incorporated into clinical decision making when selecting between reperfusion strategies. As a starting point, more attention to documentation o f cardiac patients would be ideal. For example, having the documentation o f cardiac referral times for all patients would allow for the identification o f referral to transfer time. This in turn would allow for indication as to the delay in time at the transfer hospital. Furthermore, it would allow for the opportunity to identify the time of delay from point of referral to transfer. Second, this study presents an alternative to the current practice of TIMI risk score use at UHNBC. The GRACE risk score is a validated risk prediction tool for implementation in prioritizing patient transfer for cardiac intervention. The use o f this tool may also assist physicians, who are less likely to be specialist internists, in smaller, more rural community hospitals with triaging and prioritizing patients for transfer.. Thus the implementation of this risk stratification tool can have immediate effects on assisting physicians in their clinical decision making. Third, there may be scope to introduce pre-hospital thrombolytic therapy, and pre­ hospital ECGs for eligible patients by ambulance paramedics, a method endorsed by the ACC/AHA (Levine et al., 2011). This is general practice in some parts o f the world including Europe and is strongly encouraged by the European Society o f Cardiology (ESC), despite the existence o f a larger number of PCI-capable hospitals and shorter distances to them (Van der W erf et al., 2008). While it’s implementation in North America is somewhat limited, certain Canadian cities including Houston (NS) and Edmonton (Alta) have managed to demonstrate some level of success in terms of 85 improved patient outcomes with its use (Huynh et al., 2011). This would allow for a potential reduction in infarct size, limiting myocardial damage. Furthermore, the more acute patients may then be eligible for faster transfer for PCI (Rezaee et al., 2010). The findings from this research also present some important opportunities for public health strategies. These include targeted obesity reduction approaches, smoking cessation campaigns, and healthier lifestyle interventions for high-risk patients. These public health interventions could be tailored to the high-risk patients and potentially reduce repeat visits and consequently repeat admissions to UHNBC. Conclusion In summary age was the only significant predictor o f time to treatment for PCI. 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European Heart Journal, 24, 21-23. 98 APPENDICES Appendix A: Corresponding ICD-9 Codes Disease Term ICD Number Angina Pectoris 120 Unstable Angina 120.0 Acute Transmural myocardial infarction of anterior wall 121.0 Acute Transmural myocardial infarction of other sites 121.2 Acute Transmural myocardial infarction of unspecified site 121.3 Acute subendothelial myocardial infarction 121.9 Subsequent myocardial infarction of anterior wall 122.0 Subsequent myocardial infarction of inferior wall 122.1 Subsequent myocardial infarction of other sites 122.8 Subsequent myocardial infarction of unspecified site 122.9 Post myocardial infarction angina as current complication following acute 123.2 myocardial infarction Other acute ischaemic heart disease 124 Coronary thrombosis not resulting in acute myocardial infarction 124.0 Other forms of acute ischaemic heart disease 124.8 Acute ischaemic heart disease, unspecified 124.9 99 Appendix B: STEMI Protocol j/r n o r th e r n h ealth Prince George Regional Hospital PHYSICIAN S ORDERS ST ELEVATION MYOCARDIAL INFARCTION Patient Weight: _ Date: 1. □ □ 4. □ □ 2. 3. 5. 6. 7. Door Time: First ECG: Admit to CCU and implement Physician's Orders for Coronary Routine. Morphine 2 - 5 mg IV pm for chest pain. Chew 2 x 80 mg ASA slat (check allergies first). Initiate 2 IVs (#18 - 20) in opposite arms. CBC, SeCr, PT, PTT @ baseline, then CBC q3days Enteric Coated ASA 325 mg po daily. Choose one of the following . I____ L Enoxaparin 30 mg IVbolus before TNK. TNK weight adjusted bolus over 5 sac. Enoxaparin 1 mcVka ftnax 100 rrw) SC now. then BID x 7 days. fi ;m 'j v He;> .0 >' I on!' rju . ’' . • e >•'! O C< • TNK weight adjusted botus over S sec. Hepartn nomogram on reverse with first aPTT 3 hours post TNK. | H Patient Weight w IB <60 |K § 60-<70 wm 70 - < 80 80-<90 ■ >90 □ □ □ a 9. 10. 11. 12 13. 14 15. 16. 17 TNK(me) 30 35 40 45 50 Volume (mt) 6 7 8 8 10 To use the Table: ^ Select age and gender to identify SeCr cut-off value. Values above cut-off indicate a CrCI < 30 mL/min &enoxaparin should not be used. Male 300 285 270 255 240 225 210 195 180 165 150 Age Female 40 255 45 242 230 50 55 216 60 204 65 191 70 178 75 165 80 153 85 140 127 90 II admission blood glucose > 11.0, initiate DIGAMt protocol. Beta Blocker: Choose one of the following: □ IV Metoprolol 5 mg over 2 minutes & repeat q5min x 3 doses (total * 15 mg) (consider dosage reduction if patient already on beta blocker or calcium channel blocker). □ Oral Metoprolol _________ starting at _ hours Clopidogrel 300 mg po stat and 75 mg po daily. Lipitor 80 mg po daily or mg po daily (No Substitutions) ACE Inhibitor: starting a t.......................hours 1 2 -■lead ECG 90 minutes post TNK Cholesterol, triglycerides, HDL , LDL. fasting glucose within 24 hours of admission. Smoking Cessation Initiate Nicotine Withdrawal Protocol. Cardiac Rehab Coordinator referral (fax: 250-565-2084) Pharmacist to review medications on day 4. Dietitican Consult (fax. 250-565-2889). Physician's Signature: Time: IFD Form *11-100-1049 REVUO'pc 100 Date: Appendix C: NSTEM I/UA Protocol ... ^ northern health P rince G eo rg e R egional H ospital A C U TE C O RO N A R Y SYN DRO M E O R D E R S F O R UA/NSTEM I C o n s i d e r t h e f o l l o w i n g a s p e r R i s k S t r a t i f i c a t i o n ( o n r e v e r s e ) in d icate w ith a c h e c k ( / ) fo r y e s 1. I n i t i a t e P h y s i c i a n ’s O r d e r s f o r C o r o n a r y R o u t i n e ----------------------_ P a tie n t W e ig h t 2. O T elem etry QR * O lC U ( 30 mL/min • Loading d o se 180 mcg/kg = ___ __ meg (max 22.6 mg) over 2 minutes • M aintenance d o se 2 mcg/kg/min ■ mcg/min (max 15 mg/hour) x _______ h o u rs (m ax 72 hrs) ( 3 F° r patients with CrCI < 30 mL/min • Loading d o se 180 mcg/kg = _________ meg (max 22.6 mg) over 2 minutes • M aintenance d o se 1 mcg/kg/min * _______ mcg/min (max 7.5 mg/hour) x ..... h o u rs (m ax 72 h rs) • CBC 4 hours post initiation of Eptifibatide and daily thereafter x 4 days □ 12. If ch est pain unresponsive to Nitroglycerin spray given three times 3 - 5 minutes apart, give Morphine S u lp h a te mg (V q _______ minutes pm, request STAT ECG and notify physician. 13. Cholesterol. Triglycerides, HDL, LDL. fasting sugar within 24 hours of admission. □ 14. Smoking C essation NICC referral (fax: 250-612-0810) consider Nicotine Replacem ent. 15. Cardiac R ehab Coordinator referral (fax: 250-562-2084) 16. Pharm acist to review medications on day 4 17. Dietician consult (fax: 250-565-2889) Physician's S ignature:__ D ate.............. .......... C D R F o rm « 1 1 -1 0 0 -1 0 2 3 D R A FT # 6 - 0 4 /0 7 p c 101 _.. ...................... Appendix D: Cardiac Catherization Lab Referral Form Nam*: Address: DOB: PHN: Cardiac Cath Lab Referral .. ................ Mm f ts9«ptm \_ / Va ^ uv m h o sm ta L i IflMI ll i tlt H (MU* Tofephono: R oferrtl Data: pp)f: referral form, history. ECG. lab m u t ts , echo raoort. ETT. CXR. m ad s m savnrm m Fax: Phone: Fsx: Phona: 604-875-5142 604-875-4669 Urgency Rsfarrina MD: Reforrlna tel: Reforrlna fax: First Available Cardiologist a Soactflc Cardioloaiat: Angiogram / PCI within tha last yaar by Or. Procedure^) Requested: 604-806-6637 604-806-8051 O InpaSert Hospital: 3 Emergent (pone without delay) 3 Ut (before hospital dechsrgs) Q suitable lor same day Oschg Q Outpatient Q Elective 3 Semkumsnt: reason - VH: M447S4111 SPH: 104412-2344 Indication: Meats Drovide sinale heat Indication and ahre detest If this is an ACS Q DiegnosSc Catheterteation Acute Coronary Syndromes a Cath & Possible pci a PCI (cath dona) STEMI: _ # Fibrinolysis: data/tim e:_____ □ Right Heart Cath _ _ ___ _ O Direct PCI (no (Ibrinolysa) a Pulmonary Resistance O Rescue (fated thrombolysis) □ Ranal angiogram O Fncrktated (tnromobotysh ♦ PCI) _ _ , _____ Q Post acuta STEMI □ Aortogrem _ NSTEMI or othar ACS: 1 ACS Onset pate: ACS Pain or lachamta: □ Ongoing (no complete reset) 3 Recursnt (speodrc •vonts; a Stable CAO CCS Angina Claes. 0 t II III 3 Provokabia (on stress test) IV 3 None 3 Dilated CM (scula event aettied) IV Valve 3 aortic 3 mitral □ CHF NYHA Class: 1 It HI Q Hypertrophic CM ACS Medications: Arrhythmic VTIVF3 SVTO □ Biopsy O troponin marker* ____ ___ a GPHMIIaInhibitor a ischemic ECG change (ST or T) □ Othar 3 equrvocai or no marker rise Other riak factors Prior non-lnvaaiva te s ts : Safety: Complexity: 3 hyperiipidemla Not done 3 3 ASA admmielsred 3 None 3 Olabetas □ currant smoker a Pas 3 Plavix administered 3 PVO 3 CHF (current) Height: _ _ _ _ _ 3 Neg 3 Contrast allergy 3 Prior Ml 3 Hypertension 3 Unk 3 Warfarin 3 mechanical valve □ Metformin Renal status Last creatinine 3 Prior PCI 3 Prior CABG O CarotkMvesael study Weight: 3 indaterminata QAIMLA&.USE QUL1 High 3 Congenital 3 Heparin IV or LMWH □ Post Transplant 3IVNTG Q Research Protocol only 3 Shock 3 Other disease hrttinq siavival Referring Physician History SComments: Antlcoagulatton Rlik Low Intermadtate atop Warfarin 4-5 days pn»-procedure Bndge PO HOT stop Warfarin 2** Interventional opinion 3 Surgical opinion Q pe R esearch Protocol i on Only 3 Referring Physician lii ti. l.m.,, Lmlk, . 102 Appendix E: Hospital Transfer Form TM f E B B 8 U S B ^ ' SV « * m m m k x . W n Q U B M .m M tM m M r ia K m im A W M m a x . a DO HOT t a n d a y tm m m tm u m aivm aA Y Q em ocm tam CM AAdfcndtt m j ||« n v ia » O AM S t i n t (3 AleMfeMpegfcfesinliB OMcMhiiiwli . a .CNfMNj ralpM i t a AM IW Buiw^ n ^ ly.gMHdiMilurgHK^fll a AM IWBM» 1 >| 8UM MHI) rrjrn'-*rj:ir.T.TiTTT M i BP, Ht_____ CM m Mmgum an o r use___________ § a w W d H M 3 « N lw M » m NFOlhrspw-pmaelwi. H m CMNHnMlMln ON O r h i hjsb n w im n i ftrtl ln r j* n .i mwt n m t t l im m m c o o HblQikMMtarsc ttaparinMMm on a r ON O Y an O Y LVrtVM ON ASA ON O Y LMtdoM________ m ON OY t o n O Y n m 111m ifcrtnttme am d aM felW . la m * m 4 a tm HOUk W M M i (M d*y«) U M jdow ________ rn* M adam hi d q rs) lA M d o w _ _ _ _ _ _ _ n V d * W * n e . &SSUZ&M »*** 24 h i* AN Aeeart pie * port procedure a EnUr* c h it (»ww w i n taM * M m *nd orJy) O CumntNMnry A p n y tad O Adn*MtavS«per*dan w a rd O I m w p w lw o im ry □ Altabrmdi 0 O S to rW w dfaaSonracwdfatdOT cdttsw ftr ✓ Midi* alt dame (3 PtrinrvM bMonOnge A a i omtwantrrwilarton tar nsod 3 hours after the onset of symptoms, the mortality of the TL group was higher (15.3% compared to the PCI group ( 6 %, p<0.02). Patients randomized <3 hours of symptom onset (n=551) had no difference in mortality whether treated by TL (7.4%) or transferred for PCI (7.3%). A combined end-point occurred was higher in the TL group (15.2%) vs the PCI group (8.4%, p<0/003)of the PCI group Long distance transport from a community hospital to a tertiary PCI centre in the acute phase o f AMI is safe as this strategy was associated with marked decreases in mortality in patients presenting more than 3 hours after symptom onset. However for patients presenting within 3 hours of symptom onset, TL results were similar to the results in long distance transport for PCI Ellis et al. (2004) N=300 PPCI PCI treatments; reduced-dose reteplase and abciximab combination therapy OR abciximab alone followed by PCI with abciximab alone 0 FINESSE TRIAL FemandezAviles et al. (2007) GRACIA-2 N=212 2 facilitated Full tenecteplase followed by stenting randomization within 3-12 hours of randomization PPCI with abciximab <3 hours of 106 One-year mortalities in the three groups, reduced-dose reteplase and abciximab combination therapy (6.3%) or abciximab alone followed by PCI with abciximab alone (7.4%), or PPCI, r (7.0, p = NS), representing 1.1%, 1.9%, and 2.5% increments since the 90-day outcome (p = 0.053 for combination treatment vs PPCI) Widespread use o f facilitated PCI could not be justified among all ACS patients but high-risk (i.e with anterior AMI) deserve further study Early routine post-thrombolysis PCI resulted in higher frequency (21 versus 6 %, p = 0.003) of complete epicardial and myocardial reperfusion (TIMI 3 epicardial flow and TIMI 3 myocardial perfusion and resolution of the initial sum o f ST-segment TRIAL (early routine post­ thrombolysis PCI elevation > or = 70%) following angioplasty. Both groups were similar regarding infarct size (area under the curve o f CK-MB: 4613 +/- 3373 vs 4649 +/- 3632 microg/L/h, p= 0.94); 6 -week left ventricular function (ejection fraction: 59.0 +/-11.6 vs 56.2 +/-13.2%, p= 0.11; end systolic volume index: 27.2 +/-12.8 vs 29.7 +/-13.6, p = 0 .21 ); major bleeding (1.9 vs 2.8%, p = 0.99) and 6 -month cumulative incidence o f the clinical endpoint (10 vs 12%, p = 0.57; RR: 0.80; 95% Cl: 0.37-1.74) Early routine post-fibrinolysis angioplasty safely results in better myocardial perfusion than primary angioplasty as despite its delayed application, this approach was seen to be equivalent to primary angioplasty in limiting infarct size and preserving left ventricular function Grines et al. (2002 ) N=138 Transfer for PPCI On-site thrombolysis AIR-PAMI TRIAL Patients randomized to transfer had a reduced hospital stay (6.1 +/- 4.3 vs 7.5 +/- 4.3 days, p= 0.015) and less ischemia (12.7% vs 31.8%, p = 0.007). At 30 days, a 38% reduction in major adverse cardiac events was observed for the transfer group however, because of the inability to recruit the necessary sample size, this did not achieve statistical significance (8.4% vs 13.6%, p = 0.331) High-risk patients with AMI at hospitals without a catheterization laboratory may have an improved outcome when transferred for primary PCI versus on-site thrombolysis. This suggests that the marked delay in the 107 transfer process suggests a role for triaging patients directly to specialized heart-attack centers Andersen et N=157 PPCI Thrombolysis 2 al. (2003) DAN AMI-2 TRIAL The primary study end point was a composite of death, clinical evidence of reinfarction, or disabling stroke at 30 days. Among patients who underwent randomization at referral hospitals, the primary end point was reached in 8.5% of the patients in the PCI group, as compared with 14.2% of those in the thrombolysis group (p=0.002). The results were similar among patients who were enrolled at invasive-treatment centers: 6.7% of the patients in the PCI group reached the primary end point, as compared with 12.3% in the thrombolysis group (p=0.05). Among all patients, the better outcome after PCI was driven primarily by a reduction in the rate of reinfarction (1.6 % in the PCI group vs 6.3% in the thrombolysis group, p< 0 .001 ); no significant differences were observed in the rate o f death (6.6 % vs 7.8 %, p=0.35) or the rate of stroke ( 1.1 % vs 2.0 %, p=0.15) A strategy for reperfusion involving the transfer o f patients to an invasivetreatment center for PPCI is superior to on-site thrombolysis, provided that the transfer takes two hours or less Van der W erf et al. (2006) N=166 7 PPCI with 6 hours of STEMI PCI preceded Primary endpoint (death, CHF, or shock) in 19% (151 o f 810) of by administration patients assigned facilitated PCI versus 13 % (110 of 819) o f those o f full-dose 108 tenecteplase ASSENT-4 TRIAL randomised to PPCI (relative risk 1.39, 95% Cl 1.11 -1.74; p=0.0045). During hospital stay, significantly more strokes (1.8% [15 o f 829] vs 0, p< 0 .0001 ), but not major non-cerebral bleeding complications ( 6 % [46 of 829] vs 4% [37 o f 838], p=0.3118), were reported in patients assigned facilitated rather than standard PCI. We also noted more ischaemic cardiac complications, such as reinfarction (6 % [49 o f 805] vs 4% [30 o f 820], p=0.0279) or repeat target vessel revascularisation (7% [53 o f 805] vs 3% [28 of 818], p=0.0041) within 90 days in this study group A strategy of full-dose tenecteplase with antithrombotic co-therapy, as used in this study and preceding PCI by 1-3 h, was associated with more major adverse events than PCI alone in STEMI and cannot be recommended. Nielsen et al. (2010 ) N=157 PPCI Thrombolysis 2 Follow-up to the DAN AMI-2 TRIAL 109 The composite endpoints primarily, death, clinical re-infarction, or disabling stroke, were reduced by PCI when compared with thrombolysis at 3 years (19.6% vs 25.2%, p= 0.006). For patients transferred to PCI compared with those receiving on-site thrombolysis, the composite endpoint occurred in 20.1% vs 26.7% (p= 0.007), death in 13.6 vs 16.4% (p= 0.18), clinical re-infarction in 8.9% vs 12.3% (p= 0.05), and disabling stroke in 3.2% vs 4.7% (p= 0.23) The benefit o f transfer for primary PCI based on the composite endpoint was sustained after 3 years. Nielsen et al. (2010 ) concluded that for patients with characteristics such as those in DANAMI-2, primary PCI should be the preferred treatment strategy provided that inter-hospital transfer can be completed within 2 hours Thiele et al. (2011 ) N=162 PPCI (group B) LIPSIASTEMI TRIAL Despite better pre-interventional TIMI Pre-hospitalinitiated (Thrombolysis In Myocardial Infarction) flow in Group A (71% facilitated PCI (group A) versus 35% TIMI flow grade 2 or 3; p < 0 .001 ), the infarct size tended to be worse in group A vs group B (17.9% o f left ventricle IQR: 8.4% to 35.0%) vs 13.7% IQR: 7.5% to 24.0%); p = 0.10). There was also a strong trend toward more early and late microvascular obstruction, (p = 0.06 and 0.09) and no difference in STsegment resolution (p = 0.26). The combined clinical endpoint showed a trend toward higher event rates in group A (19.8% vs 13.6%; p = 0.13, RR: 0.52, 95% Cl: 0.23-1.18) STEMI patients presenting early after symptom onset with relatively long transfer times, a thrombolytic-based facilitated PCI approach with optimal antiplatelet co-medication does not offer a benefit over primary PCI with respect to infarct size and tissue perfusion Bohmer et al. (2003) N=197 Transfer <6 hours after thrombolysis Elective PCI two weeks after 110 Immediate stenting was associated with a significant reduction o f the combined end point after six months for PCI thrombolysis SIAM-III TRIAL FemandezAviles et al. (2004) (ischemic events, death, reinfarction, target lesion revascularization 25.6% vs 50.6%, p = 0.001) Immediate stenting after thrombolysis leads to a significant reduction of cardiac events compared with a more conservative approach including delayed stenting after two weeks N=500 PPCI Angiography or PCI within 24 hours of thrombolysis GRACIA-1 TRIAL By comparison with patients receiving conservative treatment, by 1 year, patients in the invasive group had lower frequency o f primary endpoint (23 (9%) vs 51 (21%), relative risk 0.44 (95% Cl 0.28-0.70), p=0.0008), and they tended to have reduced rate o f death or reinfarction (7% vs 12%, 0.59 (0.33-1.05), p=0.07). Index time in hospital was shorter in the invasive group, with no differences in major bleeding or vascular complications. At 30 days both groups had a similar incidence o f cardiac events. Inhospital incidence of revascularisation induced by spontaneous recurrence of ischaemia was higher in patients in the conservative group than in those in the invasive group In patients with STEMI, early post­ thrombolysis catheterization and appropriate intervention is safe and might be preferable to a conservative strategy since it reduces the need for unplanned in-hospital revascularization, and improves 1year clinical outcomes I ll Di Mario et N=600 al. (2008) Thrombolysis and CARESS-in- immediate transfer for PCI AMI TRIAL Thrombolysis The primary endpoint was a and transfer composite o f death, reinfarction, or for rescue PCI refractory ischaemia at 30 days. O f the 299 patients assigned to immediate PCI, 289 (97.0%) underwent angiography, and 255 (85.6%) received PCI. Rescue PCI was done in 91 patients (30.3%) in the standard care/rescue PCI group. The primary outcome occurred in 13 patients (4.4%) in the PPCI group compared with 32 (10.7%) in the standard care/rescue PCI group (hazard ratio 0.40; 95% Cl: 0.21-0.76, p=0.004). Major bleeding was seen in ten patients in the immediate group and seven in the standard care/rescue group (3.4% vs 2.3%, p=0.47). Strokes occurred in two patients in the immediate group and four in the standard care/rescue group (0.7% vs 1.3%, p=0.50) Immediate transfer for PCI improves outcome in high-risk patients with STEMI treated at a non-interventional centre with half-dose reteplase and abciximab Bohmer et al. (2007) NORDSTE MI TRIAL N=266 Immediate transfer for angiography OR PPCI Thrombolysis in the community hospitals, with urgent transfer only for a rescue indication or with clinical deterioration 112 The primary endpoint was a composite of death, reinfarction, stroke, or new ischemia at 12 months. The primary endpoint was reached in 28 patients (21 %) in the early invasive group compared with 36 (27%) in the conservative group (hazard ratio: 0.72, 95% Cl: 0.44 to 1.18, p = 0.19). The composite o f death, reinfarction, or stroke at 12 months was significantly reduced in the early invasive compared with the conservative group (6 % vs 16%, hazard ratio: 0.36, 95% Cl: 0.16 to 0.81, p = 0.01). No significant differences in bleeding or infarct size were observed Immediate transfer for PCI did not improve the primary outcome significantly, but reduced the rate of death, reinfarction, or stroke at 12 months in patients with STEMI, treated with thrombolysis and clopidogrel in areas with long transfer distances Cantor et al. (2009) TRANSFER -AMI TRIAL N=105 9 Immediate transfer to PCI capable hospital within 6hrs post­ thrombolysis Thrombolysis with rescue PCI or delayed angiography 113 The primary end point was the composite o f death, reinfarction, recurrent ischemia, new or worsening congestive heart failure, or cardiogenic shock within 30 days. Cardiac catheterization was performed in 88.7% o f the patients assigned to standard treatment a median of 32.5 hours after randomization and in 98.5% of the patients assigned to routine early PCI a median of 2.8 hours after randomization. At 30 days, the primary end point occurred in 11 .0 % o f the patients who were assigned to routine early PCI and in 17.2% of the patients assigned to standard treatment (relative risk with early PCI, 0.64; 95% Cl: 0.47 to 0.87; p=0.004). There were no significant differences between the groups in the incidence of major bleeding. Among high-risk patients who had a myocardial infarction with ST-segment elevation and who were treated with thrombolysis, transfer for PCI within 6 hours after thrombolysis was associated with significantly fewer ischemic complications than was standard treatment. McKay et al. N=155 (2009) 3 PPCI Facilitated PCI Compared with patients who underwent primary PCI, the facilitated PCI group had longer door-to-balloon times (162 +/-57 vs 113 +/-61 minutes), higher baseline infarctvessel T IM I3 flow rates (52.8% vs 25.4%; p <0.001), and no increase in major adverse in-hospital outcomes. In patients treated with door-toballoon times greater than 90 and less thanl50 minutes, patients who underwent facilitated PCI had fewer composite major adverse clinical events (combined mortality, recurrent myocardial infarction, emergent repeated PCI, hemorrhagic and nonhemorrhagic stroke, and nonintracranial TIMI major bleeding) compared with patients who underwent primary PCI (RR 0.50, 95% Cl 0.26 to 0.96, p=0.034) Facilitated PCI can be safely used to increase pharmacological reperfusion before catheter-based therapy in patients with STEMI without an increase in clinical hazard and with fewer major adverse clinical events in patients treated with door-to-balloon times greater than 90 and less than 150 minutes 114 Appendix H: GRACE Risk Score Studies Summarized Study Patient/ Pop. Measure Result Y anet al. (2004) 4627 Examined the relationship In-hospital mortality rates were 2.4% overall and 1.5% among the between in-hospital patients with non-STrevascularization elevation ACS (n = and 1-year outcome 2925; 63.2%) in our validation cohort. Both among patients the in-hospital with non-STPURSUIT and GRACE elevation ACS, risk models showed stratified by the similar and good GRACE risk score prognostic discrimination (57.8% Cl: 0.84 and 0.83, respectively; p = .69 for difference). The GRACE model also demonstrated good calibration (HosmerLemeshow P = .40). In contrast, calibration in the PURSUIT model was poor (HosmerLemeshow p < .001), with consistent overestimation o f risks High-risk patients with ACS appear to benefit from, but are less likely to undergo, early PCI. Used with sound clinical judgment, the GRACE risk stratification tool can facilitate an evidence-based approach that tailors treatment appropriately to the individual patient Araujo et al. (2005) 460 Compared the prognostic value of three ACS risk scores (RSs) and their ability to predict benefit from myocardial revascularization performed during 460 consecutive patients admitted to coronary care unit with an ACS [age: 63±11 years, 21.5% female, 55% with myocardial infarction (MI)]. For each patient, the Thrombolysis In The GRACE risk score demonstrates good predictive accuracy for death or MI at 1 year and enabled the identification of high-risk subsets o f patients who will benefit most from myocardial revascularization performed during initial hospital stay 115 Conclusion initial hospitalization Myocardial Infarction (TIMI), Platelet glycoprotein Ilb/IIIa in Unstable angina: Receptor Suppression Using Integrilin (PURSUIT), and Global Registry of Acute Coronary Events (GRACE) RSs were calculated using specific variables collected at admission. Their prognostic value was evaluated by the combined endpoint of death or MI at 1 year. The best cut-off value for each RS, calculated with receiver operating characteristic curves, was used to assess the impact o f myocardial revascularization on the combined incidence of death or MI. Death or MI at 1 year was 15.4% (32 deaths/49 Mis). The best predictive accuracy for death or MI at 1 year was obtained by the GRACE risk score (Cl: 0.672-0.756) but the performance o f the PURSUIT risk score (Cl: 0.584-0.674), and TIMI risk score (Cl: 0.539-0.631) was also good. A statistically significant interaction 116 between the risk stratified by the best cut-off value for the GRACE and PURSUIT risk scores and myocardial revascularization, with a better prognosis for the high-risk patients was found. The highrisk patients represented the population as follows; GRACE (36.7%), PURSUIT (28.7%), and TIMI (57.8%) Alter et al. (2006) 3500 To validate the Global Registry o f Acute Coronary Events (GRACE) risk-adjustment index for 6 -month all-cause mortality across socioeconomic strata Predicted and observed mortality rates were significantly higher among patients of lower incomes and education (ie, observed 6 -month mortality: 5.1 % vs 1 .8 % among low income vs high income patients, respectively, p<.0001; 4.6% vs 2.9% among low-educated vs highly educated patients, respectively, p=.02). The predicted 6 -month mortality as derived using GRACE closely mirrored observed mortality rates with strong accuracy and precision (Cl: 0.80 for the overall cohort and within each income and education strata; 117 The GRACE risk score for 6 month all-cause mortality is an accurate, well-calibrated, and robust predictor across socioeconomic strata and can be used as a valid riskadjustment index when examining socioeconomicmortality differences after acute Ml Hosmer-Lemeshow goodness-of-fit test was not significant within each income and education strata) Bradsha w et al. (2006) 12875 To determine the validity of the GRACE prediction model for death six months after discharge in all forms of acute coronary syndrome in an independent dataset of a community based cohort o f patients with acute myocardial infarction (AMI) Post-discharge crude mortality at six months for the EFFECT study patients with AMI was 7.0%. The discriminatory capacity of the GRACE model was good overall (Cl: 0.80) and for patients with ST segment elevation AMI (STEMI) (0.81) and non-STEMI (0.78). Observed and predicted deaths corresponded well in each stratum of risk at six months, although the risk was underestimated by up to 30% in the higher range of scores among patients with nonSTEMI In an independent validation the GRACE risk model had good discriminatory capacity for predicting post-discharge death at six months and was generally well calibrated, suggesting that it is suitable for clinical use in general populations Fox et al. (2006) 24189 To determine whether revascularisation is more likely to be performed in higher-risk patients and whether the findings are influenced by hospitals adopting more or less Overall, 32.5% of patients with a non-ST elevation ACS underwent percutaneous coronary intervention (PCI; 53.7% in ST segment elevation myocardial infarction (STEMI) and 7.2% underwent coronary artery bypass A risk-averse strategy to angiography appears to be widely adopted. Proceeding to PCI relates to referral practice and angiographic findings rather than the patient’s risk status. Systematic and accurate risk stratification may allow higher-risk patients to be selected for revascularisation 118 aggressive revascularization strategies grafting (CABG; 4.0% in STEMI). The cumulative rate o f inhospital death rose correspondingly with the GRACE risk score (variables: age, Killip class, systolic blood pressure, ST-segment deviation, cardiac arrest at admission, serum creatinine, raised cardiac markers, heart rate), from 1.2 % in lowrisk to 3.3% in medium-risk and 13.0% in high-risk patients (c statistic = 0.83). PCI procedures were more likely to be performed in low- (40% nonSTEMI, 60% STEMI) than medium- (35%, 54%) or high-risk patients (25%, 41%). No such gradient was apparent for patients undergoing CABG. These findings were seen in STEMI and non-ST elevation ACS, in all geographical regions and irrespective of whether hospitals adopted low (4.2233.7%, n = 7210 observations), medium (35.7251.4%, n = 7913 observations) or high rates (52.6277.0%, n = 119 procedures, in contrast to the current international practice 8942 observations) of intervention Ramsay et al. (2007) 347 To determine the predictive accuracies o f the GRACE risk score, the TIMI risk score and clinical evaluation in unselected patients with suspected cardiac pain Overall 54 patients In unselected patients presenting with suspected (15.6%) experienced a major cardiac event (16 cardiac pain, the GRACE risk score is superior to the deaths, seven myocardial infarctions TIMI risk score in predicting major cardiac events, and (Mis), one emergency both risk scores are superior revascularization) or to using ECG and troponin emergency re­ findings at presentation admission (n=30) within 3 months. Both GRACE (p< 0.001) and TIMI scores (p< 0.001) predicted death/MI/revascularizat ion (and the composite including re­ admission), but the GRACE score was superior to the TIMI score for predicting major cardiac events (z. 2.05), and both scores were superior to clinical evaluation (ROC areas 0.82, 0.74 and 0.55 respectively). The GRACE score predicted an ACS discharge diagnosis (p< 0 .001 ) and duration o f hospital stay (p< 0 .001 ) 120 Tang et al. (2007) 1143 To determine whether GRACE is a validated risk model to predict mortality beyond 6 months 39% had ST-elevation myocardial infarction, 39% had non-STelevation infarction, and 22% had unstable angina. The mortality was 7.5% during index admission, 12.1% at 6 months, 14.8% at 1 year, 18.7% at 2 years, 25.0% at 3 years, and 39.2% at 4 years. The GRACE hospital discharge risk score calculated for 1057 hospital survivors discriminated survival from death at 6 months (Cl: 0.81), 1 year (C index, 0.82), 2 years (Cl; 0.81), 3 years (Cl; 0.81), and 4 years (Cl: 0.80). The risk score worked for all 3 subsets o f ACS at all time points, with Cl: 0.75 in all analyses. A separate multivariable mortality model for these 1057 patients over the 4years follow-up period identified 10 independent predictors o f mortality. Seven were in the GRACE risk model (age, history o f ischemic heart disease, heart failure, increased heart rate on admission, serum 121 The GRACE post-discharge risk score contains relevant prognostic factors and was found to accurately discriminate survivors from non-survivors over the longer term (up to 4 years) in all subsets of ACS patients creatine level, evidence o f myonecrosis, not receiving in-hospital PCI). Yan et al. (2007) 4144 To examine the use of in-hospital cardiac catheterization and medications in relation to risk across the broad spectrum of nonST elevation ACSs Although in-hospital mortality rates were similar, the in-hospital use o f cardiac catheterization increased significantly over time (38.8% in the ACS 1 Registry vs 63.5% in the ACS 2 Registry; p=.001). The rates o f cardiac catheterization in the low-, intermediate-, and high-risk groups were 48.0%, 41.1%, and 27.3% in the ACS 1 Registry, and 73.8%, 66.9%, and 49.7% in the ACS 2 Registry, respectively (p=.001 for trend for both). After adjusting for other confounders, intermediate-risk (adjusted odds ratio, 0.75; 95% Cl: 0.630.90; p=.001) and highrisk (adjusted odds ratio, 0.35; 95% Cl: 0.28-0.45; p=.001) patients remained less likely to undergo cardiac catheterization compared with low-risk patients. Furthermore, there existed a similar 122 Despite temporal increases in the use of cardiac catheterization and revascularization in the management o f non-ST elevation ACS, evidencebased invasive and pharmacological therapies remain paradoxically targeted toward low-risk patients. Strategies to eliminate this treatment-risk paradox must be implemented to fully realize the benefits and optimize the cost effectiveness of invasive management inverse relationship between risk and the use o f in-hospital revascularization Aragam et al. (2009) 3451 To compare the discriminative abilities of the TIMI and GRACE risk scores in a broad-spectrum, unselected ACS population and to assess the relative contributions of model simplicity and model composition to any observed differences between the two risk models UA/NSTEMI (n = 2753) and STEMI (n = 698) The predictive abilities o f the TIMI and GRACE scores for in-hospital and 6-month mortality were assessed by calibration and discrimination. There were 137 in-hospital deaths (4%), and among the survivors, 234 (7.4%) died by 6 months post-discharge. IntheUA/NSTEM I population, the GRACE risk scores demonstrated better discrimination than the TIMI UA/NSTEMI score for in-hospital (C = 0.85, 95% Cl: 0.810.89, vs 0.54, 95% Cl: 0.48-0.60; p=0.01) and 6-month (C = 0.79, 95% Cl: 0.76-0.83, vs 0.56, 95% Cl: 0.520.60; p=0.01) mortality. Among STEMI patients, the GRACE and TIMI STEMI scores demonstrated comparably excellent discrimination for inhospital (C = 0.84, 95% Cl: 0.78-0.90 vs 0.83, 123 The GRACE scores provided superior discrimination as compared with the TIMI UA/NSTEMI score in predicting in-hospital and 6month mortality in UA/NSTEMI patients, although the GRACE and TIMI STEMI scores performed equally well in STEMI patients. The observed discriminative deficit of the TIMI UA/NSTEMI score likely results from the omission of key risk factors rather than from the relative simplicity of the scoring system 95% Cl: 0.78-0.89; p = 0.83) and 6-month (C = 0.72, 95% Cl: 0.630.81, vs 0.71,95% Cl: 0.64-0.79; p = 0.79) mortality. An analysis o f refitted multivariate models demonstrated a marked improvement in the discriminative power of the TIMI UA/NSTEMI model with the incorporation of heart failure and hemodynamic variables Elbarou ni et al. (2009) 12242 To validate the GRACE risk score in a contemporary Canadian population with ACS A total of 12,242 Canadian patients with ACS were included; the median GRACE risk score was 127 (25th and 75th percentiles were 103 and 157, respectively). Overall, the GRACE risk score demonstrated excellent discrimination (c statistic 0.84, 95% Cl 0.82-0.86, p= .001) for in-hospital mortality. Similar results were seen in all the subgroups (all c statistics >0.8). However, calibration was suboptimal overall (Hosmer-Lemeshow p= .06) and in various subgroups 124 GRACE risk score is a valid and powerful predictor of adverse outcomes across the wide range o f Canadian patients with ACS. Its excellent discrimination is maintained despite advances in management over time and is evident in across all patient subgroups. However, the predicted probability of inhospital mortality may require recalibration in the specific health care setting and with advancements in treatment. Gale et al. (2009) 100886 To compare the discriminative performance o f the PURSUIT, GUSTO-1, GRACE, SRI and EMMACE risk models, assess their performance among risk supergroups and evaluate the EMMACE risk model over the wider spectrum of acute coronary syndrome (ACS) The C-indexes were: PURSUIT C-index 0.79 (95% Cl 0.78 to 0.80); GUSTO-1 0.80 (0.79 to 0.81); GRACE inhospital 0.80 (0.80 to 0.81); GRACE 6-month 0.80 (0.79 to 0.80); SRI 0.79 (0.78 to 0.80); and EMMACE 0.78 (0.77 to 0.78). EMMACE maintained its ability to discriminate 30-day mortality across different ACS diagnoses Recalibration o f the model offered no notable improvement in performance over the original risk equation. For all models the discriminative performance was reduced in patients with diabetes, chronic renal failure or angina 125 The five ACS risk models (p u r s u i t ,g u s t o - i , GRACE, SRI, EMMACE) maintained their discriminative performance in a large unselected English and Welsh ACS population, but performed less well in higher-risk sub groups. Simpler risk models had comparable performance to more complex risk models AbuAssi et al. (2010) N=1183 To assess the validity o f the GRACE risk score in a contemporary cohort o f patients admitted to a Spanish hospital Stacke et al. *2010) N=1014 To evaluate the relationship between the GRACE risk score and in-hospital mortality in patients presenting to the ED with chest pain o f all In total, 459 (38.8%) patients were admitted for ST-elevation myocardial infarction (STEMI) and 724(61.2%) for nonST-elevation myocardial infarction (NSTEMI). PCI was performed in 846 (71.5%). The median GRACE risk score was 121[IQR, 96-144], Mortality 6 months after discharge was 4.4%. The calibration of the GRACE risk score was acceptable (Hosmer-Lemeshow, P>.2) and its discriminatory capacity was excellent: the area under the curve was 0.86 (95% Cl: 0.8070.916) for all patients, 0.9 (95% Cl: 0.8290.975) for those with STEMI and 0.86 (95% Cl: 0.783-0.927) for those with NSTEMI The GRACE risk score for predicting death within 6 months o f hospital discharge was validated and can be used in patients with ACS. It would be wise to include the GRACE risk score in the medical records of these patients A total o f 94 patients died during the stay in the hospital, 83 patients with high risk, 9 with medium risk, and 2 with low risk. The risk o f in-hospital death was 24.5% for high-risk patients, 2.6% for medium-risk patients, This study shows that the GRACE risk score accurately stratifies risk of intra-hospital mortality in patients presenting to the ED with chest pain and can help guide patient triage and management 126 causes and 0.6% for patients with low risk. The correlation between the GRACE risk score and in-hospital mortality is strongly positive (p=0.01). Koziera dzka et al. (2011) N= 505 To test the of GRACE risk score prognosis of 5-year survival in a “reallife” population of patients with STelevation myocardial infarction (STEMI) treated with PPCI 32 patients died during the first 30 days (6.3%) and an additional 74 within 5 years (15.6%). PCI was successful in 95.2%(n = 481). Prognostic values (c statistics) for predicting 5-year mortality equaled: 0.742 (Cl: 0.69-0.79) for the GRACE risk score, 0.727 (Cl 0.67-0.78) for TIMI, 0.72 (Cl: 0.67-0.77) for Zwolle, and 0.687 (Cl 0.630.74) for CADILLAC. Univariate analysis all the scores were associated with the 5year outcome. 127 GRACE, TIMI, and Zwolle risk scores predicted well 5year all-cause mortality in patients with STEMI treated with PPCI. The data show that the usefulness o f initial bedside risk assessment can be further extended for long­ term follow-up