Expert recommendations from the Asia-Pacific ACS M

International Journal of Cardiology 183 (2015) 63–75

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International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard

Review

Challenges and solutions in medically managed ACS in the Asia-Pacific region: Expert recommendations from the Asia-Pacific ACS Medical Management Working Group The Asia-Pacific ACS Medical Management Working Group, Yong Huo a,⁎,1, Peter Thompson b,⁎⁎,1, Wacin Buddhari c, Junbo Ge d, Scott Harding e, Letchuman Ramanathan f, Eugenio Reyes g, Anwar Santoso h, Li-Wah Tam i, Govindan Vijayaraghavan j, Hung-I Yeh k a

Peking University First Hospital, Beijing, China University of Western Australia, Sir Charles Gairdner Hospital, Perth, Western Australia, Australia c Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand d Zhongshan Hospital, Fudan University, Shanghai, China e Wellington Cardiovascular Research Group and School of Biological Sciences, Victoria University, Wellington, New Zealand f Department of Medicine, Taiping Hospital, Taiping, Malaysia g University of the Philippines, Philippine General Hospital—Section of Cardiology, Manila, Philippines h Department of Cardiology – Vascular Medicine, Faculty of Medicine, University of Indonesia and National Cardiovascular Center, Harapan Kita, Indonesia i Kwong Wah Hospital, Kowloon, Hong Kong j Kerala Institute of Medical Sciences, Kerala, India k Mackay Memorial Hospital, Mackay Medical College, New Taipei City, Taiwan b

a r t i c l e

i n f o

Article history: Received 23 July 2014 Received in revised form 12 November 2014 Accepted 24 November 2014 Available online 28 November 2014 Keywords: Acute coronary syndromes Asia-Pacific Medical management Conservative Myocardial infarction

a b s t r a c t Acute coronary syndromes (ACS) remain a leading cause of mortality and morbidity in the Asia-Pacific (APAC) region. International guidelines advocate invasive procedures in all but low-risk ACS patients; however, a high proportion of ACS patients in the APAC region receive solely medical management due to a combination of unique geographical, socioeconomic, and population-specific barriers. The APAC ACS Medical Management Working Group recently convened to discuss the ACS medical management landscape in the APAC region. Local and international ACS guidelines and the global and APAC clinical evidence-base for medical management of ACS were reviewed. Challenges in the provision of optimal care for these patients were identified and broadly categorized into issues related to (1) accessibility/systems of care, (2) risk stratification, (3) education, (4) optimization of pharmacotherapy, and (5) cost/affordability. While ACS guidelines clearly represent a valuable standard of care, the group concluded that these challenges can be best met by establishing cardiac networks and individual hospital models/clinical pathways taking into account local risk factors (including socioeconomic status), affordability and availability of pharmacotherapies/invasive facilities, and the nature of local healthcare systems. Potential solutions central to the optimization of ACS medical management in the APAC region are outlined with specific recommendations. © 2014 Elsevier Ireland Ltd. All rights reserved.

Abbreviations: ACACIA, Australian Acute Coronary Syndromes Prospective Audit; ACCORD, ACute CORonary syndromes Descriptive study; ACCF, American College of Cardiology Foundation; ACEi, angiotensin-converting enzyme inhibitor; ACS, acute coronary syndromes; ADPi, adenosine diphosphate inhibitor; AHA, American Heart Association; ANZACS QI, All New Zealand ACS Quality Improvement; APAC, Asia-Pacific; ARB, angiotensin receptor blockers; BB, beta-blockers; BRIG, Bridging the Gap; CABG, coronary artery bypass graft; CHD, coronary heart disease; CKD, chronic kidney disease; CPACS, Clinical Pathway for Acute Coronary Syndrome in China; CRUSADE, Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the ACC/AHA guidelines; CVD, cardiovascular disease; CURE, Clopidogrel in Unstable Angina to Prevent Recurrent Events; DAPT, dual antiplatelet therapy; ECG, electrocardiogram; EPICOR, long-tErm follow-uP of antithrombotic management patterns In acute CORonary syndrome patients; ER, emergency room; GP, glycoprotein; ESC, European Society of Cardiology; GRACE, Global Registry of Acute Coronary Events; HOTPR, high on-treatment platelet reactivity; JAC, Jakarta ACS; LDL-C, low-density lipoprotein cholesterol; LMWH, low molecular weight heparin; LV, left ventricular; MI, myocardial infarction; NCVD, National Cardiovascular Disease Database; NSTEMI, non-ST-elevation myocardial infarction; PCI, percutaneous coronary intervention; PLATO, PLATelet inhibition and patient Outcomes; PURE, Prospective Urban Rural Epidemiology; PURSUIT, platelet glycoprotein IIb/ IIIa in unstable angina: receptor suppression using integrilin therapy; STEMI, ST-elevation myocardial infarction; T-ACCORD, Taiwan Acute Coronary Syndrome Descriptive Registry; TIMI, Thrombolysis in Myocardial Infarction; TSOC, Taiwan Society of Cardiology; TNK, teneceteplase; tPA, tissue plasminogen activator; UA, unstable angina; UF, unfractionated heparin ⁎ Correspondence to: Y. Huo, No. 8 Xishiku Street, Xicheng District, Beijing 100034, China. ⁎⁎ Correspondence to: P. Thompson, Heart Research Institute, Perkins Institute for Medical Research, Sir Charles Gairdner Hospital, Hospital Ave, Perth, Western Australia, Australia. E-mail addresses: [email protected] (Y. Huo), [email protected] (P. Thompson). 1 Equal contribution as Co-Chairs.

http://dx.doi.org/10.1016/j.ijcard.2014.11.195 0167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved.

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1. Introduction

2. Optimal ACS medical management: review of guidelines

Management of acute coronary syndromes (ACS) differs between countries in the Asia-Pacific (APAC) region and there is high variability in outcomes. Reported in-hospital mortality rates are generally poorer than reported globally [1,2], but vary from less than 2% in Taiwan [3] to 13% in Thailand [4]. Post-discharge 12-month mortality in the region exceeds that seen internationally [5,6], with rates of 18–25% reported in patients with ST-elevation myocardial infarction (STEMI) in some provinces of China [7]. Many ACS patients in the region – up to approximately 80% in Malaysia [8] – are treated with conservative or with purely medical management strategies, despite evidence-based guidelines that advocate invasive treatment in all but low-risk ACS patients [9–21]. Underlying this observation is a combination of unique geographical, socioeconomic, and population-specific barriers. APAC countries are diverse in size and population distribution and include a variety of models of healthcare provision and resourcing that influence how ACS patients are treated. Access to pharmacotherapy – an integral part of all treatment strategies – differs between countries, and cultural factors influence the acceptability of some therapies/interventions. Risk factors vary, with high rates of diabetes and smoking in some countries. Furthermore, genetic differences resulting from the multi-ethnic profile of the APAC region can influence outcomes and response to therapy. In November 2013, the APAC ACS Medical Management Working Group convened to review local and international ACS guidelines for medical management of ACS in the context of real-world practice in the region. Based on a systematic literature review (Supplementary Table I), the group assessed the relative strengths of the supporting global and APAC evidence base, with particular focus on the medically managed ACS population. The group identified and made initial recommendations to address five key challenges/ unmet needs in ACS medical management in the APAC region: (1) accessibility/systems of care; (2) risk stratification; (3) education; (4) optimization of pharmacotherapy and (5) cost/affordability. This article provides a summary of the Group's discussions and initial recommendations that were proposed to improve outcomes in ACS within the region.

Australia/New Zealand, China, India, Malaysia, Philippines, and Taiwan have their own local guidelines for management of ACS [10, 12–20,22–26]. Other APAC countries rely largely on the US American College of Cardiology Foundation/American Heart Association (ACCF/ AHA) and European Society of Cardiology (ESC) guidelines for management of STEMI and non-ST-segment elevation myocardial infarction (NSTEMI)/unstable angina (UA) [9,13,14,19,21,27,28], with some local modification by national reimbursement authorities (Table 1). 2.1. Risk stratification Guidelines recommend early assessment of patients presenting with chest pain or other ischemic symptoms to enable stratification according to risk of death/cardiovascular events. Initial steps involve a 12lead electrocardiogram (ECG) to detect ischemic changes/arrhythmias performed within 10 min of first medical contact, and cardiac enzyme testing [9,13,15,17–21,26], preferably with troponin (T or I) [9,13, 17–21]. The prior standard diagnostic test for creatine-kinase isoenzyme MB is no longer routinely used (beyond suspicion of re-infarction) in many APAC countries, and high-sensitivity troponin assays, which enable shorter evaluation times, are becoming more routine [24]. Guidelines differ in their promotion of formal risk stratification tools: ESC and New Zealand guidelines advocate use of the Global Registry of Acute Coronary Events (GRACE) risk score, while Indian guidelines focus on the Thrombolysis in Myocardial Infarction (TIMI) score, and others (including ACCF/AHA guidelines) indicate no preference [10,13,14,17,18,22]. 2.2. Criteria for conservative/medical management The benefit of percutaneous coronary intervention (PCI) on ACS outcomes is now widely recognized and existing guidelines concur in advocating invasive procedures in all but low-risk ACS patients, where feasible (Table 2) [9–21]. When reperfusion with fibrinolytic therapy is indicated as the primary treatment strategy in patients with STEMI, there is broad agreement between global and APAC guidelines on a door to needle time

Table 1 Overview of main international and APAC ACS guidelines. Country/region

STEMI

NSTEMI/UA

Other relevant guidelines

USA

ACCF/AHA (2013) [19]

ACCF/AHA (2012) [9,14]

Europe Australia/New Zealand

ESC (2012) [21] New Zealand Branch of CSANZ (2013) [20]

ESC (2011) [13,134] New Zealand Branch of CSANZ (2012) [18]

China

CSC CMA (2010) [22]

CSC CMA (2012) [12]

ACCF/AHA — secondary prevention (2011) [28] ACCP — primary and secondary prevention (2012) [126,127] ACCP — antithrombotic therapy (2012) [127] ESC — CVD prevention (2012) [27] NHFA Australia and CSANZ (2011) [24,135,136] ARC and NZRC Guideline (Initial medical therapy 2011) [23] Canadian Cardiovascular Society — use of antiplatelet therapy (2011 and 2013) [29,128] Chinese Expert Consensus for Antiplatelet Therapy in Non-Revascularization Patients with Acute Coronary Syndrome Working Group (2011) [25]

India

Association of Physicians India (2011) [10] Indonesian Heart Association ACS Guidelines (2014) [137]

Indonesian Heart Association ACS Guidelines (2014) [137]

Canada

Indonesia

JCS Joint Working Group — secondary prevention (2013) [138]

Japan Malaysia Philippines Taiwan Gulf states

MOH/NHFA/AMM 2007 [16] PHA (2009) [26] TSOC (2012) [15]

MOH/NHFA/AMM 2011 [17] PHA (2009) [26] Oman Heart Association (2012) [139]

ACCF, American College of Cardiology Foundation; ACCP, American College of Chest Physicians; ACS, acute coronary syndromes; AHA, American Heart Association; AMM, Academy of Medicine; ARC, Australian Resuscitation Council; CMA CSC, Chinese Medical Association Chinese Society of Cardiology; CSANZ, Cardiac Society of Australia and New Zealand; CVD, cardiovascular disease; ESC, European Society of Cardiology; JCS, Japan Circulation Society; MOH, Ministry of Health; NHFA, National Heart Foundation; NSTEMI, non-ST-segment elevation ACS; NZRC, New Zealand Resuscitation Council; PHA, Philippine Heart Association; STEMI, ST-elevation myocardial infarction; TSOC, Taiwan Society of Cardiology; UA, unstable angina.

Y. Huo et al. / International Journal of Cardiology 183 (2015) 63–75

less than 30 min [9,14–16,19,20,22]. Both US and European guidelines recommend the initiation of fibrinolysis in high-risk STEMI patients in whom primary PCI cannot be administered within 120 min of first medical contact [19,21], whereas in Australia, China, Malaysia, New Zealand and Taiwan, guidelines recommend fibrinolysis if the door to balloon time exceeds 90 min [15,16,20,22,24]. 2.3. Acute and long-term pharmacotherapy Routine recommendations from international and APAC guidelines for medical management of ACS are in broad agreement with the mainstay of therapy consisting of dual antiplatelet therapy (DAPT) with aspirin and an adenosine diphosphate (ADP) receptor antagonist, an anticoagulant (in hospital only), statin, beta-blocker (BB), with angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB), as required (Supplementary Table II) [9–21]. There is a broad agreement that, following an initial 150–325 mg loading dose of aspirin, a lower dose (within the range of 75–150 mg/day) should be maintained indefinitely to reduce the risk of bleeding. Notably, ESC STEMI guidelines differ from others by recommending a starting dose of up to 500 mg in the setting of fibrinolysis [21]. The vast majority of ACS guidelines then recommend the addition of an ADP receptor antagonist to aspirin as soon as possible with long-term continuation for 12 months. Use of the newer, faster-acting P2Y12 inhibitors ticagrelor and prasugrel is generally preferred over clopidogrel in patients undergoing PCI. Canadian, European and New Zealand guidelines also recognize the beneficial effects of ticagrelor over clopidogrel in conservatively and purely medically managed NSTEMI/UA patients [13,20,29]. Routine upstream use of platelet glycoprotein IIb/IIIa inhibitors is not recommended in medically managed ACS patients, but guidelines stipulate that patients should receive anticoagulant therapy in hospital. The selective Factor Xa inhibitor fondaparinux is now preferred over either low molecular weight heparin enoxaparin or unfractionated heparin in several guidelines in medically managed ACS [13,19,24]. Statin therapy is also widely endorsed to achieve a low-density lipoprotein cholesterol (LDL-C) level of less than 70 mg/dL (1.81 mmol/L).

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Interestingly, the Acute Coronary Syndrome Prospective Audit (ACACIA; 2005–2007), showed that adherence to guideline-recommended pharmacotherapy was generally good for invasively-treated patients, but medically managed patients received a poorer ‘package of care’, with significantly lower rates of aspirin, clopidogrel, BB, ACEi/ARB and statin use at discharge [34]. Approximately three-quarters of the ACACIA study population presented at metropolitan hospitals. More recently, the SNAPSHOT ACS study set out to characterize adherence to guideline recommendations for medical therapy in suspected ACS across a more representative distribution of hospitals in Australia and New Zealand [35]. Guidelinerecommended invasive procedures/medical therapies were provided less frequently to patients presenting to non-principal referring hospitals. Notably, poorer outcomes were seen in smaller regional hospitals providing a poorer quality of care. In a recently published study from Australia and New Zealand summarizing care received in 2012, only one-quarter of ACS patients received optimal secondary prevention in-hospital [36]. Patients who did not have PCI were less likely to receive optimal care. 3.2. China

The continuous improvement in quality of treatment in hospitals that follow guidelines is well established in ACS [30,31]. Nevertheless, the translation of best practice recommendations and their implementation to ‘real-world’ patient care is often poor. Local ACS registry data provide an overview of ‘real-world’ trends in management patterns and outcomes, and can provide a measure of implementation of best practice (Supplementary Table III).

China has a three-tier system of hospital care. Registry data reveal a disparity in quality of care in China, similar to that seen in Australia and New Zealand [35], with a greater gap between evidence-based guidance and clinical practice in secondary compared with tertiary hospitals [37–39]. The Bridging the Gap (BRIG) on Coronary Heart Disease Secondary Prevention in China study, showed that reperfusion therapy was performed more commonly in tertiary than secondary hospitals and demonstrated substantially higher rates of pharmacotherapy use at tertiary hospitals [39] (Supplementary Table III). In-hospital mortality was significantly greater at secondary compared with tertiary hospitals and was independently associated with lower aspirin, BB and ACEi/ARB use. While rates of aspirin prescription in hospital and at discharge in China are generally high (~ 90% or above) [38,40–42], DAPT rates are suboptimal and long-term compliance is poor. Data from the Clinical Pathway for Acute Coronary Syndromes in China (CPACS) registry (2004–2005) showed that less than 45% of patients received clopidogrel at discharge [40]. This reduced to less than 20% after 12 months. Indeed, only 48% of ACS patients were discharged on the guideline-recommended four-drug combination of antiplatelet, BB, ACEi/ARB and statin [40]. Data from the Prospective Urban Rural Epidemiology (PURE) study (mostly collected between 2005 and 2009) also showed suboptimal use of secondary prevention medication for cardiovascular disease (CVD) in China [43]. Strikingly, the rate of statin use in China was only 2%, compared with 16% in Malaysia and 57% in North America and Europe.

3.1. Australia and New Zealand

3.3. India

In general, Australia and New Zealand benefit from healthcare systems that permit good access to medication and the use of evidencebased ACS guidelines is actively promoted by national cardiac societies. The GRACE study showed a decrease in in-hospital events and 6-month readmissions from 2000 to 2007 in Australia and New Zealand, associated with better uptake of guideline-recommended medical therapy [30]. By contrast, a national audit of ACS patients admitted to New Zealand hospitals over a 14-day period in 2002 and 2007 revealed low rates of adherence with evidence-based guidelines that had not changed substantially over the 5-year period [32,33]. Approximately 30% of STEMI patients eligible to receive reperfusion in 2007 failed to receive it and, of those receiving reperfusion, only 15% underwent primary PCI, nevertheless prescription rates of guideline recommended secondary prevention medication was high (Supplementary Table III) [32].

It is estimated that coronary artery disease will affect more than 65 million people in India by 2015 [44]. The CREATE registry, which gathered data from nearly 21,000 patients presenting with ACS throughout India over a 4-year period to 2005, identified socioeconomic status as a key determinant of standard of care and mortality [45]. Overall, 7.5% of patients underwent PCI and 37% received fibrinolysis. In-hospital antiplatelet use was N 97% in all ACS types and 81% of patients received anticoagulants, but rates of BB, ACEi/ARB, and statin use were suboptimal. Wealthy patients were more likely to undergo invasive procedures or be treated with any of the five key pharmacotherapy agents, and had significantly lower mortality than their poorer counterparts. The southern Indian state of Kerala has the highest economic wealth per capita in India but the Kerala ACS Registry (2007–2009) still reported lower rates of primary PCI (13%) and higher in-hospital mortality rates (8%) for STEMI patients than seen globally [1,46]. Optimal medical

3. Medical management of ACS: current practice in the APAC region

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Table 2 Guideline criteria for conservative/medical management and invasive management in NSTEMI/UA. Guideline/country

Conservative/medical management

Invasive

USA ACCF/AHA 2012 [9,14]

• Low-risk score (e.g. TIMI, GRACE) • Patient or physician preference (in the absence of high-risk features)

Europe ESC 2011 [13]

• No recurrence of chest pain • No signs of HF • No abnormalities in the initial ECG or a second ECG (at 6–9 h) • No rise in troponin level (at arrival and at 6–9 h) • No inducible ischemia

Australia NHFA/CSANZ 2011 [24,135,136]

• Presentation with clinical features consistent with ACS without intermediate-risk or high-risk features. This includes onset of anginal symptoms within the last month, or worsening in severity or frequency of angina, or lowering of angina threshold.

China Chinese Society of Cardiology 2012 [12]

• Stable NSTEMI/UA patients with no serious complications and contraindications for revascularization • Low-risk patients

Malaysia MOH/NHA/AMM 2011 [17]

• No angina in the past • No ongoing angina • No prior use of anti-anginal therapy • Normal ECG • Normal cardiac biomarkers • Normal LV function • Younger age group

New Zealand New Zealand Branch of the CSANZ 2012 [18]

• As ESC criteria [13]

• Recurrent angina or ischemia at rest or with low level activities despite intensive medical therapy • Elevated cardiac biomarkers (troponin T or I) • New or presumably new ST-segment depression • Signs or symptoms of HF or new or worsening mitral regurgitation • High-risk findings from non-invasive testing • Hemodynamic instability • Sustained ventricular tachycardia • PCI within 6 months • Prior CABG • High-risk score (e.g. TIMI, GRACE) • Mild to moderate renal dysfunction • Diabetes mellitus • Reduced LV function (LVEF b 40%) Primary: • Relevant rise or fall in troponin • Dynamic ST- or T-wave changes (symptomatic or silent) Secondary: • Diabetes mellitus • Renal insufficiency (eGFR b 60 mL/min/1.73 m2) • Reduced LV function (LVEF b 40%) • Early post infarction angina • Recent PCI • Prior CABG • Intermediate to high GRACE risk score High-risk features • Repetitive/prolonged (N10 min) ongoing chest pain/discomfort • Elevated cardiac biomarkers • ST-segment depression, new T-wave inversion or transient ST-segment elevation • Hemodynamic compromise — SBP b 90 mmHg, cool peripheries, diaphoresis, Killip Class N I, and/or new-onset mitral regurgitation • Sustained ventricular tachycardia • Syncope • LV systolic dysfunction (LVEF b 0.40) • Prior PCI within 6 months or prior CABG • Diabetes or CKD Intermediate-risk features • Chest pain/discomfort within the past 48 h that occurred at rest, or was repetitive or prolonged • Age N 65 years; • Known CHD — prior MI with LVEF ≥ 0.40, or known coronary lesion more than 50% stenosed • No high-risk changes on ECG • Two or more of the following risk factors: known hypertension, family history, active smoking or hyperlipidemia • Diabetes or CKD • Prior aspirin use High-risk patients • Changes of serum cTn or ST-segment and T wave in ECG • Diabetes • Renal insufficiency (eGFR b 60 mL/min/1.73 m2) • Reduced LV function (LVEF b 40%) • Recurrent angina in the early stage after MI • Recent PCI • Prior CABG • Moderate to high GRACE risk score Early stable patients: • High risk NSTE-ACS patients without severe complications or contraindications for revascularization • Patients with recurrent chest pain • Early post infarction unstable angina • Dynamic ST-segment changes • Elevated cardiac biomarkers • Diabetes • Hemodynamic instability • Depressed LV function (LVEF b 40%) • Major arrhythmias • As ESC criteria [13]

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Table 2 (continued) Guideline/country

Conservative/medical management

Invasive

Philippines PHA 2009 [26]

• Low-risk score (TIMI, GRACE) • Patient or physician preference (in the absence of high-risk features)

• Recurrent angina/ischemia at rest or with low-level activities despite intensive anti-ischemic therapy • Elevated cardiac biomarkers • New or presumably new ST-segment depression • Signs or symptoms of heart failure or new or worsening mitral regurgitation • High-risk findings from non-invasive testing • Hemodynamic instability • Sustained ventricular tachycardia • PCI within 6 months • Prior CABG • High-risk score (e.g. TIMI, GRACE) • Reduced LV systolic function (LVEF b 40%)

ACCF, American College of Cardiology Foundation; ACS, acute coronary syndromes; AHA, American Heart Association; AMM, Academy of Medicine; CABG, coronary artery bypass graft; CHD, coronary heart disease; CKD, chronic kidney disease; CSANZ, Cardiac Society of Australia and New Zealand; ECG, electrocardiogram; eGFR, estimated glomerular filtration rate; ESC, European Society of Cardiology; GRACE, Global Registry of Acute Coronary Events; HF, heart failure; LV, left ventricular; LVEF, LV ejection fraction; MI, myocardial infarction; MOH, Ministry of Health; NHA, National Heart Association; NHFA, National Heart Foundation Australia; NSTEMI-ACS, non-ST-segment elevation myocardial infarction ACS; PCI, percutaneous coronary intervention; PHA, Philippine Heart Association; SBP, systolic blood pressure; TIMI, Thrombolysis in Myocardial Infarction; UA, unstable angina.

care was delivered in only 40% of ACS patients in hospital and 46% at discharge and was more common in academic, non-rural hospitals [47]. Notably, the provision of optimal in-hospital medical care was associated with a 21% lower risk of in-hospital major adverse cardiovascular events. 3.4. Indonesia Data from the Jakarta ACS (JAC) Registry revealed that 59% of all STEMI patients presenting between 2008 and 2009 did not receive reperfusion therapy [48]. Overall, 29% of STEMI patients underwent PCI and 12% received fibrinolysis. In-hospital mortality was 13% in STEMI patients who did not receive reperfusion therapy, compared with 6% receiving fibrinolysis and 5% undergoing primary PCI. Following the establishment of a local STEMI network in Jakarta, 2011 data from the JAC registry showed significant increases in inter-hospital referral rates for STEMI patients and rates of primary PCI procedures, but in-hospital mortality changed little between 2008 and 2009 (8% versus 7%), indicating that improvements in pre-hospital and in-hospital protocols to improve the overall standard of care are still needed [49]. 3.5. Malaysia Rates of medical management in Malaysia are among the highest in the APAC region. Data collected between 2006 and 2008 in the Malaysian National Cardiovascular Disease Database (NCVD) ACS Registry showed that 16% of STEMI patients received no reperfusion due to delayed presentation or missed diagnosis, only 6–8% underwent primary PCI, and 73% received thrombolysis [50]. Similarly, 86% of patients presenting with NSTEMI/UA were solely medically managed. Inhospital mortality was higher than those reported in GRACE (Supplementary Table III). While approximately 90% of all ACS patients received aspirin and statin therapy, only 60–70% received DAPT. Similar management patterns were seen in the Malaysia-ACute CORonary syndromes Descriptive (ACCORD) study, conducted between 2004 and 2005 [8]: 84% of patients were managed medically and only 13% of patients underwent PCI. Initial in-hospital use of aspirin was good, but prescription rates for aspirin declined post-discharge. Inhospital statin use was high (89%) and comparable to that seen in GRACE [1], but BB and ARB use was significantly lower than that seen globally. 3.6. Philippines Heart disease is the leading cause of death in the Philippines, accounting for one in five deaths. In total, 62% of STEMI patients in the Philippine Heart Association ACS Registry (2011–2013) received no

reperfusion, 25% underwent primary PCI and 12% received fibrinolysis [51]. Financial constraint was a major confounder in an additional 11% of STEMI patients in whom invasive procedures were advised but not undertaken. Between two-thirds and three-quarters of patients presenting with NSTEMI/UA were solely medically managed. In-hospital mortality of 8% for STEMI, 9% for NSTEMI, and 3% for UA was higher than reported in the GRACE study and was comparable to those reported in the NCVD ACS registry in Malaysia [50]. Despite good in-hospital adherence to guideline recommended pharmacotherapy with ≥ 90% of patients receiving DAPT, BB, and statin therapy (Supplementary Table III). 3.7. Thailand Comparison of data from phase I (2002–2004) and phase II (2007–2008) revealed an improvement in the proportion of patients receiving reperfusion (53–67%), but the number of patients undergoing primary PCI remained low (22–25%) [4,52]. Use of PCI, aspirin, BB, and ACEi were predictors of improved outcome in both STEMI [53] and NSTEMI [54] patients. Interestingly, in-hospital ADP receptor antagonist use in STEMI patients had increased from 60% during phase I to 98% during phase II, following the government's decision to reimburse generic clopidogrel and other ADP receptor antagonists. A corresponding increase from 59 to 83% was seen in NSTEMI patients. 3.8. Taiwan Taiwan benefits from a single-payer compulsory social insurance plan that covers more than 95% of residents and has both good access to invasive catheterization/cardiac surgery facilities and affordable pharmacotherapy. Rates of intervention are high. Data from patients with NSTEMI and UA collected between 2004 and 2006 in the Taiwan ACute COronary syndrome Descriptive Registry (T-ACCORD) revealed an 81% catheterization rate, with 71% of patients undergoing PCI/coronary artery bypass graft (CABG) [55]. Nevertheless, while the in-hospital DAPT rate was 72%, this declined over 12 months post-discharge to 13%. High intervention rates were also seen in a more recent analysis of the Taiwan ACS Full Spectrum Registry (2008–2010) [3,56]. In total, 97% of STEMI patients admitted within 24 h of symptom onset received primary PCI. In-hospital mortality was 2% with 12-month mortality, 8% [3,56]. While antiplatelet agents were prescribed to N90% of patients on discharge, prescription of DAPT deviated from evidence-based guidelines; only 75% received DAPT at discharge and the rate declined to 25% by 12 months. Rates of BB, ACEi, ARB, and statin therapy at discharge and follow-up were also suboptimal.

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3.9. EPICOR Asia EPICOR Asia (long-tErm follow-uP of antithrombotic management patterns In acute CORonary syndrome patients in Asia; clinicaltrials.gov NCT01361386) was a multinational, observational, prospective, longitudinal cohort study conducted in China, India, Thailand, Malaysia, South Korea, Hong Kong, Vietnam and Singapore. EPICOR Asia was designed to provide a timely estimate of inter-country antithrombotic management patterns in Asian patients with ACS and to assess the impact of variations in management on clinical outcomes, cost, and quality of life over a 2-year follow-up. Of nearly 13,000 eligible patients enrolled at 219 sites, 51% had a final diagnosis of STEMI, 20% NSTEMI, and 29% UA [57]. Approximately two-thirds of the study population had received PCI. The incidence of coronary events, ischemic stroke, and thromboembolic events at 1-year post discharge was significantly greater for patients with NSTEMI compared with STEMI. One-year mortality was significantly greater with NSTEMI compared with STEMI (hazard ratio, 1.42; p b 0.01). Full publication of the results is expected in 2015. 4. Meeting the challenges in best evidence application in ACS in the APAC region The APAC ACS Medical Management Working Group identified five categories of unmet need specific to the application of best evidence to medical management of ACS in the APAC region and made a series of recommendations to address these challenges (Supplementary Table IV). 4.1. Accessibility/systems of care 4.1.1. Pre-hospital care Timely reperfusion is clearly associated with significant outcome benefits [58], but despite the introduction of a variety of public health campaigns throughout the APAC region since the 1980s, there has been limited success in reducing the time from symptom onset to calling an ambulance to a timeframe that will prevent heart damage. In Australia and China, the average response time is approximately 3 h [59]. In Indonesia, the time from onset of infarction to hospital admission exceeds 12 h in almost 80% of cases [48]. In the Philippines, a country consisting of 7100 islands with marked geographical barriers, the average time from onset of ACS symptoms to emergency room (ER) consultation is 69 h [51]. A centralized/co-ordinated ambulance service is pivotal to optimizing time to treatment. However, geographical barriers present difficulties for ambulance services in some larger APAC countries. In some cities and provinces, for example in Jakarta, Indonesia [48], heavy traffic contributes to delays. In other regions, collaboration between ambulance services and hospitals is complicated. In Hong Kong, for example, ambulances are co-ordinated outside the healthcare system by the fire department. In India, the ambulance service provides no mechanism for transfer between private hospitals [60]. In China, few cities have qualified ambulance services with the majority of patients presenting themselves to hospital. Pre-hospital triage with ECG [61,62] performed by well-trained paramedics provides rapid diagnosis, permitting suspected STEMI patients to be transported directly to appropriate hospitals, minimizing treatment delay [63,64]. Despite recommendations for early triage and treatment initiation in current ACS guidelines, preliminary data from EPICOR Asia show that nearly two-thirds of patients presenting with ACS in Asia fail to receive any pre-hospital ECG [65]. In some APAC countries, such as Thailand and the Philippines, ambulances are not equipped with the means to monitor and transmit an ECG. Early initiation of pre-hospital fibrinolysis in STEMI reduces the risk of ischemic complications and recurrent thrombus formation. In New Zealand, paramedic staff liaise with hospital cardiologists before administering fibrinolysis in the ambulance, leading to reduced time to

treatment and rates of heart failure [66]. In Australia, regional-based initiatives have been put in place to empower appropriately trained healthcare workers to initiate fibrinolysis in pre-hospital settings in some circumstances [67]. However, resourcing an adequately trained ambulance crew to administer pre-hospital fibrinolysis is not achievable in some countries. In others, for example India, legal issues confound the personnel licensed to administer fibrinolysis. Preliminary data from EPICOR Asia show that initiation rates for medication prehospitalization are low [65]. Less than 1% of patients received fibrinolysis and only 6% received antiplatelet or anticoagulant therapy before hospitalization. In the 35% of patients who received pre-hospital ECG, pre-hospital aspirin and clopidogrel were given to 16% and 14% of STEMI patients, to 12% and 9% of NSTEMI patients, and to 4% and 3% of UA patients, respectively. Among patients who did not have a prehospital ECG, rates of pre-hospital medication use were even lower. Recommendations 1. Attempt to shorten the delay between patient first experiencing symptoms and first medical contact, recognizing that this is a significant problem and that previous attempts to modify it have been largely unsuccessful 2. Encourage regional co-ordination of ambulance services 3. Encourage ambulance services to liaise with hospitals and perform pre-hospital triage (using 12-lead ECG) and pre-hospital fibrinolysis where appropriate (i.e. where there is not access to a primary angioplasty myocardial infarction (MI) service, if there are significant transport times to hospital, and if ambulance services have the appropriate skill/support) 4. Establish rapid assessment protocols in the emergency department. 4.1.2. Access to healthcare Within the APAC region, the distance to reach specialist cardiac centers with catheterization laboratories presents barriers to guideline adherence, and explains in part the higher rates of medical management observed. In some remote areas of Australia and China, the geographical barriers are immense. Furthermore, in China, only 15% of hospitals are equipped with catheterization laboratories for emergency management of ACS. In Hong Kong and Southern Thailand the number of PCI-capable facilities is also limited. In Peninsular Malaysia, most patients can reach a secondary care hospital within 90 min, however geographical barriers exist for the population of Sarawak and Sabah in Borneo. Manpower also determines ‘access to healthcare’. While patients may be able to reach a catheterization laboratory within the guideline-specified door to balloon time, a 24/7 service may not be available. In certain APAC countries, guideline-recommended pharmacotherapies are not approved; reimbursement policy can also prevent realworld ‘access’ to approved drugs (Table 3). In Taiwan, past restrictions on the reimbursement of clopidogrel (to 9 months only) and statins (to patients with LDL-C N130 mg/dL) adversely affected adherence to guideline recommendations for secondary prevention [15]. DAPT use reduced from 75% of patients at discharge to 25% at 1-year follow-up and ‘access’ to statin therapy was prevented for a large proportion of patients [56]. Long-term follow-up is a key challenge in secondary prevention of CVD. It is estimated that one-third of patients with a history of MI do not adhere to therapy over the long term [68]. In China, hospital and community-centered care is not linked; in Australia, the two components of care are funded through different systems; and in the Philippines, patients from remote areas commonly have no access to specialists. Non-adherence does not appear to be specifically associated with class of drug [68], and interventions to improve compliance need to be broadly applied. Evidence-based guidelines have the greatest value for remote/ regional hospitals where ACS is not the major workload. In practice,

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Table 3 Approved and funded/reimbursed ACS pharmacotherapy in the APAC region.

Antiplatelets Aspirin Clopidogrel Prasugrel Ticagrelor Ticlopidine Cilostazol Glycoprotein IIb/IIIa inhibitors Abciximab Eptifibatide Tirofiban Anticoagulants Heparin Enoxaparin Dalteparin Nadroparin Parnaparin Hirudin Fondaparinux Dabigatran Bivalirudin Apixaban Rivaroxaban Otamixaban Fibrinolytic agents Streptokinase Alteplase Reteplase Tenecteplase Aldosterone antagonists Eplerenone

China

HK

Taiwan

India

Indonesia

Malaysia

Thailand

Philippines

Australia

NZ

A

F/R

A

F/R

A

F/R

A

F/R

A

F/R

A

F/R

A

F/R

A

F/R

A

F/R

A

F/R

Y Y N Y Y Y

Y Y N/A N Y Y

Y Y Y Y Y Y

Y Y Y Y N Y

Y Y N Y Y Y

Y Y N/A Y Y Y

Y Y Y Y N Y

Y Y N N N/A N

Y Y N Y Y Y

Y Y N/A N N Y

Y Y Y Y Y Y

Y Y Y Y Y Y

Y Y Y Y Y Y

Y Y N N Y N

Y Y Y Y N Y

Y Y N N N/A Y

Y Y Y Y Y Y

Y Y Y Y Y N

Y Y Y Y Y N

Y Y Na Y Y N/A

N Y Y

N/A N Y

Y Y Y

Y Y N

Y Y Y

Y Y Y

Y Y Y

N N N

N Y N

N/A Y N/A

Y Y Y

N N Y

Y Y Y

N Y N

N Y Y

N/A N N

Y Y Y

Y Y Y

Y Y Y

Y Y N

Y Y Y Y N Y Y Y Y Y Y N

Y Y Y Y N/A N N N N N Y N/A

Y Y N Y N N Y Y N Y Y N

Y Y N/A Y N/A N/A N Y N/A N Y N/A

Y Y Y Y N N Y Y Y Y Y N

Y Y Y N N/A N/A Y Y N N Y N/A

Y Y Y Y Y Y Y Y N Y Y Y

Y Y N N N N N N N/A N N N

Y Y N Y Y N Y Y N Y Y N

Y Y N/A N N N/A Y N N/A N N N/A

Y Y N N N N Y Y N N Y N

Y Y N N N N Y Y N N Y N

Y Y Y Y Y N Y Y Y Y Y N

Y Y N N N N/A Y N N N N N/A

Y Y Y Y Y N Y Y N Y Y N

Y Y Y Y N N/A Y N N/A N N N/A

Y Y Y Y N N Y Y Y Y Y N

Y Y Y N N/A N/A Y Y Y Y Y N/A

Y Y Y Y N N Y Y Y Y Y N

Y Y Y N N/A N/A N Y Yb N N N/A

Y Y Y N

Y Y N N/A

Y Y Y Y

Y Y N Y

Y Y N Y

Y Y N/A Y

Y Y Y Y

Y N N N

Y Y N N

Y Y N/A N/A

Y Y N Y

Y Y N Y

Y Y Y Y

Y Y N N

Y N N Y

Y N/A N/A N

Y Y Y Y

N N Y Y

Y Y N Y

Y N N/A Y

N

N/A

Y

Y

Y

Y

N

N

N/A

Y

N

Y

N

Y

N

Y

Y

Y

N

A, approved; F, funded; R, reimbursed. Bold indicates pharmacotherapy not available as a consequence of lack of approval and/or lack of funding/reimbursement. a Funding limited to 7 days post-STEMI or stent thrombosis. b For those undergoing PCI.

levels of guideline-recommended treatment are inferior at these centers, where familiarity and ‘comfort’ with drug administration is limited [35]. In particular, non-teaching community hospitals have distinct knowledge gaps and there is often slower uptake of new therapies, which contributes to geographical disparity in the quality of care. Quality of care in ACS can also be influenced by the public or private status of hospitals. Data from the Thai ACS Registry showed that patients were more likely to undergo invasive procedures in private hospitals; length of stay and in-hospital mortality was greater in public hospitals [69]. A key solution to improving ‘access’ to care in ACS lies in ensuring that the system of care is coordinated on a national, regional and local level. Indeed, utilizing the existing care infrastructure more efficiently through the establishment of effective cardiac networks may be a better solution than increasing the number of PCI centers in APAC countries [70]. A variety of cardiac networks have been successfully implemented worldwide [70]. Traditional ‘hub and spoke’ networks already exist in Australia, New Zealand, India, Philippines, Thailand, China and Indonesia [48,71], and have been shown to improve patient care at a regional level. Clinicians often have false beliefs about their level of guideline implementation [72]. Cardiac networks can play an important role in auditing quality of care and monitoring continuing improvement performance measures. In New Zealand, the All NZ ACS Quality Improvement (ANZACS QI) registry has recently been established to investigate national trends in ACS management, post-discharge rehabilitation and care. It will provide insights into the comparative effectiveness of care based on clinical risk and examine why certain hospitals are underperforming, in an attempt to identify solutions. Provision of data is mandated by the government.

Recommendations 5. Utilize existing infrastructure more efficiently through establishment of cardiac networks to address specific challenges on a national, regional, and local level a. National cardiac networks to i. Tackle geographical disparity in quality of care ii. Establish registries to perform audit monitoring and quality improvement performance b. Regional/local cardiac networks to i. Establish formal evidence/guideline-based regional protocols ii. Address problems with access to healthcare in regional areas – Availability of fibrinolytics, catheterization laboratory availability/distance, manpower iii. Improve community follow-up iv. Perform audit and be involved in continuous quality improvement initiatives.

4.2. Risk stratification Once vascular disease manifests, the risk of further events in the same or another vascular bed is high, even in younger patients [73]; thus, there is a need for greater awareness of the level of risk among clinicians treating ACS. Observational data suggest that high-risk patients are least likely to receive evidence-based medical treatment [40,74]. Subjective estimation of patient risk and under-estimation of treatment benefit are contributing factors [75].

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4.2.1. Risk factors Registry data highlight clear differences in risk factors for ACS within the APAC region (Supplementary Table III), reflecting ethnic diversity, varying degrees of ‘westernization’, unique gene–dietary interactions and cultural factors. In China, high incidences of smoking and high dietary salt intake contribute to cardiovascular risk. In Thailand, there are high rates of diabetes in both STEMI (37%) [76] and NSTEMI (~50%) patients [77]. In Malaysia, ACS appears to manifest at a younger age with more severe comorbidity, more severe disease, and higher rates of obesity and diabetes [50,78,79]. Even within Malaysia, risk factor profiles differ with ethnicity: NCVD ACS registry data show Malay patients have higher rates of obesity, Chinese patients have the highest rates of hypertension and dyslipidemia, and Indian patients have the highest rate of diabetes [80]. Indian patients living all over the world tend to have higher levels of diabetes and other CVD risk factors at a younger age [81]. This is thought to be attributed to a gene–dietary interaction in Indians where a highcalorie, high-protein, high-fat diet results in high levels of diabetes, dyslipidemia, and metabolic syndrome [82]. In India itself, the rate of diabetes is increasing year-on-year [83]. More than 72 million adults in the South East-Asia region (comprising India, Sri Lanka, Bangladesh, Bhutan, Mauritius and the Maldives) were estimated to have diabetes in 2013; the number is expected to exceed 123 million in 2035 [84]. The prevalence of diabetes in ACS is lower in New Zealand than in other parts of the APAC region [32,33]; however, diabetes rates are increasing, reflecting the growing Polynesian and Asian ethnic groups. High on-treatment platelet reactivity (HOTPR), which is common in clopidogrel-treated diabetic patients, and associated with poor prognosis following ACS, is also more common in Maori, Asian and Pacific Island ethnic groups in New Zealand [85]. Indeed, the incidence of CYP2C19*2 polymorphism, which is related to HOTPR, is estimated to be 55–70% in Asians, with 10–20% of the population also carrying the CYP2C19*3 allele [86–89]. 4.2.2. Risk score models While tertiary hospitals throughout the APAC region tend to utilize risk score models for risk stratification, in regional hospitals there is frequently no formal risk assessment. The GRACE score appears to provide the most accurate stratification of risk compared with the TIMI score [90] due to its inclusion of heart rate, Killip class, systolic blood pressure, and renal function [13], but the original GRACE score requires a complex calculation. The simpler, more user-friendly GRACE 2.0 risk score provides a ‘mini-GRACE’ algorithm for use when serum creatinine and Killip class are not available [91]. It is available online and for smartphone use (www.gracescore.org). In Australia and New Zealand, use of the GRACE score is strongly promoted. The GRACE score has also become popular in India because it clearly identifies patients who are at high risk. However, in Malaysia use of the TIMI score, which has been validated specifically in this population [92], predominates. In Taiwan either score is routinely used. In other APAC countries, including China, Hong Kong, Thailand and the Philippines, while hospitals with clinical pathways use TIMI or GRACE, mostly there are no structured models for risk stratification. Differences in risk factors and ethnic profiles within the APAC region, as well as genetic differences, can influence outcomes and response to therapy and validation of the major risk scores in APAC populations using local registry data might prove useful. Paradoxically, higher rates of PCI have been seen among patients with low GRACE scores [38]. Younger, fitter patients without comorbidities also paradoxically tend to receive more intervention [93,94]. Clinical judgment is imperative during risk stratification to take into account universal markers of risk (e.g. advanced age and severe renal failure [95]), other comorbidities, ability to benefit from treatment, patient preference, prior invasive procedures and access to treatment. Data from the Thai ACS Registry showed that cardiac dyspnea, shock and post cardiac arrest were independent predictors of poor prognosis in ACS [96]. Decision-

making tools can be useful in improving the accuracy of risk stratification [97,98]. In terms of bleeding risk, the CRUSADE score has been used to assess in-hospital bleeding risk; however, there is some debate over its ability to accurately predict risk on an individual patient level [99]. There is a need for more practical guidance to facilitate individualization for other complicating factors when assessing bleeding risk (e.g. anemia), or concomitant oral anticoagulant administration. Recommendations 6. Recommend risk assessment at first medical contact 7. Identify high-risk groups (ethnicity, obesity, diabetes, renal dysfunction) and treat appropriately 8. Recommend use of formal risk scores (primarily GRACE) 9. Validate TIMI and GRACE risk scores in Asian patients using APAC registry data 10. Develop decision support tools to complement risk tools, and enlist pharmaceutical industry to support development of practice tools that facilitate use of established risk stratification scores 11. Consider bleeding risk; scoring systems for this are available but are not as clinically useful as scores for overall risk stratification.

4.3. Education 4.3.1. Patients Public recognition of ACS signs and symptoms, and knowledge of what to do in the event of experiencing chest pain, is poor. There is often a sense of denial in ACS. At the root of the problem is low public education and risk factor awareness. This is an issue in all communities, and concerted public education efforts have shown how difficult it is to modify behavior [100]. Smoking cessation is one of the most effective strategies for primary and secondary prevention of ACS. The New Zealand government leads the way in the APAC region in their attempt to make the country smoke-free by 2025. Policies that include increasing the tax on cigarettes, strengthening the ban on public smoking and tobacco advertising, and introducing negative packaging have produced a gradual reduction in smoking prevalence in New Zealand [101,102]. Interestingly, much of the decline is attributed to reduced initiation rather than increased cessation, and smoking rates have declined less among the indigenous Maori population. In Thailand, 66% of younger ACS patients (aged b45 years) have a history of tobacco use [103]. Both primary measures aimed at preventing initiation of tobacco use in young people and initiatives to promote smoking cessation targeted to those groups with the highest smoking rates are required within the APAC region. Post-discharge management of ACS throughout the APAC region is sub-optimal [104]. Poor compliance, both in terms of lifestyle modification and adherence to drug therapy, complicates the secondary prevention of CVD and is independently associated with socioeconomic status, number of prescribed medications, lower educational status [105], and mortality [106,107]. While patient education programs that include information on drug compliance, diet and smoking cessation have been successfully implemented in the past by community health workers and physician assistants within the APAC region, geographical barriers in some countries prohibit formal cardiac follow-up rehabilitation programs. In China, for example, long-term follow-up is challenging as hospital and community-centered care is not linked and there is no regular cardiac follow-up program after discharge. At the very least, patients should receive a documented ACS management plan, medication list, chest pain action plan, and risk factor modification advice on discharge.

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4.3.2. Healthcare professionals Throughout the APAC region there remains clear under-utilization of invasive management and more potent P2Y12 ADP receptor antagonists, despite funding, good evidence of efficacy, and guidelines. Even in Taiwan, low adherence to the Taiwan Society of Cardiology guidelines remains a challenge in secondary prevention (especially for DAPT and statins), despite recent amendments to reimbursement policy [56]. Clinical outcomes are better in treatment environments where there is good knowledge of clinical trial evidence [108,109]. National society congresses and local educational meetings can be good forums for dissemination of knowledge and to facilitate implementation of guidelines [110]. Structured quality improvement programs have been successful in producing improvements in evidence-based treatment practice [111], and national cardiac societies within the APAC region may be able to play a role in establishing these audit systems and monitoring improvement. Lack of familiarity with new drugs among non-cardiologists/less experienced cardiologists, and concerns around compliance/side effects with newer antiplatelet agents, can contribute to poor uptake, particularly in regional hospitals. Training and experience can affect noncardiac physician attitudes to, and confidence in, using newer drugs [112]. The introduction of pocket guidelines, apps, and other educational initiatives, with balanced industry support, can help drive local implementation/wider adoption of newer agents. However, as with patient education within the APAC region, initiatives must be countryspecific, reflecting cultural barriers. Recommendations 12. Improve public awareness of ACS and widely promote a plan of action to avoid late presentation that recommends patients with chest pain lasting N 15 min present to the nearest hospital ER 13. Enlist cardiac society and industry support for nationally specific initiatives to disseminate guidelines and educate patients on healthy lifestyle, medications, and the importance of compliance 14. Promote national and individual smoking cessation initiatives 15. Educate non-cardiac physicians (emergency department, generalists, and primary care physicians) on translational cardiovascular medicine, including the appropriate use of new drugs and appropriate treatment for high-risk groups. 4.4. Optimization of pharmacotherapy While guidelines can facilitate evidence-based care, their complexity can be a barrier and simple prescriptive guidance is required in everyday practice [110]. Well-integrated clinical pathways can enhance adherence to best-practice guidelines [113,114] and should have a beneficial effect on optimization of pharmacotherapy in rural hospitals, where a larger evidence-practice gap exists [35]. Models incorporate triage, risk assessment and referral, and provide guidance at a local level that accounts for differences in clinical practice, levels of emergency care, and resource/drug availability [115]. Key features include step-by-step guides, hospital checklists for the assessment and management of patients, partnership-building between multi-disciplinary team members across the continuum of care, and treatment algorithms based on published guidelines/more recent clinical data to provide a clear hierarchy of medical therapies. Subjective underestimation of patient risk is a confounding factor in the provision of evidence-based ACS care [75]. Revascularization may not be a suitable option for some high-risk patients, such as patients who have undergone previous invasive procedures, those with diffuse distal disease and co-morbidities such as severe lung disease, chronic kidney disease, or the very elderly/frail. Nevertheless, studies have shown that these high-risk patients typically receive sub-optimal medical therapy [74]. Optimization of pharmacotherapy, particularly DAPT,

71

in these high-risk medically managed patients should improve outcomes [116]. Recommendation 16. Establish clinical pathways and evidence-based checklists to complement guidelines 17. Address gaps in local hospitals' use of appropriate therapy by promotion of guidelines and clinical pathways 18. Optimize treatment of high-risk groups (diabetes, chronic renal impairment, obesity). 4.5. Cost/affordability Many APAC countries now benefit from public-funded healthcare systems and insurance coverage policies. However, costs differ among the ACS diagnostic groups and in some countries, affordability remains an important determinant of clinical practice. Analysis of the Thai ACS Registry showed that hospital and payer type, medication used, treatment procedures, and complications were independently predictive of costs [117]. In the Philippines, healthcare remains largely funded by user fees and healthcare reform has failed to address the persistent problem of inequity in the standard of care. A large proportion of the population are of low socioeconomic status, and management decisions are often determined by the patient, primarily based on cost rather than risk assessment [51]. In India, three-quarters of ACS patients must pay for their own treatment [45]. Although approved, use of newer ADP receptor antagonists is not funded (Table 3), and costs discourage their use. For countries benefiting from public-funded healthcare systems, drug reimbursement systems determine ‘real-world’ access to pharmacotherapy. In Thailand, limitations on reimbursement of new/expensive drugs by the government present a significant barrier to implementing evidence-based guideline recommendations on a local level [118]. Pharmacoeconomic factors also play an increasing role in health technology assessment and drug reimbursement decision-making [119]. Reimbursement systems that allow high-risk patients to have timely access to ‘non-essential’ or non-generic drugs would be of benefit to the management of ACS in these countries. Where possible, ACS treatment should be prioritized using available evidence to achieve the largest benefit for available funding (Table 3). In terms of impact, cost and availability, there is no doubt that, unless contraindicated, aspirin should be administered immediately and continued indefinitely in ACS [120]. The beneficial effects of the addition of clopidogrel to aspirin in medically managed ACS patients are well established [121–123], and the long-term cost-efficacy of treatment with clopidogrel up to 12 months has since been demonstrated in both STEMI and NSTEMI/UA patients [124,125]. However, newer, more potent P2Y12 ADP receptor antagonists associated with improved outcomes in ACS now exist. On the basis of available evidence, guidelines recommend ticagrelor and prasugrel as alternatives to clopidogrel in ACS patients proceeding to PCI [9,10,13,15,17–21,24,28]. In purely medically managed NSTEMI/UA patients, US guidelines also recommend ticagrelor as an alternative to clopidogrel, and European, Canadian and New Zealand guidelines advocate ticagrelor over clopidogrel [13, 14,18,126–128]. In a sub-analysis of 5216 ACS patients from the PLATelet inhibition and patient Outcomes (PLATO) study in whom invasive procedures were not planned, ticagrelor was associated with a significantly lower incidence of vascular death, MI, or stroke and overall mortality compared with clopidogrel [129]. When cost, affordability, and availability are not major issues, optimal ACS medical therapy should, therefore, incorporate a newer potent P2Y12 inhibitor, particularly as higher risk patients may ultimately go on to receive PCI or CABG. The benefit of high-dose intensive statin therapy in the secondary prevention of CVD is widely recognized, with each 1.0 mmol/L

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(38.7 mg/dL) reduction in LDL-C reducing the incidence of major vascular events by approximately 20% [130]. During a post-hoc analysis of data from the GRACE study, statins provided the greatest benefit in terms of 6-month mortality compared with other evidence-based pharmacotherapies [131]. There are few cost barriers to widespread use of oral BBs, however, the evidence base supporting their long-term use post-MI dates from 25 years ago and there is debate over its applicability to the current treatment landscape [132]. Robust data underlie guideline recommendations for long-term use of ACEi/ARBs and aldosterone antagonists in patients with left ventricular (LV) dysfunction, but evidence for their use in conjunction with other risk reduction therapy is weak in patients other than those with hypertension, diabetes, or LV dysfunction [133]. Recommendations 19. Prioritize treatment of medically managed ACS patients using available evidence to achieve the greatest benefit with the available funding, in the following order: a. Aspirin administered immediately and continued indefinitely b. Statin therapy recommended during hospital and continued indefinitely, irrespective of LDL-C level. Type, intensity and dosage of statin must be individually selected and also depends on availability, affordability and guidance in each country c. DAPT essential for 12 months in all patients. If affordability is not a major issue, use a newer potent antiplatelet associated with improved outcomes d. Oral BBs in the medium term (the appropriateness of long-term use is less clear) e. ACEi/ARBs strongly recommended long-term in the presence of LV dysfunction. (The evidence for ACEi/ARBs is less clear in patients with preserved LV dysfunction.) f. Aldosterone antagonists appropriate in the presence of LV dysfunction (in line with international guidelines).

5. Summary Published registry-based data demonstrate clear variability in the proportion of ACS patients undergoing medical management, pharmacological practice patterns, and mortality across the APAC region. A high proportion of patients within the APAC region are solely medically managed, reaching up to 75–80% of ACS patients in India, Malaysia and Thailand. Improvements in adherence to pharmacotherapy have been observed across much of the APAC region in recent years in line with evidence-based guidance. The majority of ACS patients now receive aspirin in hospital and remain on aspirin post discharge. However, despite good evidence, registry data reveal that prescription rates of DAPT are sub-optimal and vary greatly between APAC countries. Furthermore, there is slow adoption of newer, more potent P2Y12 receptor antagonists and poor long-term compliance. Each APAC country faces a unique set of barriers that prevent optimal translation of evidence-based guideline recommendations into practice. These challenges can be broadly categorized into issues with accessibility/systems of care, risk stratification, education, optimization of pharmacotherapy, and cost/affordability. While guidelines represent a valuable standard of care and are a useful tool for influencing government, establishing cardiac networks and local/individual hospital models/clinical pathways that take into account local risk factors (including socioeconomic status), affordability/availability of pharmacotherapy and invasive facilities, and the nature of local healthcare systems, will be central to optimization of ACS medical management in the APAC region.

Funding The APAC ACS Medical Management Working Group project is funded by AstraZeneca, Shanghai, China. Conflict of interest The authors disclose the following conflict of interest: WB has received fees for service from AstraZeneca, Daichii Sankyo, MSD, Novartis, Abbot Vascular, Medtronic and ST Jude Medical and is an advisory board member for AstraZeneca, Daichii Sankyo and Novartis; AS has received fees for service for participation at advisory boards for AstraZeneca, Merck-Sharp & Dome, Pfizer, Merck and Takeda; ER has received fees for service as member of advisory board from Servier, AstraZeneca, and E. Merck, and as speaker from Natrapharm, AstraZeneca, Servier, MSD, Novartis, and Merck; GV has nothing to disclose regarding any financial interests such as employment, stock ownership, paid expert testimony, as well as any personal relationships, academic competition, and intellectual passion which may inappropriately influence his actions in the preparation of this manuscript; H-IY has received fees for service for participation as a speaker at AstraZeneca, Bayer, Boehringer Ingelheim, Daiichi Sankyo, Merck-Sharp & Dome, Pfizer, Sanofi, Servier, Takeda and Tanabe-sponsored symposia; LR has received fees for service as speaker for AstraZeneca, Servier, Novartis, Novo, Merck-Sharp & Dome and Abbott Pharmaceuticals. SH has acted in an advisory capacity for AstraZeneca, Sanofi Aventis and Eli Lilly, has received fees for service for speaking from Eli Lilly and AstraZeneca, and has received a research grant from AstraZeneca; PT has received consulting fees and speakers fees for Astra Zeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb and Pfizer. LWT, JG and HY have nothing to disclose regarding any financial interests such as employment, stock ownership, paid expert testimony, or personal relationships, academic competition, or intellectual passion that may have inappropriately influenced their actions in the preparation of this manuscript. Acknowledgments The meeting on which this report was based was supported by AstraZeneca. All authors received fees for service to support attendance at the meeting and preparation of meeting materials. All authors were provided with travel and hotel costs to attend the meeting. Melanie Jones (Prime Medica Ltd, Knutsford, Cheshire, UK) provided medical writing support during the manuscript development, funded by AstraZeneca. Responsibility for opinions, conclusions and interpretation of the data lies with the authors. Employees of AstraZeneca were permitted to read the first draft and final draft of the manuscript and make suggestions on scientific and technical accuracy only. It was the authors' decision whether to accept or reject any suggestions made by AstraZeneca. Responsibility for opinions, conclusions and interpretation of the data lies with the authors. Supplementary material Supplementary Tables I–IV can be found online at http://dx.doi.org/ 10.1016/j.ijcard.2014.11.195. References [1] K.A. Fox, S.G. Goodman, W. Klein, et al., Management of acute coronary syndromes. Variations in practice and outcome; findings from the Global Registry of Acute Coronary Events (GRACE), Eur. Heart J. 23 (2002) 1177–1189. [2] C.V. Pollack Jr., J.E. Hollander, A.Y. Chen, et al., Non-ST-elevation myocardial infarction patients who present during off hours have higher risk profiles and are treated less aggressively, but their outcomes are not worse: a report from Can Rapid Risk Stratification of Unstable Angina Patients Suppress ADverse Outcomes with Early Implementation of the ACC/AHA Guidelines CRUSADE initiative, Crit. Pathw. Cardiol. 8 (2009) 29–33.

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