Acute coronary syndrome in the Asia-Pacific region

A systematic PubMed search was conducted (29 May 2013) to identify ‘real-world’ ACS management data published in the last 20 years from the Asia-Pacific region. From 887 references identified, those considered by the discussants to provide a sufficiently broad overview of ACS management and mortality across the Asia-Pacific region (n = 54) were prioritized and used as a ‘reference’ dataset simply to support discussion (details in Supplementary materials). While potentially subjective, any additional studies/references or unpublished registry-based data available from the author's own center or region considered by the authors as appropriate to consider were included also.

Registry-based mortality data across APAC countries was considered in terms of disease status and invasive versus non-invasive intervention (Table 1 and Supplementary Table 1) [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37], [38], [39], [40], [41], [42], [43], [44], [45], [46], [47], [48], [49], [50], [51], [52], [53], [54], [55].

According to the multinational Global Registry of Acute Coronary Events (GRACE), which studied 43,810 patients from 1999–2005 in 14 countries excluding Africa and Asia [22] large differences exist in management practice both by hospital type and geographic location despite comparable use of antiplatelets and anticoagulants [22]. While mortality rates at 6 months post-discharge, for example, were comparable with in-hospital rates (~ 5%), optimal revascularization and statin use could prevent up to 32% and 10% of deaths by 6 months, respectively [23]. Greatest survival at 6 months was associated with timely CABG (odds ratio [OR] for death 0.60; 95% confidence interval [CI] 0.39–0.90) and PCI (OR 0.57; CI 0.48–0.72), and use of clopidogrel (OR 0.84; CI 0.72–0.99) and statins (OR 0.85; CI 0.73–0.99) [56], [57].

In terms of national economic status, the Organization to Assess Strategies for Ischemic Syndromes (OASIS)-1 (low- and middle-income countries, 1995–1996) and OASIS-2 (middle- and high-income countries, 1999–2000) registries – both 2-year prospective studies of outcomes in NSTE-ACS patients [19] – show little difference in 2-year mortality, despite wide variability in management practices. With the exception of China, where 2-year mortality was only 7% (attributed to an inherent low risk of patients in OASIS-2), overall event rates in OASIS-2 remained high (up to 15%), demonstrating continued risk for long-term mortality, subsequent MI, refractory angina, and stroke, and the need for new approaches to reduce risk [19].

Large registries in the Asia-Pacific region such as the Melbourne Interventional Group Registry (MIG-R) and the Acute Coronary Syndrome Prospective Audit (ACACIA) in Australia comprise populations similar to registries in Europe and Canada [24], [25], [51], [58], [59], [60]. Perhaps as expected, ACACIA, which included propensity adjusted scoring for early invasive management, showed little difference both in in-hospital and 12-month ACS-related mortality (2–5%) [26] compared with other large international registries [61], [62], [63].

In China, registry-based studies reporting guideline-recommendations show treatments are implemented in only one-third of STEMI patients, with many patients not reperfused within recommended times [28] and generally high mortality [29], [31], [32]. Here, the authors expressed caution given clear heterogeneity in the thoroughness of patient follow-up, highly variable methods of data collection and treatment preferences across China (e.g. preferred thrombolysis use in small hospitals versus PCI in grade 3 hospitals providing specialist health services), and broad geographical variation in patient risk profiles i.e., East versus West. Nevertheless, trends towards decreased mortality rates do relate to improved practice in the emergency room/coronary care unit, including increased use of coronary angiography (CS Ma, personal communication).

Data from the treatment and outcomes of acute coronary syndromes in India (CREATE) registry [33] and the more recent Kerala [34] registry show that primary PCI rate is much lower in India compared with more developed countries and while mortality rates are generally comparable they are significantly higher in ‘poor’ (8.2%) versus ‘wealthy’ patients (5.5%) [33], [34].

In PCI-oriented countries e.g., Japan and Korea, in-hospital and longer-term (6–12 months) mortality rates of 7% and 11%, respectively, were generally higher than for the non-Asian GRACE population (5–6%) [22], [23], [52], [64], [65], [66], [67]. Recent reports of low mortality rates in-hospital (2%), and at 12 (4%) and 24 (6%) months from the Prevention of AtherothrombotiC Incidents Following Ischemic Coronary Attack (PACIFIC) registry, [38], can be attributed to proactive performance of PCI. ACS-related outcomes in Korea, are generally comparable with Japan [39], although the Korea Acute Myocardial Infarction Registry (KAMIR) data did show relatively high rates for invasive intervention versus other registry reports and greater mortality for NSTEMI patients long-term (11 month) compared with in-hospital and 1-month mortality [39], [68]. These observations suggest a need for more patient-centric intensive surveillance and treatment while the KAMIR cohort data per se may present unique characteristics in Korean PCI practice as well as contemporary trends in PCI.

Based on the Malaysian National Cardiovascular Disease (NCVD)-ACS registry (Malay 49%, Chinese 23%, Indian 23%), fibrinolysis use was relatively high (> 70%) and use of invasive procedures low (13–17%) versus other registries. Reported in-hospital and 1 month mortality was reported as higher in Malay patients (7%) compared with other ethnic groups (4–6%) and rates from other Asian registries [41], [42], [54], [69], [70] and attributed to a high prevalence of risk factors and complex and high-risk coronary lesions in the Malay cohort along with relatively low use of invasive management and timely reperfusion.

Singapore is one of few countries in the Asia-Pacific region with a state-funded national MI registry i.e., the Singapore Myocardial Infarct Registry (SMIR) Patients hospitalized for AMI from 2000–2005 showed in-hospital mortality (6–10%) to be generally comparable with the non-Asian GRACE cohort (7%) [46] but higher than the cohort from the study of ACS care across Australia and New Zealand (SNAPSHOT ACS: 4.5%) [26]. It was noted, however, that the Singapore population comprises primarily third and fourth generation migrants of Han Chinese, Indian (South Asian), and Malay (Austronesian) descent.

In Taiwan, a 12-month mortality rate of ~ 8% in patients with ACS admitted to the hospital within 24 h of symptom onset and where 97% received primary PCI, was perhaps higher than expected [47], [48], [71]. Notably, there is, a significant lag/deviation from evidence-based guidelines in ACS management in Taiwan, notably, use of DAPT, which fell from 75% at discharge to 25% at 1-year follow-up, and other secondary preventive therapies [47], [71] suggest more stringent policy adherence may improve long-term outcomes in ACS patients.

Similarly high ACS-related mortality is evident in Thailand (~ 10–15% in-hospital, and up to 25% at 12 months follow up) although generally confined to elderly patients and those who received only conservative (non-invasive) treatment without coronary angiogram [49], [50], [72], [73]. A more recent evaluation of registry data did show a significant decrease in in-hospital mortality (~ 6%), with 12-month mortality for NSTEMI [25%] remaining virtually double that for STEMI [74]; however, differences in characteristics and severity of the enrolled patients confound interpretation and the invasive strategy for these groups of patients should be considered further.

Data from the MIG-R indicate significant changes in interventional management between 2004–2005 and 2007–2008, with fewer elective but more urgent PCIs, and increased long-term use of clopidogrel for DES [75]. Consequently, the generally lower ACS-related mortality seen in Australia compared with the US [61], [62], [63], for example, was attributed in part, to greater uniformity of treatment in teaching hospitals and more timely access to reperfusion including triage from ambulance to catheterization department (D Eccleston, personal communication). Additionally, transition of care is considered increasingly critical to improve outcomes and many major cities in Australia now have centers with 24/7 primary PCI facilities with paramedics ‘upskilled’ to perform ambulance-based triage (i.e., in-ambulance ECG and direct transfer to catheterization laboratory for PCI).

Benefits from optimal acute and pre-/post-discharge treatment are supported by other registry-based studies, such as the SNAPSHOT ACS study, and the Genesis Heart Care Group Registry (GHCGR), which demonstrate variability in resources and in-hospital MACE rates across different healthcare jurisdictions [26], [76].

Prospective observational studies confirm close compliance with guideline-based recommendations for medical management in China, although mortality in in-hospital and by 12 months post discharge remains high, particularly in STEMI patients (Table 1) and in women who are generally older than men, associated mainly with poor access to treatment and manifest delayed time to reperfusion [27], [28], [29], [31], [32], [77], [78]. Benefit of improved access to treatment is supported by two single-center registry studies in ACS patients (DESIRE and SUNDAY) – albeit mainly in relatively low-risk UA patients receiving PCI (61%) or CABG (94%), DAPT (60%) and antiplatelet monotherapy (30%) – where a median symptom-to-balloon time of only 8.1 h was associated with in-hospital mortality of 1%, which increased to only 4% at 2 years (DESIRE and SUNDAY; author unpublished data) (Table 1).

Benefits from optimal acute and pre-/post-discharge treatment are also supported by the Kerala registry, and the Detection and Management of Coronary Heart Disease (DEMAT) registry in India [20]. Although use of standard pharmacotherapies generally mirrors guidelines and Western registries [34], optimal in-hospital and post-discharge treatment rates are relatively low [20]. The observation that provision of optimal in-hospital medical care was associated with a 21% lower risk of in-hospital MACE and provision of optimal discharge medical care led to the suggestion that strategies to improve overall ACS care in India should initially focus on an improved in-hospital process-of-care. Indeed, in Japan where PCI is frequently used and ~ 94% of ACS patients are managed in centers with 24/7 primary PCI facilities, registry- and observational study-based data show that a shorter time from symptom onset to intervention is associated with better long-term clinical outcomes and, specifically, an onset-to-balloon time of ≤ 3 h provides better 3-year clinical outcomes [36], [38], [79].

Similarly, in Korea most ACS patients undergo PCI (~ 90% receiving DES) [39], [40], [53], [68], [80], [82], [83]. Here, triple anti-platelet therapy including adjunctive cilostazol is frequently used in high-risk PCI patients as it is more effective than standard DAPT in reducing cardiovascular and total mortality, both in-hospital and at 8 months. Although an increased pharmacotherapy index (up to nine concomitant therapies) provides a trend towards lower in-hospital mortality irrespective of disease status, the prescribing of evidence-based therapy in Korea is generally suboptimal with a need for new educational strategies to increase the use of secondary prevention measures [53], [81].

According to the Malaysian NCVD-ACS registry, approximately half of patients with ACS undergo primary PCI generally with adoption of good practice for DAPT. Notably, such patients tend to be relatively young with a high prevalence of risk factors (e.g., diabetes), complex high-risk lesions and a median door-to-balloon time for primary PCI (98 min) higher than recommended (< 90 min), nevertheless, high procedural success and good pharmacotherapy is associated with a low in-hospital mortality rate (1%) comparable with other registries [42].

In Thailand, which employs a non-PCI and a non-reimbursement policy, ACS-related mortality is generally high. Despite this, improvement in mortality was evident from the Thai Registry in Acute Coronary Syndrome (TRACS, 2007–2008) registry and attributed to a generally better disease status, more PCIs performed, and improved door-to-needle time [49], [74]. Nevertheless, ACS-related mortality remains relatively high, and reduced times between first medical contact and treatment, and optimal use of pharmacotherapy post-discharge will perhaps be key to improving outcomes.

Ethnicity is an important factor in regard to outcomes. For example, 5-year follow-up of a contemporary cohort of Singapore Indian, Chinese and Malay patients showed clear ethnic disparities in long-term outcomes despite minimal disparities in in-hospital management with Singapore Indians having the lowest long-term mortality [83]. Although the reason is unclear, Singapore Indians generally belong to the highest socio-economic class, exercise most frequently, smoke the least and adhere most often to healthy food choices [84] suggesting that differential outcomes in different ethnic groups may be due to inter-ethnic sociocultural and socioeconomic differences along with inherent (genetic) risk factors (e.g. diabetes in India). Further studies are needed to gain understanding of potential variability in compliance and racial differences in rates of disease progression or response to drug therapy.

US-based registry studies confirm that women with ACS are generally older and present more comorbidities than men [63], notably, between-gender differences in demographic, clinical, and treatment profiles are associated with greater risk of bleeding in female patients with MI undergoing PCI [85]. Similarly, in China, greater acute and post-discharge (1-year) mortality in women compared with men was associated with older age and less frequent receipt of reperfusion therapy [32]. In Korea, higher in-hospital and 1-year mortality in women was associated with a higher frequency of comorbidities, longer pain-to-door time, and more severe hemodynamic status [40], [82], [86]. In contrast, in India and Singapore, in-hospital management, discharge management, and outcomes generally did not differ between genders [20], although, in Singapore younger women with diabetes were considered to be at greater risk (adjusted hazard ratio [HR] vs > 60 years, 1.35; 95% CI, 1.04–1.75) (F Gao, personal communication).

Collectively, these observations support an association between healthcare system quality, gender inequality, and ACS management and outcomes; women tend to be undertreated and, as both genders benefit from revascularization, a more aggressive approach is needed in women, including optimization of discharge medical regimens and improved compliance.

Lack of patient education towards, chest pain awareness, the need for good treatment compliance, and the relative importance of medication types e.g., in multi-pill prescribing, alongside poor and/or delayed access to facilities, represents considerable barriers to improving outcomes. Specifically, poor patient education results in poor adherence/compliance with treatment associated with, for example, poor knowledge as to which dose/type of medication missed would present more significant consequences e.g., antiplatelet versus statin.

The implementation of post-hospital coaching programmes e.g., the Coaching patients On Achieving Cardiovascular Health (COACH) programme in Australia has been shown to be effective in improving outcomes, both short-term (12 months) and longer-term (4-year follow-up) [87], [88]; ‘aware’ patients are eight times more likely to be compliant than their counterparts as to the cardiac risks associated with non-compliance [89]. Along with the possibility the prevalence of non-compliance is likely underestimated due to recall bias and self under-reporting [89], improved patient education through sustained educational initiatives remains a key target for improving outcomes.

In Australia, clopidogrel administered in-hospital is reimbursed and largely subsidized post-discharge but a gap still exists in pharmacotherapy use for secondary prevention [90], [91], [92]. Moreover, while DAPT typifies standard of care in Australia, adherence up to 12 months is only 60–70% [92], [93] suggesting improvement in controlling risk factors, while increasing access and adherence to new pharmacologic therapies e.g., single-tablet CoPlavix, might improve compliance and outcomes. In contrast, ACS-related prescription adherence at 12 months post discharge in Singapore remains relatively high i.e., ≥ 96% including for aspirin and P2Y₁₂ antagonists but improvement is needed, in monitoring of prescription adherence and patient adherence during transition from tertiary to primary care.

In China and India there is high reliance on thrombolysis reperfusion (53%) versus PCI (12%) and CABG (0.1%) and most patients receive DAPT for at least 1 year following such procedures (Supplementary Table 2) [31], [33], [34]; there have, however, been no recent approvals for newer antiplatelet agents. Recent evidence showing that short-term DAPT (3–12 months) provides favourable clinical outcomes versus long-term use (12–24 months) [94], [95], [96], [97] and that prolonged DAPT may benefit high-risk patients (AMI, diabetic, ESRD), and those receiving intervention for management of complex lesions [98], suggests a need for patient management individualized according to patient risk factors, disease activity and severity.

Accumulating data support variable hypercoagulability and associated clinical risk, and pharmacokinetic, pharmacodynamic, and pharmacogenetic profiles of cardiovascular drugs across ethnic cohorts [99]. Compared with Western cohorts, East Asian populations (including Chinese, Japanese, and Korean) demonstrate unique clinical outcomes associated with antithrombotic therapy, including increased levels of platelet reactivity (clopidogrel) and risk of bleeding events [100], [101], [102], [103], [104], [105], [106], [107], or increased exposure to active metabolite (prasugrel and ticagrelor) [108], [109], [110]. In fact, this so-called “East Asian Paradox” has resulted in a different target international normalized ratio (1.6 to 2.6) being implemented in clinical practice among East Asian patients [111], [112].

Recent randomized clinical trials of prasugrel and ticagrelor in East Asian patients support earlier large-scale studies in demonstrating that potent P2Y₁₂ receptor inhibitors can provide clinical benefit over clopidogrel in reducing risk from serious bleeding [113], [114], [115], [116]. The modest sample sizes of Asian-specific trials does, however, limit their ability to deliver reliable conclusions, although signals of ethnic differences in the efficacy-safety balance of conventional antithrombotic drugs in East Asian patients e.g., increased tendency for bleeding for ticagrelor, may pose concern and further support tailored management. Nevertheless, such trials may help identify effective combinations of new potent antiplatelet therapies with older agents e.g., aspirin and clopidogrel, and which potentially circumvent resistance and/or non-response to these agents. However, long-term real-world data from the Asia-Pacific region are needed to fully assess the benefit to risk profile for new antiplatelet therapies.

Treatment cost to the patient is also a major barrier to long-term medication use in most countries in the Asia-Pacific region, a situation shown recently to be associated with poor patient awareness of the consequences of non-compliance [89]. In China, fewer than 40% of patients remain adherent to medication at 12 months post-discharge, mostly due to patient refusal [117] Significantly, however, patient non-adherence to antiplatelet agents is frequently due to their doctor considering them not indicated for such treatment, a situation compounded by different reimbursement mechanisms in cities versus rural areas. Cost issues also apply in India where 75% of patients pay for their own treatment. Notably, poorer patients have significantly higher mortality versus richer patients, a trend associated with lower rates of appropriate treatments and delays to intervention and door-to-balloon or -needle times frequently outside of recommended limits [33]. While delays to treatment are often economic in origin, reliance on private or public transport often further delays access to secondary- or tertiary-care hospitals [33].

In Taiwan, most patients are covered by healthcare insurance but with evident lag/deviation from evidence-based guidelines in ACS management [47], [71]. Although adherence to DAPT for ≥ 9 months is associated with significantly lower mortality at 12 months versus antiplatelet monotherapy, the prescription rate of post-PCI DAPT shows a decline following discharge to 12 months (62–13%) with physicians citing the Bureau of National Health Insurance guidelines as the reason for discontinuing [clopidogrel] in 25% of cases [47]. Additionally, reimbursement appears variable and dependent upon the treatment received and affordability, for example, clopidogrel is covered for only 3 months following BMS implantation, compared with 9 months for other treatment modalities. Thus, overall, patient/physician education, adherence both to treatment and guidelines, and appropriate cost to the patient are crucial factors towards improving outcomes across the Asia-Pacific region.

Several key areas were discussed, a consistent observation across the Asia-Pacific region being the strong emphasis on ‘benchmark’ short-term clinical outcomes (e.g. in-hospital events and those occurring within 6 months of the index event) and relatively weak emphasis on long-term outcomes associated with inherent challenges posed by long-term follow-up per se and maintaining compliance.

Continuity of care, i.e., transition from tertiary to primary care, is a major barrier to improved outcomes in Japan and Singapore, as is secondary prevention in Hong Kong. Improved patient and doctor awareness and improved outcomes might accrue through national medical education programmes (not yet implemented in Japan) and focus on educating those patients likely to understand the importance of compliance. In Singapore, improving continuity of care represents a policy-based resource allocation problem, currently better for the tertiary versus primary care sector.

The APRICOT working group made several key strategic recommendations to improve ACS outcomes in the Asia-Pacific region: longer-term patient surveillance, greater patient education (pain awareness, compliance, primary/secondary prevention), overcoming geographical challenges to pre-hospital and post-discharge care, and the adoption of value-based over cost-based healthcare systems. The group recommended a greater emphasis on improving longer-term outcomes in ACS. Also, an opportunity exists to improve follow-up and monitor compliance, particularly where patient history is already on record; programmes such as the ongoing NCDR-GWTG programme in the USA [118] have confirmed that recording of treatment received and outcomes achieved improved quality of care [119]. Poor patient compliance and adherence may be improved through community outreach to record adherence at 12 months, possibly via mail, telephone questionnaire, or during a hospital visit. Selected high-risk/low-compliance patients may then be entered into a compliance pathway to allow focus of resources towards patients most at risk. Technology-based solutions such as telemedicine may also aid community outreach programmes by circumventing the need to commute long distances between remote regions and healthcare facilities.

Greater patient education is needed to improve awareness of ACS-related chest pain to reduce time-to-treatment, and understanding of the need for adherence. Likewise, the US NCDR initiative has shown that performance measurement and feedback to hospitals and healthcare providers is effective in improving adherence to guidelines and could form a basis for medical reform and development of quality-of-care indicators. Against this scenario, patient engagement might be improved through implementation of broad community outcomes, including online consultation programs in large community hospitals.

Although large-scale randomized clinical trials such as TRITON-TIMI 38 [115] and PLATO [116] show an overall benefit of potent P2Y₁₂ inhibitors versus clopidogrel in ACS, these studies enrolled only less than 6% of patients from the Asia-Pacific region. Significantly, many cardiovascular drugs show differing pharmacokinetic, pharmacodynamic, and pharmacogenetic profiles across ethnic cohorts. For example, East Asian patients (including China, Japan, and Korea) show a lower antiplatelet effect to clopidogrel compared with Western patients, due to genetic polymorphisms that confer resistance to this drug [120], [121], [122], [123]; recent clinical studies have shown East Asians may have an inherently different therapeutic zone of platelet reactivity during P2Y₁₂ inhibitor treatment and require different dosing regimens compared with Western populations [99]. The recent PRASFIT-ACS study supported this concept, showing that low-dose prasugrel therapy (20 mg loading and 3.75 mg daily) reduced the risk of composite ischemic events by 23% compared with standard-dose clopidogrel therapy (300 mg loading and 75 mg daily) [113]. Dedicated pharmacodynamic studies and clinical trials are urgently required to elucidate specific guidelines for antiplatelet agents among East Asians, in particular, antiplatelet effects with prasugrel and ticagrelor. We also need to strongly consider the paradigm shift from ‘one-guideline-fits-all races’ to ‘tailored antiplatelet therapy’ for different ethnic cohorts.

Asian subjects derive similar benefits as Western subjects at lower statin doses [124]. Unfortunately, the pharmaceutical industry often considers it financially non-viable to fund a large Asian-specific late-phase trial after a successful pivotal trial. A possible alternative would be to design and perform registry-based randomized controlled trials, such as the Thrombus Aspiration in ST-Elevation myocardial infarction in Scandinavia (TASTE) trial [125], that leverage existing ACS registries in Asia-Pacific countries.

It was generally acknowledged that multi-pill prescribing can adversely impact upon compliance in many countries disadvantaged by geographic distance, while randomized controlled trials of the poly-pill formulation have shown significantly improved medication adherence in patients at high CVD risk [127] and potential utility in the acute ACS setting [34]. Strategies to improve in-hospital and discharge medical therapies, perhaps including the poly-pill formulation in the acute phase along with timely reperfusion, are important towards improving local process-of-care measures and ACS outcomes in remote geographic regions [20].