Tiong Kiam Ong

Trial of Everolimus-Eluting Stents or Bypass Surgery for Coronary Disease

BACKGROUND Most trials comparing percutaneous coronary intervention (PCI) with coronary-artery bypass grafting (CABG) have not made use of second-generation drug-eluting stents. METHODS We conducted a randomized noninferiority trial at 27 centers in East Asia. We planned to randomly assign 1776 patients with multivessel coronary artery disease to PCI with everolimus-eluting stents or to CABG. The primary end point was a composite of death, myocardial infarction, or target-vessel revascularization at 2 years after randomization. Event rates during longer-term follow-up were also compared between groups. RESULTS After the enrollment of 880 patients (438 patients randomly assigned to the PCI group and 442 randomly assigned to the CABG group), the study was terminated early owing to slow enrollment. At 2 years, the primary end point had occurred in 11.0% of the patients in the PCI group and in 7.9% of those in the CABG group (absolute risk difference, 3.1 percentage points; 95% confidence interval [CI], -0.8 to 6.9; P=0.32 for noninferiority). At longer-term follow-up (median, 4.6 years), the primary end point had occurred in 15.3% of the patients in the PCI group and in 10.6% of those in the CABG group (hazard ratio, 1.47; 95% CI, 1.01 to 2.13; P=0.04). No significant differences were seen between the two groups in the occurrence of a composite safety end point of death, myocardial infarction, or stroke. However, the rates of any repeat revascularization and spontaneous myocardial infarction were significantly higher after PCI than after CABG. CONCLUSIONS Among patients with multivessel coronary artery disease, the rate of major adverse cardiovascular events was higher among those who had undergone PCI with the use of everolimus-eluting stents than among those who had undergone CABG. (Funded by CardioVascular Research Foundation and others; BEST ClinicalTrials.gov number, NCT00997828.).

Catastrophic health expenditure on acute coronary events in Asia: a prospective study.

Abstract Objective To estimate out-of-pocket costs and the incidence of catastrophic health expenditure in people admitted to hospital with acute coronary syndromes in Asia. Methods Participants were enrolled between June 2011 and May 2012 into this observational study in China, India, Malaysia, Republic of Korea, Singapore, Thailand and Viet Nam. Sites were required to enrol a minimum of 10 consecutive participants who had been hospitalized for an acute coronary syndrome. Catastrophic health expenditure was defined as out-of-pocket costs of initial hospitalization > 30% of annual baseline household income, and it was assessed six weeks after discharge. We assessed associations between health expenditure and age, sex, diagnosis of the index coronary event and health insurance status of the participant, using logistic regression models. Findings Of 12 922 participants, 9370 (73%) had complete data on expenditure. The mean out-of-pocket cost was 3237 United States dollars. Catastrophic health expenditure was reported by 66% (1984/3007) of those without insurance versus 52% (3296/6366) of those with health insurance (P < 0.05). The occurrence of catastrophic expenditure ranged from 80% (1055/1327) in uninsured and 56% (3212/5692) of insured participants in China, to 0% (0/41) in Malaysia. Conclusion Large variation exists across Asia in catastrophic health expenditure resulting from hospitalization for acute coronary syndromes. While insurance offers some protection, substantial numbers of people with health insurance still incur financial catastrophe.

Rationale, Design, and Baseline Characteristics of the EPICOR Asia Study (Long‐tErm follow‐uP of antithrombotic management patterns In Acute CORonary Syndrome patients in Asia)

In‐hospital and postdischarge mortality for acute coronary syndromes (ACS) vary across Asia and remain generally poorer than globally. The relationship between real‐life antithrombotic management patterns (AMPs) and ACS‐related outcomes in Asia is unclear.

Characteristics and outcomes of medically managed patients with non-ST-segment elevation acute coronary syndromes: Insights from the multinational EPICOR Asia study

BACKGROUND Many patients with non-ST-segment elevation acute coronary syndromes (NSTE-ACS) are medically managed without coronary revascularization. The reasons vary and may impact prognosis. METHODS EPICOR Asia (NCT01361386) is a prospective study of hospital survivors post-ACS enrolled in 218 hospitals from 8 countries/regions in Asia (06/2011-05/2012). All medically managed NSTE-ACS patients were classified into 3 groups: 1) no coronary angiography (CAG-); 2) non-significant coronary artery disease (CAD) on angiogram (CAG+ CAD-); and 3) significant CAD (CAG+ CAD+). We compared baseline differences between patients medically managed and patients undergoing revascularization, and also between the medically managed groups. Adverse events were reported and compared up to 2years. RESULTS Of 6163 NSTE-ACS patients, 2272 (37%) were medically managed, with 1339 (59%), 254 (11%), and 679 (30%) in the CAG-, CAG+ CAD-, and CAG+ CAD+ groups, respectively. There were marked differences in the proportion of medically managed patients among the 8 countries/regions (13-81%). Medically managed patients had higher mortality at 2years compared with revascularization (8.7% vs. 3.0%, p<0.001). Among medically managed patients, CAG- patients were older, more likely to have pre-existing cardiovascular disease, and had the highest 2-year mortality (10.5% vs. 4.3% [CAG+ CAD-] and 6.6% [CAG+ CAD+], p<0.001). Mortality differences persisted after adjusting for other patient risk factors. CONCLUSIONS Medically managed NSTE-ACS patients are a heterogeneous group with different risk stratification and variable prognosis. Identification of reasons underlying different management strategies, and key factors adversely influencing long-term prognosis, may improve outcomes.

Association of CYP2C19*2 polymorphism with clopidogrel response and 1-year major adverse cardiovascular events in a multiethnic population with drug-eluting stents

BACKGROUND Patients undergoing elective percutaneous coronary intervention (PCI) with drug-eluting stents (DES) who have impaired clopidogrel response, have a higher risk of subsequent major adverse cardiovascular events (MACE). AIM OF THE STUDY To establish the relationship between CYP2C19 genotype, clopidogrel responsiveness and 1-year MACE. MATERIALS & METHODS Aspirin/clopidogrel responses were assessed with Multiplate Analyzer and CYP2C19*2 allele by SpartanRx. RESULTS A total of 42.0% carried ≥1 CYP2C19*2 allele. Prevalences of aspirin and clopidogrel high on-treatment platelet reactivity (HPR; local cutoffs: 300 AU*min for aspirin and 600 AU*min for clopidogrel) were 11.5% and 19.8% respectively. In multivariate ana-lysis, clopidogrel HPR was found to be an independent predictor for 1-year MACE (adj HR: 3.48, p = 0.022 ). CONCLUSION Having clopidogrel HPR could be a potentially modifiable risk factor guided by phenotyping.

Increased serum levels of interleukin-6 and von Willenbrand Factor in early phase of acute coronary syndrome in a young and multiethnic Malaysian population

Objective Interleukin-6 (IL6; proinflammatory marker), von Willebrand Factor (vWF; endothelial dysfunction marker) and P-selectin (platelet activation marker), may play important roles in defining the pathogenesis of vulnerable plaques in acute coronary syndrome (ACS). This study aims to investigate the expression and relationship of these markers in early phases of ACS in a young and multiethnic Malaysian population. Design Peripheral whole blood mRNA, and serum levels of IL6, vWF and P-selectin were measured in 22 patients with ACS, and in 28 controls with angiographically significant coronary artery disease without previous ACS events. Venous blood from ACS patients was obtained within 1 h of hospital admission. Results No significant differences of IL6, vWF and P-selectin mRNA levels between ACS and controls were seen. ACS patients had significantly higher serum levels of IL6 and vWF (p<0.001), compared with controls. P-selectin correlated with IL6 (r=0.697, p=0.003) and vWF (r=0.497, p=0.05) at mRNA levels, indicating a possible association between these three indices of ACS pathogenesis. Conclusions Increased serum levels of IL6 and vWF suggest that inflammation and endothelial dysfunction may play a prominent role in the pathogenesis of the disease during the early phase of ACS.

CYTOCHROME P450 2C19 POLYMORPHISM AND PLATELET AGGREGATION IN CLOPIDOGREL-TREATED PATIENTS AMONG MALAYSIAN MULTIETHNIC POPULATION

Objectives Cytochrome P450 2C19 (CYP2C19) *2 (681G>A; rs4244285) and CYP2C19*3 (636G>A; rs4986893) null alleles are responsible for the phenotypes of poor CYP2C19 enzyme function, hence adversely affecting the ability of clopidogrel to inhibit platelet aggregation. In recent years, a novel CYP2C19 gene variant, CYP2C19*17 (−3402C>T; rs11188072), has been identified and is associated with ultrarapid metabolism of CYP2C19 substrate. To date, there is limited data on CYP2C19 prevalence rates in a multiracial Malaysian population with coronary artery disease planned for percutaneous coronary intervention (PCI), and their impact on clopidogrel-mediated platelet aggregation (CPA). Therefore, the primary objective of this study was to assess the impact of CYP2C19 *2, *3 and *17 on CPA in patients planned for PCI. Methods From the 323 consecutive patients planned for PCI, 237 patients≥18 years of age, underwent either aspirin alone or both aspirin and clopidogrel therapy, were recruited from Sarawak General Hospital Heart Centre (Kota Samarahan, Malaysia). Venous blood samples were collected from each participant before their scheduled appointment for PCI. The CYP2C19*2, *3 and *17 were genotyped by PCR—restriction fragment linked polymorphism (PCR-RFLP) method. The antiplatelet effect of clopidogrel, as assessed by ADP-induced platelet aggregation, was measured by Multiplate impedance aggregometry. Results Of the 237 subjects (mean age 57.6±11.1), 77.6% were male and 22.4% were female. Ethnic group distribution was: Chinese 50.6% (n=120), Malay 21.1% (n=50), Iban 19.0% (n=45) and other races 9.3% (n=22) The allelic frequency of the CYP2C19 *1, *2, *3 and *17 were 63.0% (95% CI 62.1% to 59.0%), 29.0% (95% CI 28.7% to 29.3%), 6.0% (95% CI 5.9% to 6.1%) and 2% (95% CI 1.6% to 2.4%), respectively. Genotype determination revealed that 38.8% were extensive metabolisers (EM: *1/*1, *2/*17), 45.1% intermediate metabolisers (IM: *1/*2, *1/*3), 12.7% poor metabolisers (PM: *2/*2, *2/*3, *3/*3), 3.0% intermediate ultrarapid metaboliser (IUM: *1/*17) and 0.4% ultrarapid metaboliser (UM: *17/*17). The frequencies of the CYP2C19*2 variant allele and of the homozygous genotype were higher in Chinese descent individuals (35.8%; 12.5%) compared with other ethnic groups (p=0.010; p=0.022, respectively). Meanwhile, a similar proportion of CYP2C19*3 allele was observed in all ethnic groups (p=0.071). Overall, the PM genotypic prevalence rate was 15.0% in Chinese, 10.0% in Malays, 8.9% in Iban and 18.2% in other subjects (p=0.042). One Chinese subject shown to be homozygous *2 and heterozygous *17, hence resulting in a new combination of *2/*17. The predicted metabolic phenotype for this combination is unknown and we assume that the ultrarapid clopidogrel metabolism by *17 allele may be suppressed by loss-of-function *2 alleles, thus resulting in a functional metabolising enzyme phenotype. Hence, we grouped this individual as EM. Linkage disequilibrium analysis showed that the *17 were in different linkage disequilibrium with *2 and *3. Among the 118 subjects who underwent a similar double antiplatelet loading strategy (75 mg loading doses of aspirin for at least 2 days+75 mg loading doses of clopidogrel for at least 4 days), the prevalence rate of PM remains high within Chinese group (17.5%) compared to other ethnic groups (p=0.036). The CPA was observed to be higher in PM (333.6 aggregation unit×min (AU*min)), followed by IM (319.7 AU*min), EM (278.7 AU*min) and lowest in IUM (264.5 AU*min) (p>0.05). The *2 and *3 carriers also demonstrated higher platelet aggregation (310.6 AU*min) compared to *17 carriers (264.1 AU*min) (p=0.412). The absence of statistically significant differences between the different phenotypic groups could be attributed to the relatively small sample size. Nevertheless, there was a significant influence of CYP2C19 polymorphism on CPA in Chinese subjects only (p=0.032) even after adjustment for various cardiovascular risk factors. Conclusions The CYP2C19*2 is found at high frequency in Malaysians, especially in Chinese subjects, consistent to that found in other Asian populations of Chinese ethnic origin. Other CYP2C19 polymorphisms, particularly *17 were rare in the Malaysian population. However, carriers of *17 demonstrated better CPA compared to *2 and *3 carriers. Our findings indicate a broad inter-ethnic difference in CYP2C19 allelic frequencies. As both the presence of certain genotypes especially *2, and a lower CPA, have been shown to be associated with higher adverse cardiovascular event rates in patients prescribed clopidogrel, subsequent outcome studies in our multiethnic population are warranted.

TCTAP C-150 Acute ST Elevation Myocardial Infarction with Total Occluded Left Main Stem and Cardiogenic Shock - PCI or Emergency CABG?

### Patient Initials or Identifier Number DJ ### Relevant Clinical History and Physical Exam Mr. DJ, 57-year-old, active smoker. No other medical illness. At 22:40, he presented to other hospital for chest pain for past 3 hours. At ED, BP 66/52, bibasal lungs crepitation, SPO2 92% on high flow

Comparison of the treatment practice and hospitalization cost of percutaneous coronary intervention between a teaching hospital and a general hospital in Malaysia: A cross sectional study

Introduction The increasing disease burden of coronary artery disease (CAD) calls for sustainable cardiac service. Teaching hospitals and general hospitals in Malaysia are main providers of percutaneous coronary intervention (PCI), a common treatment for CAD. Few studies have analyzed the contemporary data on local cardiac facilities. Service expansion and budget allocation require cost evidence from various providers. We aim to compare the patient characteristics, procedural outcomes, and cost profile between a teaching hospital (TH) and a general hospital (GH). Methods This cross-sectional study was conducted from the healthcare providers’ perspective from January 1st to June 30th 2014. TH is a university teaching hospital in the capital city, while GH is a state-level general hospital. Both are government-funded cardiac referral centers. Clinical data was extracted from a national cardiac registry. Cost data was collected using mixed method of top-down and bottom-up approaches. Total hospitalization cost per PCI patient was summed up from the costs of ward admission and cardiac catheterization laboratory utilization. Clinical characteristics were compared with chi-square and independent t-test, while hospitalization length and cost were analyzed using Mann-Whitney test. Results The mean hospitalization cost was RM 12,117 (USD 3,366) at GH and RM 16,289 (USD 4,525) at TH. The higher cost at TH can be attributed to worse patients’ comorbidities and cardiac status. In contrast, GH recorded a lower mean length of stay as more patients had same-day discharge, resulting in 29% reduction in mean cost of admission compared to TH. For both hospitals, PCI consumables accounted for the biggest proportion of total cost. Conclusions The high PCI consumables cost highlighted the importance of cost-effective purchasing mechanism. Findings on the heterogeneity of the patients, treatment practice and hospitalization cost between TH and GH are vital for formulation of cost-saving strategies to ensure sustainable and equitable cardiac service in Malaysia.

Cost of elective percutaneous coronary intervention in Malaysia: a multicentre cross-sectional costing study

Objectives Limitations in the quality and access of cost data from low-income and middle-income countries constrain the implementation of economic evaluations. With the increasing prevalence of coronary artery disease in Malaysia, cost information is vital for cardiac service expansion. We aim to calculate the hospitalisation cost of percutaneous coronary intervention (PCI), using a data collection method customised to local setting of limited data availability. Design This is a cross-sectional costing study from the perspective of healthcare providers, using top-down approach, from January to June 2014. Cost items under each unit of analysis involved in the provision of PCI service were identified, valuated and calculated to produce unit cost estimates. Setting Five public cardiac centres participated. All the centres provide full-fledged cardiology services. They are also the tertiary referral centres of their respective regions. Participants The cost was calculated for elective PCI procedure in each centre. PCI conducted for urgent/emergent indication or for patients with shock and haemodynamic instability were excluded. Primary and secondary outcome measures The outcome measures of interest were the unit costs at the two units of analysis, namely cardiac ward admission and cardiac catheterisation utilisation, which made up the total hospitalisation cost. Results The average hospitalisation cost ranged between RM11 471 (US