Heart Failure Clinical Trials in East and Southeast Asia: Understanding the Importance and Defining the Next Steps.

Heart failure (HF) is a major and increasing global public health problem. In Asia, aging populations and recent increases in cardiovascular risk factors have contributed to a particularly high burden of HF, with outcomes that are poorer than those in the rest of the world. Representation of Asians in landmark HF trials has been variable. In addition, HF patients from Asia demonstrate clinical differences from patients in other geographic regions. Thus, the generalizability of some clinical trial results to the Asian population remains uncertain. In this article, we review differences in HF phenotype, HF management, and outcomes in patients from East and Southeast Asia. We describe lessons learned in Asia from recent HF registries and clinical trial databases and outline strategies to improve the potential for success in future trials. This review is based on discussions among scientists, clinical trialists, industry representatives, and regulatory representatives at the CardioVascular Clinical Trialist Asia Forum in Singapore on July 4, 2014.

Impact Of Sex On Clinical Characteristics And In-Hospital Outcomes In A Multi-Ethnic Southeast Asian Population Of Patients Hospitalized For Acute Heart Failure.

OBJECTIVES: To study sex differences in clinical characteristics and outcomes among multi-ethnic Southeast Asian patients with hospitalized heart failure (HHF). BACKGROUND: HHF is an important public health problem affecting man and women globally. Reports from Western populations suggest striking sex differences in risk factors and outcomes in HHF. However, this has not been studied in a multi-ethnic Asian population. METHODS: Using the population-based resources of the Singapore Cardiac Data Bank, we studied 5,703 consecutive cases of HHF admitted across hospitals in the Southeast Asian nation of Singapore from 1st January, 2008 through 31st December, 2009. RESULTS: Women accounted for 46% of total admissions and were characterized by older age (73 vs. 67 years; p<0.001), higher prevalence of hypertension (78.6 vs. 72.1%; p<0.001) or atrial fibrillation (22.2 vs. 18.1%; p<0.001), and lower prevalence of coronary artery disease (33.8 vs. 41.0%; p<0.001) or prior myocardial infarction (14.9 vs. 19.8%; p<0.001). Women were more likely than men to have HHF with preserved ejection fraction (42.5% versus 20.8%, p < 0.001). Women were less likely than men to receive evidencebased therapies at discharge, both in the overall group and in the sub-group with reduced ejection fraction. Women had longer lengths of stay (5.6 vs. 5.1 days; p<0.001) but similar in-hospital mortality and one-year rehospitalization rates compared to men. Independent predictors of mortality or rehospitalization in both men and women included prior myocardial infarction and reduced ejection fraction. Among women alone, additional independent predictors were renal impairment, atrial fibrillation, and diabetes. Prescription of beta-blockers and ACE-inhibitors at discharge was associated with better outcomes. CONCLUSION: Among multi-ethnic Asian patients with HHF, there are important sex differences in clinical characteristics and prognostic factors. These data may inform sex-specific strategies to improve outcomes of HHF in Southeast Asians.

Myocardial contractile dysfunction associated with increased 3-month and 1-year mortality in hospitalized patients with heart failure and preserved ejection fraction.

BACKGROUND: There is a clinical need for a contractility index that reflects myocardial contractile dysfunction even when ejection fraction (EF) is preserved. We used novel relative load-independent global and regional contractility indices to compare left ventricular (LV) contractile function in three groups: heart failure (HF) with preserved ejection fraction (HFPEF), HF with reduced ejection fraction (HFREF) and normal subjects. Also, we determined the associations of these parameters with 3-month and 1-year mortality in HFPEF patients. METHODS: 199 HFPEF patients [median age (IQR): 75 (67-80) years] and 327 HFREF patients [69 (59-76) years] were recruited following hospitalization for HF; 22 normal control subjects [65 (54-71) years] were recruited for comparison. All patients underwent standard two-dimensional Doppler and tissue Doppler echocardiography to characterize LV dimension, structure, global and regional contractile function. RESULTS: The median (IQR) global LV contractility index, dσ*/dtmax was 4.30s(-1) (3.51-4.57s(-1)) in normal subjects but reduced in HFPEF [2.57 (2.08-3.64)] and HFREF patients [1.77 (1.34-2.30)]. Similarly, median (IQR) regional LV contractility index was 99% (88-104%) in normal subjects and reduced in HFPEF [81% (66-96%)] and HFREF [56% (41-71%)] patients. Multi-variable logistic regression analysis on HFPEF identified sc-mFS <76% as the most consistent predictor of both 3-month (OR=7.15, p<0.05) and 1-year (OR=2.57, p<0.05) mortality after adjusting for medical conditions and other echocardiographic measurements. CONCLUSION: Patients with HFPEF exhibited decreased LV global and regional contractility. This population-based study demonstrated that depressed regional contractility index was associated with higher 3-month and 1-year mortality in HFPEF patients.

Improving door-to-balloon times in primary percutaneous coronary intervention for acute ST-elevation myocardial infarction: the value of an audit-driven quality initiative.

INTRODUCTION: The study was designed to reduce door-to-balloon times in primary percutaneous coronary intervention for patients presenting to the Emergency Department with acute ST-elevation myocardial infarction, using an audit as a quality initiative. MATERIALS AND METHODS: A multidisciplinary work group performed a pilot study over 3 months, then implemented various process and work-flow strategies to improve overall door-to-balloon times. RESULTS AND CONCLUSION: We developed a guideline-based, institution-specific written protocol for triaging and managing patients who present to the Emergency Department with symptoms suggestive of STEMI, resulting in shortened median door-to-balloon times from 130.5 to 109.5 minutes (P<0.001).

Pattern and outcome of subsidised referrals to cardiology specialist outpatient clinics.

INTRODUCTION: Increasing demand for public healthcare and access to specialist care has become a major concern. Characterising the referral pattern to a national centre's cardiology specialist outpatient clinics (SOCs) and the diagnostic outcomes may be useful in formulating referral guidelines to contain rising demand. MATERIALS AND METHODS: A prospective observational followup study was conducted of all consecutive new patient referrals to the cardiology SOCs of the National Heart Centre over a 1-month period. The records of these 1224 patients were reviewed following their first visit and again after 3 months of evaluation and investigation. Patients' demographics, referral sources, indications of referral, risk factors, provisional and final diagnoses were collected. Referrals from the top 2 volume sources (government polyclinics and hospital Emergency Department) accounted for 600 referrals. These subsidised referrals formed the study group for analysis. RESULTS: The mean age of referred patients was 56 +/- 15.2 years, with equal proportion of males and females. Most patients had known cardiac risk factors of hypertension (53.2%) and hyperlipidaemia (42.3%). Only 23% of referrals had significant cardiac abnormalities. Referrals for typical chest pain derived the highest yield whereas referrals for atypical chest pain, non-cardiac chest pain derived the lowest yield. Referrals for asymptomatic electrocardiogram (ECG) changes (except for atrial flutter/fibrillation) did not yield cardiac abnormalities. Multivariate analysis of chest pain referrals showed typical chest pain and hyperlipidaemia to be statistically significant predictors for coronary artery disease. CONCLUSION: Referrals to cardiology outpatient specialist clinics should be based on the presence of patient symptoms, particularly that of typical chest pain. In asymptomatic patients, routine ECG screening did not appear to yield significant cardiac abnormalities.

Improving access to outpatient cardiac care at the national heart centre--a partnership between specialists and primary care.

Ensuring timely access to specialist care is an important indicator of the quality of a health service. Demand for cardiology outpatient appointments has grown considerably in the last decade, leading to increased waiting time for cardiology appointments at public hospitals. This paper examines the effectiveness of past and ongoing strategies initiated by the National Heart Centre, many of which were in collaboration with SingHealth Polyclinics, documents the lessons learnt, and provides a framework for approaching this problem. Instead of a simplistic approach where institutions react to long waiting times by growing capacity to meet demand, this paper emphasises the need to focus on the final intended outcome (timely diagnosis and treatment) rather than on a single performance indicator, such as waiting time. A broad systems approach at the national level is advocated, rather than piecemeal, uncoordinated actions by individual hospitals.

Heart failure mortality in Southeast Asian patients with left ventricular systolic dysfunction.

BACKGROUND: Prognostic indicators and mortality in multiethnic Southeast Asian patients with heart failure (HF) may be different. METHODS AND RESULTS: The study population comprised 225 inpatients with HF with a left ventricular ejection fraction of 40% or less who were discharged alive. Five years later, survival and causes of death were determined. Proportionally, more Malay and Indian patients were admitted compared with Chinese patients (P < .001). There were 55.6% in New York Heart Association (NYHA) class III or IV. Ischemic heart disease was the most common cause (85.8%). At 5 years, 152 patients (67.5%) had died. Angiotensin-converting enzyme inhibitors were prescribed to 79.1% of patients on discharge. Cardiovascular causes accounted for 69.7% of deaths. Predictors of mortality include female gender (P = .046), age 70 years or more (P = .017), renal impairment (P = .008), NYHA class III or IV (P = .03), and non-use of angiotensin-converting enzyme inhibitors (P = .005). On multivariate analysis, increasing age (P = .001) and renal impairment (P = .019) were independent predictors of all-cause mortality. Cardiovascular death was more likely with NYHA class III or IV (P = .004) and renal impairment (P = .012). CONCLUSION: Mortality is unusually high in this group of patients despite treatment. Greater use of evidence-based therapies in HF-management programs may arrest this trend.

Analysis of survivors more than 10 years after heart transplantation in the cyclosporine era: Stanford experience.

BACKGROUND: Truly long term survival post heart transplantation has become increasingly frequent over the past two decades. METHODS: We analyzed multiple clinical outcomes in the cohort of 140 patients in the Stanford database who underwent heart transplantation after the introduction of cyclosporine-based immunosuppression in 1980 and survived >10 years after transplantation. RESULTS: We found generally excellent functional status in these patients, but a high incidence of hypertension, renal dysfunction, and graft CAD as well as malignancy. CONCLUSION: With continued improvement in post-transplant survival rates, providing complex care for such long-term recipients as these will assume increasing clinical importance in the everyday practice of transplant medicine and these data highlight the problems to be anticipated.

The impact of brain death on survival after heart transplantation: time is of the essence.

BACKGROUND: It has been suggested that the modality of brain death and time from brain death until harvest impact survival and rejection after heart transplantation. METHODS: Donor files from 475 adult heart-transplant recipients were examined. From these files, a total management time (time from incident leading to brain death until aortic cross clamp) was determined, and the cause of brain death was noted. Recipient characteristics, details of postoperative course, as well as survival were obtained from the Stanford University Medical Center Heart Transplantation Database. RESULTS: Two hundred and thirty (48.4%) donors sustained traumatic injuries, 112 (23.6%) suffered a subarachnoid hemorrhage, and 102 (21.4%) died of a gunshot wound to the head. The modality of brain death did not influence medium and long-term survival. A management time longer than 72 hours was associated with poorer outcome of the heart-transplant recipients. There were significantly more treated rejection episodes in recipients whose donor sustained traumatic injuries. CONCLUSION: Modality of brain death does not impact survival but appears to influence rejection. Increased management time is associated with adverse survival trends in heart-transplant recipients.

Post-operative conversion from cyclosporine to tacrolimus in heart transplantation: a single-center experience.

BACKGROUND: Tacrolimus is a potent calcineurin inhibitor that was introduced to heart transplantation in the early 1990s. The side-effect profile of tacrolimus is more favorable than that of cyclosporine and some reports have suggested an advantage of tacrolimus in the treatment of rejection. The present study was undertaken to determine whether a late conversion to tacrolimus affords these benefits to heart transplant recipients. METHODS: Charts from 109 patients who underwent conversion from cyclosporine to tacrolimus for recurrent rejection or adverse effects were retrospectively reviewed. RESULTS: During the year after conversion to tacrolimus, there was a significant decrease in treated rejection episodes. Conversion to tacrolimus rapidly resulted in an improved lipid profile. Two years after conversion blood pressure was significantly reduced. Apart from rejection, these benefits were found mainly among individuals converted to tacrolimus within 1 year of heart transplantation. CONCLUSIONS: Conversion from cyclosporine to tacrolimus is safe and results in a more favorable risk factor profile. However, most of the benefits are seen in individuals converted within 1 year of transplantation.

Mycophenolic acid concentrations in long-term heart transplant patients: relationship with calcineurin antagonists and acute rejection.

BACKGROUND: When used in conjunction with steroids and cyclosporin, mycophenolate mofetil (MMF) has been shown to significantly reduce mortality and incidence of rejection in the first year after heart transplantation. It also appears that in this early post-transplantation period, the monitoring of immunosuppressive therapies may be warranted. The current study was undertaken to determine if such monitoring is still useful more than 1 yr after heart transplantation. METHODS: Twenty-six patients who had survived the first year after orthotopic heart transplantation and had been on MMF therapy for more than 3 months were prospectively followed. At the time of their routine endomyocardial biopsy blood samples were taken to monitor immunosuppressive therapy. Most patients had two samples taken, on average 109 d apart. RESULTS: There were 22 episodes of asymptomatic rejection documented on a total of 48 biopsies. Of these, only two were of ISHLT (International Society for Heart and Lung Transplantation) grade 3A the remainder being of ISHLT grades 1 or 2. There was no relation between immunosuppressive regimen (tacrolimus and MMF or cyclosporin and MMF) and rejection. There was no relation between monitored immunosuppressive levels and rejection. Patients with the combination of MMF and tacrolimus had significantly higher plasma mycophenolic acid levels despite significantly lower daily MMF dose. CONCLUSION: There does not appear to be a benefit in continued monitoring of plasma mycophenolic acid levels beyond the first year of heart transplantation. There were significant differences in plasma mycophenolic acid levels depending on the type of calcineurin inhibitor concomitantly used.