Anwar Santoso

Prior smoking status, clinical outcomes, and the comparison of ticagrelor with clopidogrel in acute coronary syndromes—Insights from the PLATelet inhibition and patient Outcomes (PLATO) trial

BACKGROUND Habitual smoking has been associated with increased platelet reactivity, increased risk of thrombotic complications and greater efficacy of clopidogrel therapy over placebo. In the PLATO trial, ticagrelor compared to clopidogrel in patients with acute coronary syndromes (ACS) reduced the primary composite end point of vascular death, myocardial infarction and stroke, without increasing overall rates of major bleeding. We evaluated the results in relation to smoking habits. METHODS Interactions between habitual smokers (n = 6678) and in ex/nonsmokers (n = 11,932) and the effects of randomized treatments on ischemic and bleeding outcomes were evaluated by Cox regression analyses. RESULTS Habitual smokers had an overall lower risk profile and more often ST-elevation ACS. After adjustment for baseline imbalances, habitual smoking was associated with a higher incidence of definite stent thrombosis (adjusted HR, 1.44 [95% CI, 1.07-1.94]); there were no significant associations with other ischemic or bleeding end points. The effects of ticagrelor compared to clopidogrel were consistent for all outcomes regardless of smoking status. Thus, there was a similar reduction in the primary composite end point for habitual smokers (adjusted HR, 0.83 [95% CI, 0.68-1.00]) and ex/nonsmokers (adjusted HR, 0.89 [95% CI, 0.79-1.00]) (interaction P = .50), and in definite stent thrombosis for habitual smokers (adjusted HR, 0.59 [0.39-0.91]) and ex/nonsmokers (adjusted HR, 0.69 [95% CI, 0.45-1.07]) (interaction P = .61). CONCLUSIONS In patients hospitalized with ACS, habitual smoking is associated with a greater risk of subsequent stent thrombosis. The reduction of vascular death, myocardial infarction, stroke, and stent thrombosis by ticagrelor compared to clopidogrel is consistent regardless of smoking habits.

Ticagrelor Versus Clopidogrel in Patients With Acute Coronary Syndromes and Chronic Obstructive Pulmonary Disease: An Analysis From the Platelet Inhibition and Patient Outcomes (PLATO) Trial

Background Patients with chronic obstructive pulmonary disease (COPD) experiencing acute coronary syndromes (ACS) are at high risk for clinical events. In the Platelet Inhibition and Patient Outcomes (PLATO) trial, ticagrelor versus clopidogrel reduced the primary endpoint of death from vascular causes, myocardial infarction, or stroke after ACS, but increased the incidence of dyspnea, which may lead clinicians to withhold ticagrelor from COPD patients. Methods and Results In 18 624 patients with ACS randomized to treatment with ticagrelor or clopidogrel, history of COPD was recorded in 1085 (5.8%). At 1 year, the primary endpoint occurred in 17.7% of patients with COPD versus 10.4% in those without COPD (P<0.001). The 1‐year event rate for the primary endpoint in COPD patients treated with ticagrelor versus clopidogrel was 14.8% versus 20.6% (hazard ratio [HR]=0.72; 95% confidence interval [CI]: 0.54 to 0.97), for death from any cause 8.4% versus 12.4% (HR=0.70; 95% CI: 0.47 to 1.04), and for PLATO‐defined major bleeding rates at 1 year 14.6% versus 16.6% (HR=0.85; 95% CI: 0.61 to 1.17). Dyspnea occurred more frequently with ticagrelor (26.1% vs. 16.3%; HR=1.71; 95% CI: 1.28 to 2.30). There was no differential increase in the relative risk of dyspnea compared to non‐COPD patients (HR=1.85). No COPD status‐by‐treatment interactions were found, showing consistency with the main trial results. Conclusions In this post‐hoc analysis, COPD patients experienced high rates of ischemic events. Ticagrelor versus clopidogrel reduced and substantially decreased the absolute risk of ischemic events (5.8%) in COPD patients, without increasing overall major bleeding events. The benefit‐risk profile supports the use of ticagrelor in patients with ACS and concomitant COPD. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT00391872.

Ticagrelor versus clopidogrel in Asian patients with acute coronary syndrome: A retrospective analysis from the Platelet Inhibition and Patient Outcomes (PLATO) Trial

BACKGROUND In the PLATO trial, ticagrelor was superior to clopidogrel in reducing cardiovascular events among patients with acute coronary syndrome (ACS) at the expense of increased nonfatal bleeding. Because Asian patients, when compared with non-Asian patients, are believed to be more susceptible to bleeding, we evaluated the effects of ticagrelor compared with clopidogrel in Asian (n=1,106) and non-Asian (n=17,515) patients with acute coronary syndrome enrolled in the PLATO study. METHODS AND RESULTS Interaction between Asian/non-Asian and primary efficacy end point (a composite of vascular death, myocardial infarction, and stroke) and net clinical benefit (composite of primary efficacy end point and coronary artery bypass graft [CABG] surgery or non-CABG-related major bleeding) were evaluated with a Cox proportional hazards model. Baseline demographics and comorbidities were different between Asians and non-Asians. The overall cardiovascular event rates were higher in Asians, but bleeding rates were similar. Despite these observed differences, the effects of ticagrelor versus clopidogrel were not significantly different between Asians and non-Asians with respect to the primary efficacy outcome (hazard ratio for Asians vs non-Asians, 0.84 [95% CI 0.61-1.17] vs 0.85 [95% CI 0.77-0.93], P=.974), net clinical benefit (0.85 [95% CI 0.65-1.11] vs 0.93 [95% CI 0.86-0.99], P=.521), or individual efficacy end points. There was no significant interaction for bleeding (PLATO major bleeding, 1.02 [95% CI 0.70-1.49] vs 1.04 [95% CI 0.95-1.14], P=.938) and other related adverse events with ticagrelor compared with clopidogrel between Asians and non-Asians. CONCLUSIONS We observed consistency of effects in Asian patients receiving ticagrelor and clopidogrel in the PLATO study. The relatively modest number of Asian patients in this analysis supports further investigation of larger cohorts to confirm our observations.

Challenges and solutions in medically managed ACS in the Asia-Pacific region: Expert recommendations from the Asia-Pacific ACS Medical Management Working Group

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.

Genetic polymorphism in postoperative sepsis after open heart surgery in infants.

Background Sepsis is one of the complications following open heart surgery. Toll-like receptor 2 and toll-interacting protein polymorphism influence the immune response after open heart surgery. This study aimed to assess the genetic distribution of toll-like receptor 2 N199N and toll-interacting protein rs5743867 polymorphism in the development of postoperative sepsis. Methods A prospective cohort study was conducted in 108 children <1-year old who underwent open heart surgery with a Basic Aristotle score ≥6. Patients with an accompanying congenital anomaly, human immunodeficiency virus infection, or history of previous open heart surgery were excluded. The patients’ nutritional status and genetic polymorphism were assessed prior to surgery. The results of genetic polymorphism were obtained through genotyping. Patients’ ages on the day of surgery and cardiopulmonary bypass times were recorded. The diagnosis of sepsis was established according to Surviving Sepsis Campaign criteria. Results Postoperative sepsis was observed in 21% of patients. There were 92.6% patients with toll-like receptor 2 N199N polymorphism and 52.8% with toll-interacting protein rs5743867 polymorphism. Conclusions Toll-like receptor 2 N199N polymorphism tends to increase the risk of sepsis (odds ratio = 1.974; 95% confidence interval: 0.23–16.92; p = 0.504), while toll-interacting protein rs5743867 polymorphism tends to decrease the risk of sepsis (odds ratio = 0.496; 95% confidence interval: 0.19–1.27; p = 0.139) in infants <1-year old undergoing complex open heart surgery.

Oral triiodothyronine normalizes triiodothyronine levels after surgery for pediatric congenital heart disease

Objectives: This study was conducted to determine if oral triiodothyronine supplementation could prevent the decrease of serum triiodothyronine levels that commonly occurs after cardiopulmonary bypass for pediatric congenital heart surgery. Secondary objectives included identifying any significant adverse effects of oral triiodothyronine supplementation, including any effects on the thyroid/pituitary axis. Design: Randomized, placebo-controlled, doubleblind clinical trial Setting: Operating room and ICU. Subjects: Infants and children younger than 2 years of age undergoing congenital heart surgery using cardiopulmonary bypass (n = 43). Interventions: Subjects were assigned to placebo (n = 15, group A) or one of two treatment groups: a low-dose group (group B, n = 14, 0.5 mcg/kg triiodothyronine orally every 24 hr for 3 d) or a high-dose group (group C, n = 14, 0.5 mcg/kg triiodothyronine orally every 12 hr for 3 d). Measurements and Main Results: Thyroid hormone, including total and free triiodothyronine levels at predetermined time points, potential side effects indicatinghyperthyroidism, indicators of the thyroid-pituitary axis, and clinicalendpoints. Oral triiodothyronine supplementation twice-daily maintainedserum triiodothyronine levels within normal limits in groupC, whereas serum levels progressively declined in groups A and B. A statistically significant difference in triiodothyronine levels between the treatment groups occurred between 18 and 36 hourspost cross-clamp release, with the largest difference in serum levelsbetween group C and group A noted at 36 hours post cross-clamprelease (total triiodothyronine, 0.71 ± 0.15 [0.34–1.08] ng/mL [p < 0.01]; free triiodothyronine, 2.56 ± 0.49 [1.33–3.79] pg/mL [p < 0.01]). There was no evidence of hyperthyroidism or suppressionof the pituitary-thyroid axis in either treatment group Conclusions: Oral triiodothyronine supplementation at a dose of 0.5 mcg/kg every 12 hours for 3 days can maintain total and free triiodothyronine levels within normal limits after open-heart surgery using cardiopulmonary bypass for congenitalheart disease.

Lowering Inflammation Level by Lp-PLA2 Inhibitor (Darapladib) in Early Atherosclerosis Development: in vivo Rat Type 2 Diabetes Mellitus Model

Background: The etiology of the ventricular dilation and dysfunction that occurs in idiopathic dilated cardiomyopathy (DCM) is unknown. Aim: The present study was aimed to study clinical characteristics of the patients admitted with idiopathic DCM and compare them with healthy controls. Methods: Thirty newly diagnosed patients with DCM and 30 healthy control were enrolled from Cardiology OPD, PGIMER, Chandigarh from Jan 2011 to Jun 2012. Patients with heart failure secondary to idiopathic DCM of age >18 years were included if they were willing, provide written informed consent and does not meet any of the exclusion criteria. Idiopathic DCM was diagnosed by the presence of left ventricular dilatation and systolic dysfunction (LVEF Results: Mean age of idiopathic DCM patients and control was 48.37±10.82 years and 49.2±9.27 (P=0.75) respectively. There were more males (66.7%) than females (33.3%) in the patient group. It was observed that the treatment with beta blockers, furosemide, spironolactone, ACE inhibitors, and ARBs significantly improved ejection fraction (EF) (P=0.000), and LVES (P=0.000). Conclusion: In our study, treatment with the medications significantly improved EF and LVES. However, there was no treatment-based difference in the patients on ACE inhibitors or ARBs in the improvement in EF. Our study also observed significance difference in platelets count, SGOT, SGPT, and LDL levels in idiopathic DCM patients when compared with healthy controls. Key words: DCM, LVEF, LVES, NYHA Class, ACE Inhibitors, ARBs

Role of terminal warm blood cardioplegia in complex congenital heart surgery

Introduction Myocardial protection is vital to ensure successful open heart surgery. Cardioplegic solution is one method to achieve good myocardial protection. Inevitably, ischemia-reperfusion injury occurs with aortic crossclamping. Histidine-tryptophan-ketoglutarate solution is a frequently used cardioplegia for complex congenital heart surgery. We postulated that addition of terminal warm blood cardioplegia before removal of the aortic crossclamp might improve myocardial protection. Method A randomized controlled trial was conducted on 109 cyanotic patients aged, 1 to 5 years who underwent complex biventricular repair. They were divided into a control group of 55 patients who had histidine-tryptophan-ketoglutarate only and a treatment group of 54 who had histidine-tryptophan-ketoglutarate with terminal warm blood cardioplegia. Endpoints were clinical parameters, troponin I levels, and caspase-3 as an apoptosis marker. Results The incidence of low cardiac output syndrome was 34%, with no significant difference between groups (35.2% vs. 33.3%, p = 0.84). The incidence of arrhythmias in our treatment group was lower compared to the control group (36% vs. 12%, p = 0.005). Troponin I and caspase-3 results did not show any significant differences between groups. For cases with Aristotle score ≥ 10, weak expression of caspase-3 in the treatment group post-cardiopulmonary bypass was lower compared to the control group. Conclusion For complex congenital cardiac surgery, the addition of terminal warm blood cardioplegia does not significantly improve postoperative clinical or metabolic markers.

The third international Polycap study (TIPS-3): Design, baseline characteristics and challenges in conduct

Background It is hypothesized that in individuals without clinical cardiovascular disease (CVD), but at increased CVD risk, a 50% to 60% reduction in CVD risk could be achieved using fixed dose combination (FDC) therapy (usually comprised of multiple blood‐pressure agents and a statin [with or without aspirin]) in a single “polypill”. However, the impact of a polypill in preventing clinical CV events has not been evaluated in a large randomized controlled trial. Methods TIPS‐3 is a 2x2x2 factorial randomized controlled trial that will examine the effect of a FDC polypill on major CV outcomes in a primary prevention population. This study aims to determine whether the Polycap (comprised of atenolol, ramipril, hydrochlorothiazide, and a statin) reduces CV events in persons without a history of CVD, but who are at least at intermediate CVD risk. Additional interventions in the factorial design of the study will compare the effect of (1) aspirin versus placebo on CV events (and cancer), (2) vitamin D versus placebo on the risk of fractures, and (3) the combined effect of aspirin and the Polycap on CV events. Results The study has randomized 5713 participants across 9 countries. Mean age of the study population is 63.9 years, and 53% are female. Mean INTERHEART risk score is 16.8, which is consistent with a study population at intermediate CVD risk. Conclusion Results of the TIP‐3 study will be key to determining the appropriateness of FDC therapy as a strategy in the global prevention of CVD.

Early Exercise Program for Patients with Heart Failure after Hospital Discharge

Background: The exercise program (EP) demonstrated beneficial effects on survival and morbidity of patients with chronic and stable heart failure (HF), but there were no evidence of safety and benefit when the EP was implemented early. Objectives: This study aimed to investigate the effects of early EP for patients with HF. Methods: We randomly recruited 48 patients with systolic HF early after acute HF hospitalisation, with ejection fraction <40%, age <65 years, resting heart rate <100 bpm, and able to walk more than 100 meters as the intervention group (IG). They participated in in-hospital, low-to-moderate intensity, symptom-limited EP for 1 month. Meanwhile, 65 patients with similar characteristic or refused to be recruited to the IG were allocated as control group (CG) underwent usual care. Pre and post study measurement of 6-minutes walking test (6MWT) distance, NTproBNP level, quality of life parameters (Minnesota Living with Heart Failure Questionnaire and SF-36), and first major adverse cardiac event (mortality, rehospitalisation or clinical worsening) within 1 month study period. Results: Both groups had similar baseline characteristics. The patients in IG initiated the early EP on day 5.1+3.5 from hospital discharge. Major adverse cardioascular events were experienced by 9 (18.8%) of the IG and by 26 (40%) of the CG (p=0.016). At the end of study, the 6MWT distance of IG was higher than that of CG: 398.9 (95% CI: 383.8-414.0) versus 352.7 (95% CI: 318.4-387.0) meters, p=0.016. Mean NT-proBNP level did not change in IG (from 3774 to 3563 pg/mL, p=0.568) nor in CG (from 3784 to 4931 pg/mL, p=0.150). Quality of life parameters improved in IG, but not in CG. Conclusion: Early EP for patients with HF was safe and effective in improving physical fitness level and quality of life and it did not harm the myocardium.