Songsak Kiatchoosakun

Angiotensin Receptor Neprilysin Inhibition Compared With Enalapril on the Risk of Clinical Progression in Surviving Patients With Heart Failure

Background— Clinical trials in heart failure have focused on the improvement in symptoms or decreases in the risk of death and other cardiovascular events. Little is known about the effect of drugs on the risk of clinical deterioration in surviving patients. Methods and Results— We compared the angiotensin-neprilysin inhibitor LCZ696 (400 mg daily) with the angiotensin-converting enzyme inhibitor enalapril (20 mg daily) in 8399 patients with heart failure and reduced ejection fraction in a double-blind trial. The analyses focused on prespecified measures of nonfatal clinical deterioration. In comparison with the enalapril group, fewer LCZ696-treated patients required intensification of medical treatment for heart failure (520 versus 604; hazard ratio, 0.84; 95% confidence interval, 0.74–0.94; P=0.003) or an emergency department visit for worsening heart failure (hazard ratio, 0.66; 95% confidence interval, 0.52–0.85; P=0.001). The patients in the LCZ696 group had 23% fewer hospitalizations for worsening heart failure (851 versus 1079; P<0.001) and were less likely to require intensive care (768 versus 879; 18% rate reduction, P=0.005), to receive intravenous positive inotropic agents (31% risk reduction, P<0.001), and to have implantation of a heart failure device or cardiac transplantation (22% risk reduction, P=0.07). The reduction in heart failure hospitalization with LCZ696 was evident within the first 30 days after randomization. Worsening of symptom scores in surviving patients was consistently more common in the enalapril group. LCZ696 led to an early and sustained reduction in biomarkers of myocardial wall stress and injury (N-terminal pro–B-type natriuretic peptide and troponin) versus enalapril. Conclusions— Angiotensin-neprilysin inhibition prevents the clinical progression of surviving patients with heart failure more effectively than angiotensin-converting enzyme inhibition. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT01035255.

A putative placebo analysis of the effects of LCZ696 on clinical outcomes in heart failure

Aims Although active-controlled trials with renin–angiotensin inhibitors are ethically mandated in heart failure with reduced ejection fraction, clinicians and regulators often want to know how the experimental therapy would perform compared with placebo. The angiotensin receptor-neprilysin inhibitor LCZ696 was compared with enalapril in PARADIGM-HF. We made indirect comparisons of the effects of LCZ696 with putative placebos. Methods and results We used the treatment-arm of the Studies Of Left Ventricular Dysfunction (SOLVD-T) as the reference trial for comparison of an ACE inhibitor to placebo and the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity-Alternative trial (CHARM-Alternative) as the reference trial for comparison of an ARB to placebo. The hazard ratio of LCZ696 vs. a putative placebo was estimated through the product of the hazard ratio of LCZ696 vs. enalapril (active-control) and that of the historical active-control (enalapril or candesartan) vs. placebo. For the primary composite outcome of cardiovascular death or heart failure hospitalization in PARADIGM-HF, the relative risk reduction with LCZ696 vs. a putative placebo from SOLVD-T was 43% (95%CI 34–50%; P < 0.0001) with similarly large effects on cardiovascular death (34%, 21–44%; P < 0.0001) and heart failure hospitalization (49%, 39–58%; P < 0.0001). For all-cause mortality, the reduction compared with a putative placebo was 28% (95%CI 15–39%; P < 0.0001). Putative placebo analyses based on CHARM-Alternative gave relative risk reductions of 39% (95%CI 27–48%; P < 0.0001) for the composite outcome of cardiovascular death or heart failure hospitalization, 32% (95%CI 16–45%; P < 0.0001) for cardiovascular death, 46% (33–56%; P < 0.0001) for heart failure hospitalization, and 26% (95%CI 11–39%; P < 0.0001) for all-cause mortality. Conclusion These indirect comparisons of LCZ696 with a putative placebo show that the strategy of combined angiotensin receptor blockade and neprilysin inhibition led to striking reductions in cardiovascular and all-cause mortality, as well as heart failure hospitalization. These benefits were obtained even though LCZ696 was added to comprehensive background beta-blocker and mineralocorticoid receptor antagonist therapy.

Geographic variations in the PARADIGM-HF heart failure trial

Aims The globalization of clinical trials has highlighted geographic variations in patient characteristics, event rates, and treatment effects. We investigated these further in PARADIGM-HF, the largest and most globally representative trial in heart failure (HF) to date. Methods and results We looked at five regions: North America (NA) 602 (8%), Western Europe (WE) 1680 (20%), Central/Eastern Europe/Russia (CEER) 2762 (33%), Latin America (LA) 1433 (17%), and Asia-Pacific (AP) 1487 (18%). Notable differences included: WE patients (mean age 68 years) and NA (65 years) were older than AP (58 years) and LA (63 years) and had more coronary disease; NA and CEER patients had the worst signs, symptoms, and functional status. North American patients were the most likely to have a defibrillating-device (54 vs. 2% AP) and least likely prescribed a mineralocorticoid receptor antagonist (36 vs. 65% LA). Other evidence-based therapies were used most frequently in NA and WE. Rates of the primary composite outcome of cardiovascular (CV) death or HF hospitalization (per 100 patient-years) varied among regions: NA 13.6 (95% CI 11.7–15.7) WE 9.6 (8.6–10.6), CEER 12.3 (11.4–13.2), LA 11.2 (10.0–12.5), and AP 12.5 (11.3–13.8). After adjustment for prognostic variables, relative to NA, the risk of CV death was higher in LA and AP and the risk of HF hospitalization lower in WE. The benefit of sacubitril/valsartan was consistent across regions. Conclusion There were many regional differences in PARADIGM-HF, including in age, symptoms, comorbidity, background therapy, and event-rates, although these did not modify the benefit of sacubitril/valsartan. Clinical trial registration URL http://www.clinicaltrials.gov. Unique identifier: NCT01035255.

Blood Transfusion After Percutaneous Coronary Intervention and Risk of Subsequent Adverse Outcomes: A Systematic Review and Meta-Analysis

OBJECTIVES This study sought to define the prevalence and prognostic impact of blood transfusions in contemporary percutaneous coronary intervention (PCI) practice. BACKGROUND Although the presence of anemia is associated with adverse outcomes in patients undergoing PCI, the optimal use of blood products in patients undergoing PCI remains controversial. METHODS A search of EMBASE and MEDLINE was conducted to identify PCI studies that evaluated blood transfusions and their association with major adverse cardiac events (MACE) and mortality. Two independent reviewers screened the studies for inclusion, and data were extracted from relevant studies. Random effects meta-analysis was used to estimate the risk of adverse outcomes with blood transfusions. Statistical heterogeneity was assessed by considering the I(2) statistic. RESULTS Nineteen studies that included 2,258,711 patients with more than 54,000 transfusion events were identified (prevalence of blood transfusion 2.3%). Crude mortality rate was 6,435 of 50,979 (12.6%, 8 studies) in patients who received a blood transfusion and 27,061 of 2,266,111 (1.2%, 8 studies) in the remaining patients. Crude MACE rates were 17.4% (8,439 of 48,518) in patients who had a blood transfusion and 3.1% (68,062 of 2,212,730) in the remaining cohort. Meta-analysis demonstrated that blood transfusion was independently associated with an increase in mortality (odds ratio: 3.02, 95% confidence interval: 2.16 to 4.21, I(2) = 91%) and MACE (odds ratio: 3.15, 95% confidence interval: 2.59 to 3.82, I(2) = 81%). Similar observations were recorded in studies that adjusted for baseline hematocrit, anemia, and bleeding. CONCLUSIONS Blood transfusion is independently associated with increased risk of mortality and MACE events. Clinicians should minimize the risk for periprocedural transfusion by using available bleeding-avoidance strategies and avoiding liberal transfusion practices.

Resolution of Left Atrial Thrombus after 6 Months of Anticoagulation in Candidates for Percutaneous Transvenous Mitral Commissurotomy

Context Patients with a left atrial thrombus cannot have percutaneous transvenous mitral commissurotomy for mitral stenosis because of the embolic risk. Contribution This prospective study from a university medical center showed that oral anticoagulation for 6 months resolved the atrial thrombus in 24% of 219 patients with mitral stenosis. These patients subsequently had successful percutaneous transvenous mitral commissurotomy. Eighteen of the 219 patients had minor bleeding during anticoagulation. Implications In patients with atrial thrombus and mitral stenosis who do not need immediate surgery, a 6-month trial of oral anticoagulation might increase the number eligible for percutaneous transvenous mitral commissurotomy. The Editors Percutaneous transvenous mitral commissurotomy (PTMC) is a successful alternative to surgical treatment for mitral stenosis when regurgitation and valvular calcifications are limited (1-4). The presence of a left atrial thrombus is a contraindication for this procedure because of the risk for embolism (1-3). Under some conditions, complete resolution of the thrombus can be achieved with long-term oral anticoagulation, which in turn allows safe PTMC (5-11). In a preliminary study with 75 patients, the size of the thrombus and the severity of left atrial spontaneous echocardiographic contrast were significantly related to thrombus resolution (10). Using a larger sample (11), we devised a model based on the New York Heart Association (NYHA) classification system (12) and the original thrombus size to predict thrombus disappearance after 6 to 34 months of follow-up. However, the short-term effect of oral anticoagulation on a thrombus at specified times is much more clinically important. We therefore estimated the disappearance rate of left atrial thrombi among PTMC candidates treated with 6 months of oral anticoagulation and determined the significant predictors of that rate. Methods Study Participants Between 1 August 1996 and 1 February 2002, candidates for PTMC who had symptomatic (12) severe mitral stenosis (that is, a mitral valve area 1.0 cm2, a total echocardiographic score for the mitral valve of 11, and a mitral regurgitation score of 2+) (13) were consecutively recruited at a university referral hospital in northeastern Thailand. The patients underwent both transthoracic and multiplane transesophageal echocardiographic studies before PTMC; those with a thrombus formed the cohort. We excluded patients who had received an oral anticoagulant for more than 72 hours before study entry, who were pregnant, or who had a contraindication to transesophageal echocardiography. Echocardiographic Method Standard transthoracic and multiplane transesophageal echocardiography (14) were performed using a 2.5- or 3.5-MHz color Doppler system and a 5.0-MHz multiplane transducer (Hewlett-Packard Imaging System Sonos 1000 and, since August 1999, Sonos 5500, Hewlett-Packard, Andover, Massachusetts). Within 24 hours of the transthoracic echocardiographic study, echocardiographers who were blinded to those findings performed transesophageal echocardiography. The diagnosis of thrombus, the severity of left atrial spontaneous echocardiographic contrast (15), and the echocardiographic measurements have been described elsewhere (10, 11). The maximal area of the thrombus was measured by planimetry using the built-in software. When more than 2 thrombi were identified, we analyzed each independently. We recorded the transthoracic and transesophageal echocardiographic studies on VHS videotapes for determination and verification of a thrombus, left atrial spontaneous echocardiographic contrast, maximal area, and mobility of the thrombus. Three echocardiographers independently performed all echocardiographic measurements and then resolved discrepancies by consensus. Management of the Patients At enrollment, we recorded the NYHA functional class, the elapsed time between first symptoms and the first echocardiographic study, history of systemic embolism, and the presence of hemoptysis and syncope. All bleeding and thromboembolic events during follow-up were recorded, including the international normalized ratio (INR) value the day the event occurred. Each patient provided written informed consent, and our institutional ethics committee approved the research protocol. After we identified the presence of thrombi, all patients began taking oral anticoagulants to maintain an INR between 2.0 and 3.0 (16, 17), beginning with weekly adjustments for the first 2 weeks and then changing to monthly adjustments. The presence and size of thrombi were studied by using results from both transthoracic and transesophageal echocardiographic studies at the first 6-month follow-up. Patients with complete thrombus resolution underwent PTMC. All patients received follow-up care at our hospital. We followed patients with potential adverse effects by mail and telephone. Statistical Analysis The rates of thrombus resolution after the first 6 months and the corresponding 95% CIs were estimated on the basis of a binomial distribution. For patients whose thrombus persisted, we calculated the relative reduction in size over the first 6 months and the CI based on a normal distribution and tested whether the mean change was zero by using the paired t-test. A univariate logistic regression was used to assess the effects of selected factors on thrombus resolution. Continuous variables were categorized by tertiles. Patients were ranked according to the scores of the corresponding variable, then divided into 3 equal groups, which allowed assessment of linearity. In relation to the INR, in patients who had 6 available measurements, the mean for each patient was used for all analyses. (The 2 highest tertiles of some variables were combined because no outcomes occurred in either.) Possible confounding and interaction effects were investigated through modeling. The initial model contained clinically important variables and those with a P value of 0.2 or less in the univariate analysis, namely, 3 continuous variables (the time elapsed from the first symptoms, the initial thrombus area, and the mean INR at 6 months); 2 dichotomous variables (the NYHA functional class and the left atrial spontaneous echocardiographic contrast); and the interaction term of the NYHA functional class and the initial thrombus area. The assumption of linearity was assessed for each continuous variable by plotting the log odds against the categories of each. Thrombus area and the INR departed from linearity and were therefore dichotomized on the basis of univariate analysis and the restricted cubic spline functions (18). Backward elimination was used for variable selection, according to Kleinbaum and colleagues (19). Model adequacy and goodness of fit were tested according to Hosmer and Lemeshow (20). Predicted probabilities of left atrial thrombus resolution by all possible combinations of significant predictors were then estimated from the final model. A probability of 0.05 was set for statistical significance. All analyses were done by using Stata (Stata Corp., College Station, Texas). Results Patient Characteristics Of 687 consecutive patients with severe mitral stenosis, 523 were candidates for PTMC. Of these, 219 patients between 19 and 62 years of age (mean age [SD], 39.67.4 years) who had left atrial thrombus demonstrated by transesophageal echocardiography formed the study cohort (Figure). All patients underwent the first 6-month follow-up echocardiography. Figure. Patients that formed the study cohort. Effect of Anticoagulant Therapy Complete disappearance of thrombus was documented in 53 patients at the first 6-month follow-up, with an overall disappearance rate of 24.2% (95% CI, 18.5% to 29.9%), and all of these patients underwent successful and uneventful PTMC. Among the 166 patients whose thrombus persisted, the mean area was reduced from the baseline by approximately 24% (P< 0.001). None of the 27 patients with a thrombus in the left atrial body had thrombus resolution, nor did thrombi in an appendage resolve, although they were reduced approximately 6% from the baseline. Table 1 shows the percentage of left atrial thrombus resolution at 6 months for selected factors. Table 1. Percentage of Left Atrial Thrombus Resolution at the Sixth Month of Follow-up Factors Affecting Thrombus Resolution The final model using multiple logistic regression suggested that the factors significantly associated with thrombus resolution were NYHA functional class 1 or 2, a small left atrial appendage thrombus less than 1.6 cm2 at the first study, a left atrial spontaneous echocardiographic contrast of grade 1 or less, and an INR of 2.5 or more (Table 2). Patients with all of these predictors had a 94.4% (CI, 84.4% to 98.1%) chance of complete thrombus resolution. This model fit the data satisfactorily (P> 0.2 [HosmerLemeshow statistic]). Table 2. Predicted Probabilities of Left Atrial Thrombus Resolution at the Sixth Month of Follow-up Intensity of Oral Anticoagulation and Its Adverse Effects During the 6-month study, INR was measured monthly in all 219 patients. Among the total 1314 INR measurements, the mean (SD) and median (range) were 2.530.39 and 2.52 (range, 1.72 to 3.92), respectively. The percentage of patients whose INR was between 2 and 3 (using 219 as the denominator for each of the 6 months) was 95.0%, 84.5%, 71.7%, 79.0%, 82.2%, and 73.5%, respectively, while the percentage of patients with an INR greater than 3 was 2.7%, 7.8%, 18.7%, 13.2%, 10.5%, and 19.6%, respectively. The INR of 217 of the patients (99.1%) was between 2 and 3 for at least 50% of the follow-up period. During follow-up, none of the patients had major bleeding. Eighteen had minor bleeding, 12 of whom had an INR of less than 2.5 and 6 of whom had an INR of 3.6 or more the day the event occurred. There were 61 systemic embolic events (2.1 per 100 patient-months) before study entry. After oral antico

Right ventricular systolic pressure assessed by echocardiography: a predictive factor of mortality in patients with scleroderma.

Pulmonary arterial hypertension (PAH) is a well‐known complication of systemic sclerosis (SSc). Doppler echocardiographic screening for the detection of PAH (by measuring right ventricular systolic pressure [RVSP]) is therefore recommended for all patients with SSc. However, the validity of RVSP as a predictor of mortality in patients with SSc is not well established.

Correlation of Causes and Outcomes in Stroke in the Young

BACKGROUND We studied the association of causes and stroke outcome of stroke in the young in Thailand. METHODS A retrospective study was performed at Srinagarind Hospital, Khon Kaen University, Thailand. All patients under 45 years of age who were diagnosed with stroke between 1996 and 2010 and who had complete workups for causes of stroke in the young were enrolled. Stroke outcome was defined as favorable or nonfavorable at approximately 1 year of follow-up. If the patient had normal functional ability or mild disability but the patient was fully employed, the outcome was classified as favorable. Clinical features of strokes and the potential stroke risk factors were compared between the favorable and nonfavorable groups. RESULTS Eighty-five patients were enrolled. About half of patients were male (47 patients; 55.3%). The mean age (SD) was 35.9 (6.2) years. Three-fourths of male patients had a stroke after 30 years of age, while female patients developed stroke in all age ranges equally. More than half of patients (45 patients; 52.9%) had cardiac causes of stroke. Rheumatic mitral stenosis accounted for 68% (31 patients), and 45% (14 patients) had atrial fibrillation. There were 64 patients (79%) who had a favorable outcome. Cardiac causes, particularly mitral stenosis and alcohol intake, were significantly associated with a nonfavorable outcome. CONCLUSIONS Stroke in the young generally has a favorable outcome. Factors associated with a nonfavorable outcome of stroke in the young were cardiac abnormalities and alcohol intake. A prospective study to evaluate the association of causes and outcome is needed.

Prognostic factors of mortality and 2-year survival analysis of systemic sclerosis with pulmonary arterial hypertension in Thailand.

Aims:  Pulmonary arterial hypertension (PAH) is a major complication and cause of death in systemic sclerosis (SSc). Our objective was to identify the predictive factors of mortality and the 2‐year survival rate among Thai sufferers of PAH‐SSc.

Melioidosis Pericarditis Mimicking Tuberculous Pericarditis

Cases of melioidosis (N = 2) and tuberculous pericarditis (N = 33) during 1996-2006 were reviewed. Clinical presentations were similar, but pericardial pathological findings were not. Nine of 12 patients with melioidosis required pericardectomy. In areas where these diseases are endemic, pericardial fluid culture and pericardial biopsy can differentiate between melioidosis and tuberculosis.

Prognostic factors of in-hospital mortality in all comers with ST elevation myocardial infarction undergoing primary percutaneous coronary intervention

Background The prognostic factors of in-hospital mortality in all comers and unselected patients with ST elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI) have not been well established. Objective To identify the predictive factors of in-hospital mortality in patients with STEMI undergoing primary PCI in a tertiary heart centre. Methods Between January 2008 and December 2011, all patients with STEMI undergoing primary PCI were retrospectively included in this study. Baseline characteristics and angiographic data were reviewed and recorded. The study endpoint was all-cause in-hospital mortality. Results Of the 541 patients included in the study, 63 (11.6%) died during hospitalisation. Cardiogenic shock at admission was recorded in 301 patients (55.6%) and 424 patients (78%) had multivessel disease. Median door-to-device time was 65 min. After adjustment for baseline variables, the factors associated with in-hospital mortality included age >60 years (OR 2.98, 95% CI 1.17 to 7.05; p=0.01), left ventricular ejection fraction <40% (OR 2.53, 95% CI 1.20 to 5.36; p=0.02), and final TIMI flow grade 0/1 (OR 20.55, 95% CI 3.49 to 120.94; p=0.001). Conclusions Age, left ventricular function and final TIMI flow are significant predictors of adverse outcomes in unselected patients with STEMI undergoing primary PCI.