Correlation of multiple endpoints in the first-line chemotherapy of advanced gastric cancer: Pooled analysis of individual patient data from Japanese Phase III trials.

BACKGROUND: Individual-level surrogates are important for management in patients treated for advanced gastric cancer (AGC). This study aimed to comprehensively investigate the correlation of multiple clinical endpoints in the first-line chemotherapy of AGC. METHODS: Individual patient data (IPD) were collected from four Japanese Phase III trials comparing S-1-based first-line chemotherapies (SPIRITS, START, GC0301/TOP-002, and G-SOX trials). Patients without Response Evaluation Criteria in Solid Tumors (RECIST)-based radiological assessments were excluded. Spearman's rank correlation coefficient was tested for correlation among overall survival (OS), progression-free survival (PFS), and postprogression survival (PPS). OS, PFS, and PPS were compared between responders (best response: complete response or partial response) and nonresponders (best response: stable disease or progressive disease). RESULTS: The study included a total of 1492 patients. Eighty percent of the patients (n = 1190) received subsequent chemotherapies after the failure of each trial's treatment protocol. PFS moderately correlated with OS (Spearman correlation coefficient = 0.66, p < 0.005), whereas the correlation between PPS and OS was strong (Spearman correlation coefficient = 0.87, p < 0.005). Responders had significantly longer OS (median, 17.7 vs. 9.1 months, p < 0.005), PFS (median, 6.9 vs. 2.8 months, p < 0.005), and PPS (median, 10.5 vs. 6.0 months, p < 0.005) than nonresponders. CONCLUSIONS: Our results reacknowledged the mild surrogacy of PFS and importance of postprogression treatments in patients with AGC receiving first-line chemotherapy. Consistent longer survival outcomes in better RECIST categories suggested that tumor response might be a useful individual-level surrogate.

Effect of Late Androgen Replacement Therapy on Erectile Function Through Structural Changes in Castrated Rats.

BACKGROUND: Because androgen replacement therapy (ART) is not performed immediately after the onset of androgen deficiency, the treatment is considered to be late. AIM: To investigate the effects of late ART, starting 4 weeks after castration of rats, on erectile function and structural changes in the corpus cavernosum. METHODS: Rats were subjected to ART for 4 (Late-ART [4w]) or 8 (Late-ART [8w]) weeks. In either case, rats were assigned to the following groups: castrated (Cast), castrated with subcutaneous administration of testosterone (3 mg/kg/day; Cast+T), and sham (Sham). Cast + T rats received daily subcutaneous doses of testosterone starting 4 weeks after castration for 4 or 8 weeks whereas Sham and Cast rats received only the vehicle. OUTCOMES: Erectile function was assessed by evaluating intracavernosal pressure (ICP) and mean arterial pressure (MAP) after electrical stimulation of the cavernous nerve, corporal veno-occlusive function using dynamic infusion cavernosometry, and histology using Masson's trichrome staining. RESULTS: No increase in the ICP was observed in Cast+T rats in the Late-ART (4w) group (0.47 ± 0.02, P > .05), whereas, in Cast+T rats in the Late-ART (8w) group, there was a significant increase in the ICP/MAP ratio (0.60 ± 0.02, P < .05), drop rate, and smooth muscle/collagen ratio. CLINICAL TRANSLATION: The present study provides scientific evidence for the effect of late ART on erectile function. STRENGTHS AND LIMITATIONS: This study provides insights into the influence of late ART on erectile function through improvements in the structure of corpus cavernosum. The major limitation of this study is the difference in the time required for healing between the humans and rats, which might have a bearing on the translational relevenace of the results. CONCLUSIONS: Late ART could improve erectile function. However, as improvement requires a considerable time period, it is necessary to persist with therapy patiently for optimal results. Kataoka T, Hotta Y, Yamamoto Y, et al. Effect of Late Androgen Replacement Therapy on Erectile Function Through Structural Changes in Castrated Rats. Sex Med 2021;XX:XX-XXX.

Meta-Enrichment Analyses to Identify Advanced Gastric Cancer Patients Who Achieve a Higher Response to S-1/Cisplatin.

The Multicenter phase III comparison of cisplatin/S-1 with cisplatin/infusional fluorouracil in advanced gastric or gastroesophageal adenocarcinoma study (FLAGS) and the Diffuse Gastric and Esophagogastric Junction Cancer S-1 Trial (DIGEST) have shown that patients with advanced gastric cancer treated with S-1/Cisplatin (CS) have similar overall survival (OS) compared to 5-fluorouracil/cisplatin (CF). The purpose of this analysis was to identify patients who may specifically benefit from CS using meta-enrichment analysis of the combined two datasets. Eleven clinico-pathological factors were selected and a high response enrichable population was determined. The efficacy of CS in the combined data set of 1365 patients (n = 1019 from FLAGS and n = 346 from DIGEST) was analyzed. We identified 683 patients (n = 374 from CS, n = 309 from CF) as the high response enrichable population who were classified as those with Eastern Cooperative Oncology Group Performance Status (ECOG PS) 1, more than two metastatic sites and low neutrophil-lymphocyte ratio (log(NL ratio)). In the high response enrichable population, the median OS in the CS group was 241 days compared to 210 days in the CF group (hazard ratio 0.776; 95% confidence interval 0.658 to 0.915; p-value 0.004). Through meta-enrichment analysis, the high response enrichable population to CS was identified. Our findings show the clinical importance of selecting the appropriate treatment based on specific patient characteristics.

S-1 versus placebo in patients with sorafenib-refractory advanced hepatocellular carcinoma (S-CUBE): a randomised, double-blind, multicentre, phase 3 trial.

BACKGROUND: Unresectable advanced hepatocellular carcinoma is a heterogeneous disease, for which sorafenib is the first targeted agent approved for first-line therapy, and treatment options for patients with sorafenib-refractory advanced hepatocellular carcinoma are limited. We assessed the efficacy and safety of S-1, a chemotherapeutic agent based on fluorouracil, in patients with sorafenib-refractory advanced hepatocellular carcinoma. METHODS: We did a randomised, double-blind, placebo-controlled, phase 3 study done at 57 sites in Japan. Patients with advanced hepatocellular carcinoma who were ineligible for surgical or local-regional therapy and judged refractory to sorafenib (ie, had progressed on sorafenib or had discontinued sorafenib because of adverse events) were randomly assigned (2:1) to receive oral S-1 (weight-banded 80 mg/m2 [80-120 mg per day]), or placebo, twice per day for 28 days consecutively, followed by a minimum 14 day drug-free period. This cycle was repeated until disease progression or the patient became intolerant to the study treatment. Patients were stratified by site and presence or absence of extrahepatic metastasis or vascular invasion. The primary endpoint was overall survival, assessed in the full analysis set (ie, all patients who were treated with study drug except any individuals who were found not to have hepatocellular carcinoma or who were found to have active double cancer). Patients, medical staff, investigators, and the sponsor were masked to treatment assignment. Blinding was maintained even after study treatment concluded. This study is registered with JapicCTI, number JapicCTI-090920, and has been completed. FINDINGS: Between Oct 26, 2009, and Aug 22, 2012, we screened 399 patients. 65 patients were excluded due to not meeting criteria (n=61), declining to participate (n=3), or other reasons (n=1). 334 patients were randomly assigned to receive either S-1 (n=223) or placebo (n=111). One patient in the S-1 group did not receive treatment, and was thus excluded from analyses. At data cutoff, median follow-up was 32·4 months (IQR 24·0-34·7) in the S-1 group and 32·9 months (23·7-39·5) in the placebo group. Median overall survival was 11·1 months (95% CI 9·7-13·1) in the S-1 group and 11·2 months (9·2-12·8) in the placebo group (hazard ratio 0·86, 95% CI 0·67-1·10; p=0·220). The most frequently reported adverse events were skin hyperpigmentation (123 [55%] of 222 patients in the S-1 group vs nine [8%] of 111 patients in the placebo group), decreased appetite (104 [47%] vs 21 [19%]), fatigue (102 [46%] vs 20 [18%]), diarrhoea (77 [35%] vs 14 [13%]), and increased blood bilirubin (77 [35%] vs 14 [13%]). Serious adverse events were reported in 90 (41%) of 222 patients in the S-1 group and 24 (22%) of 111 patients in the placebo group. Five treatment-related deaths were reported in the S-1 group. INTERPRETATION: S-1 did not prolong overall survival in patients with sorafenib-refractory advanced hepatocellular carcinoma. Further research is needed to identify subgroups of patients who might benefit from S-1. FUNDING: Taiho Pharmaceuticals.

Traditional Risk Factors Versus Biomarkers for Prediction of Secondary Events in Patients With Stable Coronary Heart Disease: From the Heart and Soul Study.

BACKGROUND: Patients with stable coronary heart disease (CHD) have widely varying prognoses and treatment options. Validated models for risk stratification of patients with CHD are needed. We sought to evaluate traditional and novel risk factors as predictors of secondary cardiovascular (CV) events, and to develop a prediction model that could be used to risk stratify patients with stable CHD. METHODS AND RESULTS: We used independent derivation (912 participants in the Heart and Soul Study) and validation (2876 participants in the PEACE trial) cohorts of patients with stable CHD to develop a risk prediction model using Cox proportional hazards models. The outcome was CV events, defined as myocardial infarction, stroke, or CV death. The annual rate of CV events was 3.4% in the derivation cohort and 2.2% in the validation cohort. With the exception of smoking, traditional risk factors (including age, sex, body mass index, hypertension, dyslipidemia, and diabetes) did not emerge as the top predictors of secondary CV events. The top 4 predictors of secondary events were the following: N-terminal pro-type brain natriuretic peptide, high-sensitivity cardiac troponin T, urinary albumin:creatinine ratio, and current smoking. The 5-year C-index for this 4-predictor model was 0.73 in the derivation cohort and 0.65 in the validation cohort. As compared with variables in the Framingham secondary events model, the Heart and Soul risk model resulted in net reclassification improvement of 0.47 (95% CI 0.25 to 0.73) in the derivation cohort and 0.18 (95% CI 0.01 to 0.40) in the validation cohort. CONCLUSIONS: Novel risk factors are superior to traditional risk factors for predicting 5-year risk of secondary events in patients with stable CHD.

Differential influence of distinct components of increased blood pressure on cardiovascular outcomes: from the atherosclerosis risk in communities study.

Elevation in blood pressure (BP) increases risk for all cardiovascular events. Nevertheless, the extent to which different indices of BP elevation may be associated to varying degrees with different cardiovascular outcomes remains unclear. We studied 13340 participants (aged 54 ± 6 years, 56% women and 27% black) of the Atherosclerosis Risk in Communities Study who were free of baseline cardiovascular disease. We used Cox proportional hazards models to compare the relative contributions of systolic BP, diastolic BP, pulse pressure, and mean arterial pressure to risk for coronary heart disease, heart failure, stroke, and all-cause mortality. For each multivariable-adjusted model, the largest area under the receiver-operating curve (AUC) and smallest -2 log-likelihood values were used to identify BP measures with the greatest contribution to risk prediction for each outcome. A total of 2095 coronary heart disease events, 1669 heart failure events, 771 stroke events, and 3016 deaths occurred during 18 ± 5 years of follow-up. In multivariable analyses adjusting for traditional cardiovascular risk factors, the BP measures with the greatest risk contributions were the following: systolic BP for coronary heart disease (AUC=0.74); pulse pressure for heart failure (AUC=0.79); systolic BP for stroke (AUC=0.74); and pulse pressure for all-cause mortality (AUC=0.74). With few exceptions, results were similar in analyses stratified by age, sex, and race. Our data indicate that distinct BP components contribute variably to risk for different cardiovascular outcomes.

Heart failure with preserved ejection fraction in African Americans: The ARIC (Atherosclerosis Risk In Communities) study.

OBJECTIVES: In an entirely African-American cohort, we compared clinical characteristics, cardiac structure and function, and all-cause mortality in patients with heart failure (HF) with preserved ejection fraction (HFpEF) in relation to patients with heart failure with reduced ejection fraction (HFrEF) and those without HF. BACKGROUND: African Americans are at increased risk for HF. Nevertheless, there are limited phenotypic and prognostic data in African Americans with HFpEF compared with those with HFrEF and those without HF. METHODS: Middle-aged African Americans from the Jackson, Mississippi, cohort of the ARIC (Atherosclerosis Risk In Communities) study (n = 2,445) underwent echocardiography between 1993 and 1995. HF prevalence was available in 1,962 patients for whom left ventricular ejection fraction (LVEF) could be quantified. Participants with HF were categorized as having HFpEF (LVEF ≥50%), HFrEF (LVEF <50%), or no HF, with comparisons made between groups. RESULTS: HF was identified in 116 (5.9%) participants (HFpEF n = 85 [73%]; HFrEF n = 31 [27%]). Compared with those without HF, those with HFpEF were older, were more likely to be female, and had more frequent comorbidities and concentric hypertrophy. In relation to HFrEF, those with HFpEF were more likely to be female but less likely to have coronary heart disease, diabetes mellitus, chronic kidney disease, left atrial enlargement, and eccentric hypertrophy. Over a median 13.7 years of follow-up, risk of death differed between groups, with age- and sex-adjusted hazard ratios of 1.51 (95% confidence interval: 1.01 to 2.25) for HFpEF versus those without HF and 2.50 (95% confidence interval: 1.37 to 4.58) for HFrEF versus HFpEF. CONCLUSIONS: In this cohort of middle-aged African Americans, HFpEF was the most common form of HF and was associated with a substantially better prognosis than HFrEF but worse than those without HF.

Right ventricular function, pulmonary pressure estimation, and clinical outcomes in cardiac resynchronization therapy.

BACKGROUND: Right ventricular function (RVF) is an important determinant of outcome in patients with heart failure, and those with severe RV dysfunction have worse outcome after cardiac resynchronization therapy (CRT). We used data from the Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy (MADIT-CRT) Trial to determine whether therapy with CRT is influenced by or affects RV function and to define the relationship between RV function and outcomes. METHODS AND RESULTS: A total of 1820 patients were randomly assigned to CRT plus implantable cardioverter defibrillator or implantable cardioverter defibrillator-only in a 3:2 ratio. We assessed RVF as RV fractional area change by echocardiography at baseline and after 1 year of therapy (n=1511 and 1273, respectively). The median RV fractional area change was 41%, with 10.9% of patients <35% at baseline. Baseline RVF did not modify the treatment effect of CRT on the primary outcome (interaction P=0.19). Randomization to CRT-implantable cardioverter defibrillator was associated with a greater improvement in RVF (ΔRV fractional area change 8.1% versus 5.4%; P<0.001), and improvement in RVF was related to subsequent outcomes. Every 5-point increase in RV fractional area change was associated with a 22% reduction in event rates (hazard ratio, 0.78; 95% confidence interval, 0.66-0.92; P=0.003), although this was not independent of the concurrent improvement in left ventricular function. Baseline tricuspid regurgitant velocity, a measure of pulmonary systolic pressure, was predictive of events in a multivariate analysis (hazard ratio, 1.86; 95% confidence interval, 1.24-2.8; P=0.003). CONCLUSIONS: In this population with mild heart failure symptoms, CRT was associated with improvement in RVF, which improved in parallel with improvement in left ventricular function. Patients with the best RVF at 1 year demonstrated the lowest subsequent event rates. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01294449.

Utility of lung ultrasound in predicting pulmonary and cardiac pressures.

AIMS: Quantification of linear lung ultrasound (LUS) artefacts (B-lines) represents a novel, non-invasive approach to assess pulmonary congestion. We investigated the relationship between the number of B-lines (vertical artefacts arising from the pleural line) and intracardiac pressures. METHODS AND RESULTS: Prior to scheduled right heart catheterization (RHC), 100 subjects underwent LUS of eight zones. A reviewer blinded to the haemodynamic data quantified the number of sonographic B-lines. Of 92 subjects who completed RHC, 79 had adequate LUS data of all zones [median age 61 years, 26 women, median left ventricular ejection fraction (LVEF) 58%, 35 with history of heart failure; 22 postcardiac transplantation]. The number of B-lines correlated with measured right atrial (r = 0.32), pulmonary artery diastolic (PADP) (r = 0.34), mean pulmonary artery (mPAP) (r = 0.43), pulmonary artery systolic (PASP) (r = 0.48) pressures, and pulmonary vascular resistance (PVR) (r = 0.51) (P < 0.005 for all), but not with pulmonary capillary wedge pressure. There was a graded association between tertiles of B-line number and increasing PADP, mPAP, PASP, and PVR (P for trend ≤0.001 for all). Each additional B-line was associated with an increase in PASP of 1 mmHg and an increase in PVR of 0.1 Wood units. These associations remained robust after multivariable adjustment (P = 0.002). Assessment of two inferior lateral zones resulted in similar correlations to the eight-zone method. CONCLUSIONS: Easily obtainable, LUS may be useful in the estimation of right-sided cardiac pressures and PVR. Further evaluation of lung ultrasound as an adjunct to heart failure diagnosis, monitoring, and prognosis is warranted.

The angiotensin receptor neprilysin inhibitor LCZ696 in heart failure with preserved ejection fraction: a phase 2 double-blind randomised controlled trial.

BACKGROUND: Heart failure with preserved ejection fraction is associated with substantial morbidity and mortality, but effective treatments are lacking. We assessed the efficacy and safety of LCZ696, a first-in-class angiotensin receptor neprilysin inhibitor (ARNI), in patients with this disorder. METHODS: PARAMOUNT was a phase 2, randomised, parallel-group, double-blind multicentre trial in patients with New York Heart Association (NYHA) class II-III heart failure, left ventricular ejection fraction 45% or higher, and NT-proBNP greater than 400 pg/mL. Participants were randomly assigned (1:1) by central interactive voice response system to LCZ696 titrated to 200 mg twice daily or valsartan titrated to 160 mg twice daily, and treated for 36 weeks. Investigators and participants were masked to treatment assignment. The primary endpoint was change in NT-proBNP, a marker of left ventricular wall stress, from baseline to 12 weeks; analysis included all patients randomly assigned to treatment groups who had a baseline and at least one postbaseline assessment. This trial is registered at Clinicaltrials.gov, number NCT00887588. FINDINGS: 149 patients were randomly assigned to LCZ696 and 152 to valsartan; 134 in the LCZ696 group and 132 in the valsartan group were included in analysis of the primary endpoint. NT-proBNP was significantly reduced at 12 weeks in the LCZ696 group compared with the valsartan group (LCZ696: baseline, 783 pg/mL [95% CI 670-914], 12 weeks, 605 pg/mL [512-714]; valsartan: baseline, 862 pg/mL [733-1012], 12 weeks, 835 [710-981]; ratio LCZ696/valsartan, 0·77, 95% CI 0·64-0·92, p=0·005). LCZ696 was well tolerated with adverse effects similar to those of valsartan; 22 patients (15%) on LCZ696 and 30 (20%) on valsartan had one or more serious adverse event. INTERPRETATION: In patients with heart failure with preserved ejection fraction, LCZ696 reduced NT-proBNP to a greater extent than did valsartan at 12 weeks and was well tolerated. Whether these effects would translate into improved outcomes needs to be tested prospectively. FUNDING: Novartis.

Association of heart rate and outcomes in a broad spectrum of patients with chronic heart failure: results from the CHARM (Candesartan in Heart Failure: Assessment of Reduction in Mortality and morbidity) program.

OBJECTIVES: The aim of this study was to explore the relationship between baseline resting heart rate and outcomes in patients with chronic heart failure (HF) according to baseline left ventricular ejection fraction (LVEF) and cardiac rhythm. BACKGROUND: Elevated resting heart rate is associated with worse outcomes in patients with HF and reduced LVEF. Whether this association is also found in patients with HF and preserved LVEF is uncertain, as is the predictive value of heart rate in patients in atrial fibrillation (AF). METHODS: Patients enrolled in the CHARM (Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity) Program were divided into groups by tertiles of baseline heart rate. Cox proportional hazard models were used to investigate the association between heart rate and pre-specified outcomes in the overall population as well as in subgroups defined according to LVEF (≤ 40% vs. >40%) and presence (or absence) of AF at baseline. RESULTS: After adjusting for predictors of poor prognosis, patients in the highest heart rate tertile had worse outcomes when compared with those in the lowest heart rate group (e.g., for the composite of cardiovascular death or HF hospital stay hazard ratio: 1.23, 95% confidence interval: 1.11 to 1.36, p < 0.001). The relationship between heart rate and outcomes was similar across LVEF categories and was not influenced by beta-blocker use (p value for interaction >0.10 for both endpoints). However, amongst patients in AF at baseline, heart rate had no predictive value (p value for interaction <0.001). CONCLUSIONS: Resting heart rate is an important predictor of outcome in patients with stable chronic HF without AF, regardless of LVEF or beta-blocker use.

Influence of diabetes on efficacy of aliskiren, losartan or both on left ventricular mass regression.

UNLABELLED: HYPOTHESIS/ INTRODUCTION: We investigated whether diabetes modified the effectiveness of renin-angiotensin-aldosterone system (RAAS) inhibition on left ventricular hypertrophy (LVH) regression in hypertensive patients in the Aliskiren in Left Ventricular Hypertrophy (ALLAY) trial. MATERIALS AND METHODS: Participants (n=465) with LVH and a BMI > 25 kg/m(2) were randomized to aliskiren 300mg, losartan 100mg or both daily for 36 weeks, and LVH regression was assessed by cardiac magnetic resonance imaging. Renin concentration, plasma renin activity and aldosterone were assessed in a subset of patients. RESULTS: Patients with diabetes mellitus (DM) (n=111, 24%) were older (61±9 vs. 58±11 years, p=0.03), had higher BMI (32.2±4.2 vs. 30.7 ± 4 kg/m(2), p=0.004), higher systolic blood pressure (148±14 vs. 145±14mmHg, p=0.03) and lower eGFR (79±16 vs. 84±16ml/min, p=0.03) at baseline. Combination therapy with aliskiren plus losartan was associated with greater LVH reduction than losartan alone in patients with DM (p=0.01), but not in patients without DM (p=0.91; unadjusted interaction p=0.06; adjusted p = 0.038). In a subset of 138 participants, plasma aldosterone was reduced to a greater extent in patients with DM (p-interaction = 0.004). CONCLUSIONS: Patients with DM and LVH may derive differential benefit with dual RAAS inhibition with a combination of aliskiren and losartan compared with losartan alone with respect to LVH reduction. Whether these findings will result in improved outcomes will be further explored in larger studies.

Current status of phase I clinical trials in Asia: an academic perspectives.

Clinical trials increasingly occured in Asia during the past years as pharmaceutical industries embraced globalization in the clinical research fields. The trend is true with phase III clinical trials but not for early stage/phase I clinical trials in Asian countries is still under-represented. The conduct of phase I clinical trials is considered more sophisticated and difficult than the later stage clinical trials. There are continuing concerns from the pharmaceutical industries about the capacity of Asian countries in conducting this type of clinical trials. We highlighted several problems concerning the ethical and scientific issues, the implementation of ICH-GCP and local regulations, investigators and clinical trial subjects. The purpose of this paper is to give some perspectives addressing the problems in conducting phase I clinical trials. Improving collaboration and capacity building among the Asian countries is a solution that we proposed in order to increase the quality and quantity of phase I clinical trials in Asian countries.

Left ventricular systolic and diastolic function, remodelling, and clinical outcomes among patients with diabetes following myocardial infarction and the influence of direct renin inhibition with aliskiren.

AIMS: We assessed the relationship between diabetes and cardiac structure and function following myocardial infarction (MI) and whether diabetes influences the effect of direct renin inhibition on change in left ventricular (LV) size. METHODS AND RESULTS: The ASPIRE trial enrolled 820 patients 2-8 weeks after MI with ejection fraction ≤ 45% and randomized them to the direct renin inhibitor aliskiren (n= 423) or placebo (n = 397) added to standard medical therapy. Echocardiography was performed at baseline and after 36 weeks in 672 patients with evaluable paired studies. Compared with non-diabetic patients, diabetic patients (n = 214) were at higher risk for a composite of cardiovascular (CV) death, heart failure hospitalization, recurrent MI, stroke, or aborted sudden death (14 vs. 7%; adjusted hazard ratio 1.63, 95% confidence interval 1.01-2.64, P= 0.045), despite similar left ventricular ejection fraction (37.9 ± 5.3 vs. 37.6 ± 5.2%, P= 0.48) and end-systolic volume (ESV) (84 ± 25 vs. 82 ± 28 mL, P= 0.46). Diabetic patients demonstrated greater concentric remodelling (relative wall thickness 0.38 ± 0.07 vs. 0.36 ± 0.07, P= 0.0002) and evidence of higher LV filling pressure (E/E' 11.1 ± 5.3 vs. 9.1 ± 4.3, P= 0.0011). At 36 weeks, diabetic patients experienced similar per cent reduction in ESV overall (-4.9 ± 17.9 vs. -5.5 ± 16.9, P= 0.67) but tended to experience greater reduction in ESV than non-diabetic patients when treated with aliskiren (interaction P = 0.08). CONCLUSIONS: Compared with non-diabetic patients, diabetic patients are at increased risk of CV events post-MI despite no greater LV enlargement or reduction in systolic function. Diabetic patients demonstrate greater concentric remodelling and evidence of higher LV filling pressure, suggesting diastolic dysfunction as a potential mechanism for the higher risk observed among these patients.

A meta-analysis on treatment effects of thiazolidinediones for type 2 diabetes mellitus in Asian populations.

AIM: to assess the effects of thiazolidinediones (pioglitazone and rosiglitazone) in the treatment of T2DM in Asian population. METHODS: randomized controlled trials of T2DM patients in Asian population that compared pioglitazone or rosiglitazone with other treatments for more than 3 months and reported HbA1c data were included. Analyses for all outcomes were calculated using random effect model. RESULTS: the analyses included 37 studies in approximately 3,000 patients. Thiazolidinediones had beneficial effect on HbA1c (glycosylated hemoglobin/hemoglobin A1c) compared with control (weighted mean difference (WMD) -0.12%; 95% CI [confidence interval], -0.54 to -0.19% for pioglitazone and -0.47%; 95% CI, -0.89 to -0.40% for rosiglitazone). Overall, TZDs showed significant benefit on glycemic outcomes measured by HbA1c as main surrogate outcome compared with previous glycemic control but not with other anti-diabetics. CONCLUSION: thiazolidinediones treatment resulted in favorable effects on glycemic control in Asian patients with T2DM. Long-term efficacy and safety data of TZD could not yet be confirmed due to the lack of randomized studies with patient-oriented outcomes.