Comparison of efficacy and safety between third-dose triple and third-dose dual antihypertensive combination therapies in patients with hypertension.

We compared the efficacy and safety of third-standard-dose triple and third-standard-dose dual antihypertensive combination therapies in patients with mild to moderate hypertension. This was a phase II multicenter, randomized, double-blind, parallel-group trial. After a 4-week placebo run-in period, 245 participants were randomized to the third-dose triple combination (ALC group; amlodipine 1.67 mg + losartan potassium 16.67 mg + chlorthalidone 4.17 mg) or third-dose dual combination (AL group; amlodipine 1.67 mg + losartan potassium 16.67 mg, LC group; losartan potassium 16.67 mg + chlorthalidone 4.17 mg, AC group; amlodipine 1.67 mg + chlorthalidone 4.17 mg) therapy groups and followed up for 8 weeks. The mean systolic blood pressure (BP) reduction was -18.3 ± 13.2, -13.0 ± 13.3, -16.3 ± 12.4, and -13.8 ± 13.2 mmHg in the ALC, AL, LC, and AC groups, respectively. The ALC group showed significant systolic BP reduction compared to the AL and AC groups at weeks 4 (P = .010 and P = .018, respectively) and 8 (P = .017 and P = .036, respectively). At week 4, the proportion of systolic BP responders was significantly higher in the ALC group (42.6%) than in the AL (22.0%), LC (23.3%), and AC (27.1%) groups (P = .013, P = .021, and P = .045, respectively). At week 8, the proportion of systolic and diastolic BP responders was significantly higher in the ALC group (59.7%) than in the AL (39.3%) and AC (42.4%) groups (P = .022 and P = .049, respectively) at week 8. Third-standard-dose triple antihypertensive combination therapy demonstrated early effective BP control compared to third-standard-dose dual combination therapies, without increasing adverse drug reactions in patients with mild-to-moderate hypertension.

Efficacy and Safety of DP-R202 in Patients with Chronic Artery Occlusive Disease: Multicenter Randomized Double-blind Active-controlled Parallel Group Phase III Clinical Study.

PURPOSE: Sarpogrelate hydrochloride, a selective 5-hydroxytryptamine 2A antagonist, is a widely used antiplatelet agent for the treatment of peripheral arterial disease (PAD). DP-R202 is a new sarpogrelate hydrochloride product with an improved dosage regimen compared with the agent in current use. The aim of this study was to compare the efficacy and safety profile of DP-R202 and Anplag(⁎) Tab in patients with PAD. METHODS: This study was a 12-week, multicenter, randomized, double-blinded, active-controlled, parallel group comparative Phase III clinical trial. One hundred fifty-one volunteer patients with PAD were randomized to receive DP-R202 300 mg once daily or Anplag Table 100 mg TID for 12 weeks. The primary end point was a change in patient assessment of lower leg pain intensity with the use of a visual analog scale (VAS) after 12 weeks of treatment. Results after 4, 8, and 12 weeks of treatment were compared with baseline and between treatment groups, and all patients were assessed for adverse events (AEs), clinical laboratory data, and vital signs. FINDINGS: Two hundred thirty-one patients from 25 medical centers were assessed, and 151 were enrolled and randomly assigned to 1 of 2 treatment groups. Seventy-five patients received DP-R202 300 mg once daily and 76 patients received Anplag Table 100 mg TID for 12 weeks. Analysis of the change in lower leg pain intensity as determined by VAS score between baseline and week 12 (mean [SD], 20.72 [20.06] mm vs 15.55 [21.44] mm) suggested that DP-R202 was not inferior to Anplag Tab, and no significant differences were found in the secondary end points. No significant between-group differences were observed in the prevalence of drug-related clinical- or laboratory-determined AEs. For tolerability, no specific issue was found during the treatment period. IMPLICATION: The results of this study suggest that DP-R202 was not inferior to Anplag Tab for efficacy in patients with PAD and indicated a good safety profile.

SUrvey of Guideline Adherence for Treatment of Systolic Heart Failure in Real World (SUGAR): a multi-center, retrospective, observational study.

BACKGROUND: Clinical practice guidelines have been slowly and inconsistently applied in clinical practice, and certain evidence-based, guideline-driven therapies for heart failure (HF) have been significantly underused. The purpose of this study was to survey guideline compliance and its effect on clinical outcomes in the treatment of systolic HF in Korea. METHOD AND RESULTS: The SUrvey of Guideline Adherence for Treatment of Systolic Heart Failure in Real World (SUGAR) trial was a multi-center, retrospective, observational study on subjects with systolic HF (ejection fraction <45%) admitted to 23 university hospitals. The guideline adherence indicator (GAI) was defined as a performance measure on the basis of 3 pharmacological classes: angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor II blocker (ARB), beta-blocker (BB), and aldosterone antagonist (AA). Based on the overall adherence percentage, subjects were divided into 2 groups: those with good guideline adherence (GAI ≥50%) and poor guideline adherence (GAI <50%). We included 1319 regional participants as representatives of the standard population from the Korean national census in 2008. Adherence to drugs at discharge was as follows: ACEI or ARB, 89.7%; BB, 69.2%; and AA, 65.9%. Overall, 82.7% of the patients had good guideline adherence. Overall mortality and re-hospitalization rates at 1 year were 6.2% and 37.4%, respectively. Survival analysis by log-rank test showed a significant difference in event-free survival rate of mortality (94.7% vs. 89.8%, p = 0.003) and re-hospitalization (62.3% vs. 56.4%, p = 0.041) between the good and poor guideline-adherence groups. CONCLUSIONS: Among patients with systolic HF in Korea, adherence to pharmacologic treatment guidelines as determined by performance measures, including prescription of ACEI/ARB and BB at discharge, was associated with improved clinical outcomes.

Enhanced cardioprotective effects by coexpression of two isoforms of hepatocyte growth factor from naked plasmid DNA in a rat ischemic heart disease model.

BACKGROUND: The therapeutic potential of pCK-HGF-X7, a naked DNA designed to express two isoforms of hepatocyte growth factor (HGF(723) and HGF(728) ), was studied in the rat ischemic heart disease model. METHODS: First, the kinetics of gene expression was examined by injecting pCK-HGF-X7 DNA into the rat heart. Second, the cardioprotective effects were compared between the two naked DNA constructs, expressing a single (HGF(728) ) or both isoforms (HGF(728) and HGF(723) ) of HGF, in the rat ischemic heart disease model. The ischemic injury to the rat heart was created by ischemia-reperfusion in the anterior descending artery. The respective naked DNA constructs were injected into the anterior wall of the rat heart with the ischemia-reperfusion injury. Cardiac function, capillary density and anti-fibrotic activity were compared between the two naked DNA constructs. RESULTS: The intramyocardial administration of pCK-HGF-X7 resulted in transient and localized HGF expression for 3 weeks. At its peak, approximately 678 pg (per mg of tissue protein) of HGF was produced in the injected heart without an increase of HGF protein level in other tissues, and serum. pCK-HGF-X7 more efficiently improved the left ventricular ejection fraction and the systolic anterior wall thickness, increased the capillary density, and inhibited myocardial fibrosis, in a statistically significant manner, compared to the identical vector encoding HGF(728) only. CONCLUSIONS: These results demonstrate that transfer of the genomic-cDNA hybrid expressing both isoforms of the HGF gene might provide higher therapeutic effects than the cDNA sequence producing HGF(728) alone in the treatment of ischemic heart disease.

Left ventricular hypertrophy determines the severity of diastolic dysfunction in patients with nonvalvular atrial fibrillation and preserved left ventricular systolic function.

Regression of left ventricular (LV) hypertrophy (LVH) is known to be related to a lower incidence of stroke in hypertensive patients with nonvalvular atrial fibrillation (NV-AF). However, its mechanism remains controversial. Recently, diastolic dysfunction (DD) was reported to be correlated with ischemic stroke in NV-AF. We hypothesized that hypertension (HTN) and resultant LVH might be associated with the severity of DD in NV-AF. Two hundred and ninety-four patients (204 males, age 66 ± 12 y) with NV-AF with preserved LV systolic function were included. Clinical and echocardiographic data were compared between patients with enlarged left atrial (LA) volume (n = 237) and patients with normal LA. Age (60 ± 12 vs. 67 ± 11 years), sex (male; 81 vs. 62%), duration of NV-AF (4.1 ± 7.8 vs. 45.7 ± 49.0 months), brain natriuretic peptide (108.3 ± 129.3 vs. 236.1 ± 197.0 pg/mL), right ventricular systolic pressure (24.5 ± 5.5 vs. 33.1 ± 11.1 mmHg), mitral inflow velocity (E [77.4 ± 22.2 vs. 88.3 ± 22.0 cm/s]), LV mass index (LVMI [87.6 ± 22.2 vs. 105.1 ± 23.2 g/m(2)]), peak systolic mitral annular velocity (S' [7.2 ± 2.0 vs. 5.8 ± 1.8 cm/s]), and mitral inflow velocity to diastolic mitral annular velocity (E/E' [9.8 ± 3.4 vs. 12.1 ± 4.4]) were significantly different between the two groups, respectively (P < 0.05). In multivariate analysis, LVMI was independently correlated with increased LA volume (OR: 1.037 [95% CI: 1.011-1.063], P < 0.05), whereas HTN was not. LA enlargement, which reflects the severity and chronicity of DD, is independently associated with LVH in patients with NV-AF. Therefore, regression of LVH with anti-hypertensive treatment may lead to improvement of diastolic function and favorable clinical outcomes in hypertensive patients with NV-AF.

Tissue Doppler index, E/E', and ischemic stroke in patients with atrial fibrillation and preserved left ventricular ejection fraction.

BACKGROUND: Although several risk factors for stroke have been reported in patients with atrial fibrillation (AF), the relation of LV diastolic dysfunction to stroke is still uncertain in these patients. We evaluated the relationship between tissue Doppler-derived index, E/E', as well as other clinical and echocardiographic parameters and ischemic stroke by this cross-sectional study. METHODS: Three hundred thirty patients with persistent AF who had preserved LV ejection fraction were included from 6 centers. Clinical data were obtained and standard transthoracic echocardiography was performed. Patients without a history of ischemic stroke (n=280) were compared with patients with this complication (n=50). Potential determinants of ischemic stroke were identified by logistic regression analyses. RESULTS: In univariate analyses, age, history of hypertension, diabetes mellitus, hyperlipidemia and symptomatic heart failure, plasma brain natriuretic peptide (BNP) level, early mitral inflow velocity (E), diastolic mitral annular velocity (E'), and E/E' ratio were significantly correlated to ischemic stroke. Multivariate regression analyses identified two significant variables that were independently associated with ischemic stroke: hypertension (odds ratio=6.03, p=0.008), and E/E' (odds ratio=1.21, p=0.002). CONCLUSIONS: These findings may have clinical implications that LV diastolic dysfunction, reflected by E/E', is a significant determinant of ischemic stroke in AF. A larger prospective data is needed to confirm the value of E/E' in risk stratification for ischemic stroke in this population.

Serial assessment of myocardial properties using cyclic variation of integrated backscatter in an adriamycin-induced cardiomyopathy rat model.

Although adriamycin (Doxorubicin) is one of the most effective and useful antineoplastic agents for the treatment of a variety of malignancies, its repeated administration can induce irreversible myocardial damage and resultant heart failure. Currently, no marker to detect early cardiac damage is available. The purpose of this study was to investigate whether an assessment of the acoustic properties of the myocardium could enable the earlier detection of myocardial damage after adriamycin chemotherapy. Forty Wistar rats were treated with adriamycin (2 mg/kg, i.v.) once a week for 2, 4, 6 or 8 weeks consecutively. Left ventricular ejection fraction (LVEF) was calculated using M-mode echocardiography data. The magnitude of cardiac cycle dependent variation of integrated backscatter (CVIB) of the myocardium was measured in the mid segment of the septum and in the posterior wall of the left ventricle, using a real time two dimensional integrated backscatter imaging system. LVEF was significantly lower in the adriamycin-treated 8-week group than in the controls (75+/-9 vs 57+/-8%, p<0.05). Myocyte damage was only seen in the 8-week adriamycin-treated group. However, no significant changes of CVIB were observed between baseline or during follow-up in the ADR or control group. In conclusion, serial assessment of the acoustic properties of the myocardium may not be an optimal tool for the early detection of myocardial damage after doxorubicin chemotherapy in a rat model.