Efficacy and Safety of SID142 in Patients With Peripheral Arterial Disease: A Multicenter, Randomized, Double-Blind, Active-Controlled, Parallel-Group, Phase III Clinical Trial.

PURPOSE: Renexin® is a combination pill of cilostazol and Ginkgo biloba leaf extract that is used for the improvement of ischemic symptoms associated with peripheral arterial disease (PAD). SID142 is a controlled-release tablet of cilostazol (200 mg) and G biloba leaf extract (160 mg) that was developed to address the limitation of BID administration with Renexin. This study aimed to verify that SID142 was not inferior to Renexin in the treatment of patients with PAD. METHODS: This was a multicenter, randomized, double-blind, active-controlled, parallel-group, Phase III clinical trial. Study subjects were randomized to receive SID142 once daily or Renexin twice a day for 12 weeks. The primary end point was a change in the patient assessment of lower leg pain intensity with the use of a visual analog scale (VAS) after 12 weeks of treatment. If the lower limit of the two-sided 95% CI was greater than -10, the study drug was declared noninferior to the reference drug. Secondary efficacy end points included cold sensation, ankle-brachial index, ankle systolic pressure, maximum walking distance, pain-free walking distance, and investigator's global assessment. Study group results were compared 4, 8, and 12 weeks after treatment. Adverse events were assessed as a safety end point. FINDINGS: In total, 344 subjects from 19 medical centers were screened, and a total of 170 subjects were randomly assigned to either the SID142 (n = 86) or the Renexin (n = 84) group. Analysis of the change in lower extremity pain at 12 weeks compared with baseline revealed that SID142 was not inferior to Renexin (21.44 [19.23] vs 22.30 [17.75]; 95% CI, -7.70 to 5.97; P = 0.5942). No significant differences were found between groups in any secondary efficacy end point. However, the incidence of adverse reactions was significantly lower in the SID142 group (22.35% vs 39.29%; P = 0.0171). IMPLICATIONS: SID142 once daily was not inferior to Renexin twice a day for efficacy in patients with PAD. SID142 had a favorable safety profile. CLINICALTRIALS: gov identifier: NCT03318276.

Comparison of the Efficacy and Safety of Atorvastatin 40 mg/ω-3 Fatty Acids 4 g Fixed-dose Combination and Atorvastatin 40 mg Monotherapy in Hypertriglyceridemic Patients who Poorly Respond to Atorvastatin 40 mg Monotherapy: An 8-week, Multicenter, Randomized, Double-blind Phase III Study.

PURPOSE: Residual cardiovascular risk in patients with hypertriglyceridemia, despite optimal low-density lipoprotein cholesterol levels being achieved with intensive statin treatment, is a global health issue. The purpose of this study was to investigate the efficacy and tolerability of treatment with a combination of high-dose atorvastatin/Ω-3 fatty acid compared to atorvastatin + placebo in patients with hypertriglyceridemia who did not respond to statin treatment. METHODS: In this multicenter, randomized, double-blind, placebo-controlled study, patients who had residual hypertriglyceridemia after a 4-week run-in period of atorvastatin treatment were randomly assigned to receive UI-018 (fixed-dose combination atorvastatin/Ω-3 fatty acid 40 mg/4 g) or atorvastatin 40 mg + placebo (control). The primary efficacy end points were the percentage change from baseline in non-high density lipoprotein cholesterol (non-HDL-C) level at the end of treatment and the adverse events recorded during treatment. A secondary end point was the percentage change from baseline in triglyceride level. FINDINGS: After 8 weeks of treatment, the percentage changes from baseline in non-HDL-C (-4.4% vs +0.6%; p = 0.02) and triglycerides (-18.5% vs +0.9%; p < 0.01) were significantly greater in the UI-018 group (n = 101) than in the control group (n = 99). These changes were present in subgroups of advanced age (≥65 years), status (body mass index ≥25 kg/m2), or without diabetes. The prevalences of adverse events did not differ between the 2 treatment groups. IMPLICATIONS: In patients with residual hypertriglyceridemia despite receiving statin treatment, a combination of high-dose atorvastatin/Ω-3 fatty acid was associated with a greater reduction of triglyceride and non-HDL-C compared with atorvastatin + placebo, without significant adverse events.

Safety of the Up-titration of Nifedipine GITS and Valsartan or Low-dose Combination in Uncontrolled Hypertension: the FOCUS Study.

PURPOSE: Doubling the dose of antihypertensive drugs is necessary to manage hypertension in patients whose disease is uncontrolled. However, this strategy can result in safety issues. This study compared the safety and efficacy of up-titration of the nifedipine gastrointestinal therapeutic system (GITS) with up-titration of valsartan monotherapy; these were also compared with low-dose combinations of the two therapies. METHODS: This prospective, open-label, randomized, active-controlled, multicenter study lasted 8 weeks. If patients did not meet the target blood pressure (BP) after 4 weeks of treatment with low-dose monotherapy, they were randomized to up-titration of the nifedipine GITS dose from 30 mg (N30) to 60 mg or valsartan from 80 mg to 160 mg or they were randomized to receive a low-dose combination of N30 and valsartan 80 mg for another 4 weeks. BP variability was assessed by using the SD or the %CV of the short-term BP measured at clinic. FINDINGS: Of the 391 patients (20~70 years with stage II or higher hypertension) screened for study inclusion, 362 patients who had 3 BP measurements were enrolled. The reduction in the mean systolic/diastolic BP from baseline to week 4 was similar in both low-dose monotherapy groups with either N30 or valsartan 80 mg. BP variability (SD) was unchanged with either therapy, but the %CV was slightly increased in the N30 group. There was no significant difference in BP variability either in SD or %CV between responders and nonresponders to each monotherapy despite the significant difference in the mean BP changes. The up-titration effect of nifedipine GTS from 30 to 60 mg exhibited an additional BP reduction, but this effect was not shown in the up-titration of valsartan from 80 to 160 mg. Although the difference in BP was obvious between high-dose nifedipine GTS and valsartan, the BP variability was unchanged between the 2 drugs and was similar to the low-dose combinations. There was a low rate of adverse events in all treatment groups. In addition, escalating the dose of either nifedipine GITS or valsartan revealed a similar occurrence of adverse effects with low-dose monotherapy or the low-dose combination. IMPLICATIONS: Compared with up-titration of the angiotensin receptor blocker valsartan, up-titration of the calcium channel blocker nifedipine GITS provided no additional increased safety concerns and revealed better mean reductions in BP without affecting short-term BP variability. ClinicalTrials.gov identifier: NCT01071122.

Interatrial septal thickness as a marker of structural and functional remodeling of the left atrium in patients with atrial fibrillation.

BACKGROUND/AIMS: There have been reports that interatrial septal (IAS) thickness is increased in patients with atrial fibrillation (AF). This study was performed to investigate whether IAS thickness determined by transthoracic echocardiography (TTE) represents the amount of left atrium (LA) structural and functional remodeling. METHODS: The study population consisted of 104 consecutive patients who underwent catheter ablation (CA) for AF (paroxysmal atrial fibrillation [PAF], 82; persistent atrial fibrillation [PeAF], 22). IAS thickness and left atrium volume (LAV) using TTE, and LA voltage (LA(VOL)) using 3-dimensional electroanatomical mapping system were assessed during sinus rhythm. RESULTS: IAS thickness was significantly correlated with maximal LAV (LAV(max)) (r = 0.288, p = 0.003), mean LA(VOL) (r = -0.537, p < 0.001), total left atrium emptying fraction (LAEF(total); r = -0.213, p = 0.030), and active LAEF (LAEF(active); r = -0.249, p = 0.014). IAS thickness was greater in the high-risk group (≥ 2) compared to other groups according to CHA2DS2-VASc score (p = 0.019). During a follow-up of 19.6 months, 23 subjects (22.1%; PAF, 17; PeAF, 6) had recurrence of arrhythmia. Univariate analysis showed that LAV(max), minimal LAV, mean LA(VOL), LVEF(total), LVEF(active), and IAS thickness were associated with recurrence of arrhythmia. However, on multivariate analysis, only mean LA(VOL) and LAEF(active) were independent risk factors for recurrence. CONCLUSIONS: Although IAS thickness showed significant correlations with parameters for LA structural and functional remodeling, this parameter alone could not independently predict recurrence of arrhythmia after CA for AF.

Impact of low dose atorvastatin on development of new-onset diabetes mellitus in Asian population: Three-year clinical outcomes.

BACKGROUND: High dose atorvastatin is known to be associated with new onset diabetes mellitus (NODM) in patients with high risk for developing diabetes mellitus (DM). However, low dose atorvastatin is more commonly used as compared with high dose atorvastatin. The aim of this study is to investigate the impact of low dose atorvastatin (LDA, 10mg or 20mg) on the development of NODM up to three years in Asian patients. METHODS: From January 2004 to September 2009, we investigated a total of 3566 patients who did not have DM. To adjust for potential confounders, a propensity score matching (PSM) analysis was performed using the logistic regression model. After PSM (C-statistics: 0.851), a total of 818 patients (LDA group, n=409 patients and control group, n=409 patients) were enrolled for analysis. RESULTS: Before PSM, the cumulative incidence of NODM (5.8% vs. 2.1%, p<0.001), myocardial infarction (0.5% vs. 0.1%, p-value=0.007), and major adverse cardio-cerebral event (MACCE, 1.8% vs. 0.7%, p-value=0.012) at three-years were higher in the LAD group. However, after PSM, there was a trend toward higher incidence of NODM (5.9% vs. 3.2%, p=0.064) in the LDA group, but the incidence of MACCE (1.2% vs. 1.5%, p-value=1.000) was similar between the two groups. In multivariable analysis, the LDA administration was tended to be an independent predictor of NODM (OR: 1.99, 95% CI: 1.00-3.98, p-value 0.050). CONCLUSIONS: In this study, the use of LDA tended to be a risk factor for NODM in Asian patients and reduced clinical events similar to the control group. However, large-scale randomized controlled trials will be needed to get the final conclusion.

Does isolation of the left atrial posterior wall improve clinical outcomes after radiofrequency catheter ablation for persistent atrial fibrillation?: A prospective randomized clinical trial.

INTRODUCTION: Although posterior wall of left atrium (LA) is known to be arrhythmogenic focus, little is known about the effect of posterior wall isolation (PWI) in patients who undergo radiofrequency catheter ablation (RFCA) for persistent atrial fibrillation (PeAF). METHODS: We randomly assigned 120 consecutive PeAF patients to additional PWI [PWI (+), n=60] or control [PWI (-), n=60] groups. In all patients, linear ablation was performed after circumferential pulmonary vein isolation (PVI). Linear lesions included roof, anterior perimitral, and cavotricuspid isthmus lines with conduction block. In PWI (+) group, posterior inferior linear lesion was also conducted. Creatine kinase-MB (CK-MB) and troponin-T levels were measured 1day after RFCA. LA emptying fraction (LAEF) was assessed before and 12 months after RFCA. RESULTS: A total of 120 subjects were followed for 12 months after RFCA. There were no significant differences between two groups in baseline demographics and LA volume (LAV). The levels of CK-MB and troponin-T and procedure time were not significantly different between the groups. AF termination during RFCA was more frequently observed in PWI (+) than control (P=0.035). During follow-up period, recurrence occurred in 10 (16.7%) patients in PWI (+) and 22 (36.7%) in control (P=0.02). The change in LAEF was not significantly different between the groups. On multivariate analysis, smaller LAV and additional PWI were independently associated with procedure outcome. CONCLUSIONS: PWI in addition to PVI plus linear lesions was an efficient strategy without deterioration of LA pump function in patients who underwent RFCA for PeAF.

Does the amount of atrial mass reduction improve clinical outcomes after radiofrequency catheter ablation for long-standing persistent atrial fibrillation? Comparison between linear ablation and defragmentation.

BACKGROUND: Although a large isolated surface area of the left atrium (LA) may improve the success rate of catheter ablation (CA) for paroxysmal atrial fibrillation (AF), little is known about the relation between clinical outcomes and the amount of atrial mass reduction (AMR: ratio of total isolated and ablated areas to LA surface area) in different ablation strategies for patients with long-standing persistent AF (L-PeAF). METHODS: We randomly assigned 119 consecutive L-PeAF patients to adjunctive linear ablation (n=60) or complex fractionated atrial electrogram (CFAE)-guided ablation (n=59) after circumferential antral pulmonary vein isolation (PVI). Linear lesions included roof and anterior lines with conduction block. LA defragmentation was performed with an automated CFAE-detection algorithm. Cavotricuspid isthmus block was performed in all patients. Creatine kinase-MB (CK-MB) and troponin-T levels were measured 1 day post-CA. RESULTS: CK-MB and troponin-T levels were higher, ablation time was longer, and AMR was greater in the CFAE-guided ablation group than in the linear ablation group. AF termination during CA was more frequently observed in the linear ablation group than in the CFAE-guided ablation group (P=0.031). Twelve months after a single procedure, recurrence occurred in 16 (26.7%) patients with linear ablation and 27 (45.8%) patients with CFAE-guided ablation (P=0.023). On multivariate analysis, LA volume and ablation method were the only independent risk factors for arrhythmia recurrence. CONCLUSION: Conduction block through linear lines+PVI was an efficient ablation strategy for L-PeAF, whereas the AMR amount did not influence clinical outcomes.

Comparison of the efficacy and safety of fixed-dose amlodipine/losartan and losartan in hypertensive patients inadequately controlled with losartan: a randomized, double-blind, multicenter study.

BACKGROUND: Fixed-dose combination drugs may enhance blood pressure (BP) goal attainment through complementary effects and reduced side effects, which leads to better compliance. OBJECTIVE: This study aimed to evaluate the efficacy and safety profiles of once-daily combination amlodipine/losartan versus losartan. METHODS: This was an 8-week, double-blind, multicenter, randomized phase III study conducted in outpatient hospital clinics. Korean patients with essential hypertension inadequately controlled on losartan 100 mg were administered amlodipine/losartan 5 mg/100 mg combination versus losartan 100 mg. The main outcome measures were changes in sitting diastolic blood pressure (DBP) and sitting systolic blood pressure (SBP) and BP response rate from baseline values, which were assessed after 4 and 8 weeks of treatment. Safety and tolerability were also assessed. RESULTS: At week 8, both groups achieved significant reductions from baseline in DBP (11.7 ± 7.0 and 3.2 ± 7.9 mmHg), which was significantly greater in the amlodipine/losartan 5 mg/100 mg combination (n = 70) group (p < 0.0001). Additionally, the amlodipine/losartan 5 mg/100 mg combination group achieved significantly greater reductions in SBP at week 8 and in SBP and DBP at week 4 compared with the losartan 100 mg (n = 72) group (all p < 0.0001). Response rates were significantly higher in the amlodipine/losartan 5 mg/100 mg group versus the losartan 100 mg group (81.4% vs 63.9% at week 4, p < 0.0192; 90.0% vs 66.7% at week 8, p < 0.001). Both treatments were generally well tolerated. CONCLUSION: Switching to a fixed-dose combination therapy of amlodipine/losartan 5 mg/100 mg was associated with significantly greater reductions in BP and superior achievement of BP goals compared with a maintenance dose of losartan 100 mg in Korean patients with essential hypertension inadequately controlled on losartan 100 mg. CLINICAL TRIAL REGISTRATION: Registered at Clinicaltrials.gov as NCT00940680.

Mechanisms responsible for the initiation and maintenance of atrial fibrillation assessed by non-contact mapping system.

BACKGROUND: This study is aimed to assess the initiation and maintenance mechanisms of atrial fibrillation (AF) and their relationships with the anatomical structures of the left atrium (LA) and pulmonary veins (PVs). METHODS: Thirty-seven patients (pts; 33 men, mean age 50+/-12, range 25-68 years) with paroxysmal AF (n=29) and persistent AF (n=8) who underwent mapping of the LA and PV using 3D non-contact endocardial mapping system (EnSite 3000) were included. Atrial premature complexes (APCs) which triggered the initiation of AF lasted longer than 1 min were mapped and the activation sequence on isopotential color maps was analyzed. RESULTS: Wave front dynamics and the relationship with the underlying anatomical structures were assessed. APCs from PV were related to the initiation of AF, but not to the maintenance of AF in 59.5% of the pts (focally triggered type) whereas APCs from PV not only initiated AF but also maintained AF without continuous triggering in 27% (focally driven type). Mixed type and indeterminate type of AF was in 4.5% and 13.5%, respectively. During AF, the mean number of wavelet was 1.45 (maximum 3 in 76.5%). Anatomical structures showing frequent wave break and slow conduction were mostly located at the septopulmonary bundle (86.5%) and the posterior LA roof between left superior PV and right superior PV (54.1%). CONCLUSION: Focal repetitive activity from PV played an important role in both initiation and maintenance of AF using NCM study. Specific anatomical structures such as septopulmonary bundle or posterior LA roof were associated with the spontaneous wave break and heterogeneous conduction delay, which was also appears to be important in the maintenance of AF.