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The aim of this study was to evaluate the blood pressure–lowering and cholesterol-lowering effects of a fixed-dose combination therapy using candesartan (CND)/rosuvastatin (RSV) compared with CND or RSV monotherapy in patients with hypertension and hypercholesterolemia. This study was a 12-week, randomized, double-blind, placebo-controlled, multicenter study. A total of 394 patients were screened. After a 4-week run-in period, 219 of these patients with hypertension and primary hypercholesterolemia were randomized. Patients received 1 of 3 regimens for 8 weeks: (1) CND 32 mg/RSV 20 mg, (2) RSV 20 mg, or (3) CND 32 mg. The primary outcome variables were changes in the systolic blood pressure (SBP) and diastolic blood pressure (DBP) and the percentage changes in LDL-C from baseline to the drug treatment at 8 weeks. The secondary outcome variables were percentage changes of total cholesterol, triglycerides, HDL-C, non–HDL-C, apolipoprotein B, apolipoprotein A-I, high-sensitivity C-reactive protein, and glucose metabolic indices, including percentage changes of the homeostasis model assessment of insulin resistance (HOMA-IR), adiponectin, and hemoglobin A1c. Tolerability of combination therapy was compared with other monotherapy groups. The percentage changes of LDL-C were −48.6% (from 157.2 to 80.1 mg/dL) in the RSV group and −49.8% (from 160.2 to 78.9 mg/dL) in the CND/RSV group from baseline to the end of 8 weeks of treatment. Mean SBP and DBP were significantly decreased in the CND/RSV and CND groups after 8 weeks (P < 0.001 for all); however, no significant differences were found between the 2 groups. Total cholesterol levels, triglycerides, non–HDL-C, and apolipoprotein B were significantly reduced in the CND/RSV and RSV groups, with no significant differences between the groups compared with the CND group (P < 0.001 for all). The percentage changes of HOMA-IR, adiponectin, and hemoglobin A1c had no significant differences between the combination groups and monotherapy groups. However, in a 2-sample t test, HOMA-IR was significantly decreased in the CND/RSV group compared with the RSV group in nondiabetic patients (mean [SD] percentage change of HOMA-IR, −8.7% [37.6%] vs 17.1% [53.1%]; P = 0.048). There were no significant differences in metabolic indices between the diabetic groups. Adverse events in the CND/RSV group were similar to those in the monotherapy group. Once-daily fixed-dose combination therapy with CND/RSV is an effective, tolerable, convenient treatment option for patients with essential hypertension and hypercholesteremia. ClinicalTrials.gov identifier: NCT02770261.

The objective of this study was to evaluate the efficacy and tolerability of a triple combination of amlodipine/losartan/rosuvastatin in patients with hypertension and hypercholesterolemia. A randomized, multicenter, double-blind, placebo-controlled study was conducted. Eligible patients with hypertension and a sitting diastolic blood pressure (SiDBP) of >90 mm Hg and LDL-C levels <250mg/dL were screened. After a 4-week run-in period with therapeutic lifestyle changes and losartan potassium 100mg once daily, patients who met both blood pressure criteria (80 mm Hg ≤ SiDBP < 110 mm Hg) and the LDL-C level criteria (defined in the National Cholesterol Education Program Adult Treatment Panel III cardiovascular risk categories) were randomized to 1 of 3 groups and treated once daily for 8 weeks: losartan potassium 100mg + rosuvastatin 20mg treatment (L/R 100/20) group, amlodipine camsylate 5mg + losartan potassium 100mg treatment (A/L 5/100) group, and amlodipine 5mg+ losartan potassium 100mg + rosuvastatin 20mg (A/L/R 5/100/20) group. The primary efficacy variables were the percent change in LDL-C in the A/L/R 5/100/20 and A/L 5/100 groups and the mean change of SiDBP in the A/L/R 5/100/20 and L/R 100/20 groups after 8 weeks of treatment, relative to baseline values. A total of 146 patients were enrolled and the demographic characteristics were similar among the 3 treatment groups. After 8 weeks of treatment, the mean (SD) percent change in LDL-C was significantly greater in the A/L/R group than in the A/L group (–48.40% [2.77%] vs –6.70% [3.00%]; P < 0.0001). Moreover, the mean change in SiDBP was significantly greater in the A/L/R group than in the L/R group (–9.75 [0.92] mm Hg vs –1.73 [1.03] mm Hg; P < 0.0001). SiDBP and LDL-C reductions in the A/L/R group were comparable to reductions in the A/L and L/R groups, respectively. Ten adverse events were reported in 7 patients (4.83%), and 1 patient from the A/L group (0.69%) experienced 2 adverse drug reactions (tachycardia and face edema), which were mild and resolved without specific treatment. There were no clinically significant tolerability issues during the treatment period. Triple combination therapy with amlodipine/losartan/rosuvastatin can be an effective therapeutic strategy in patients with hypertension combined with dyslipidemia. These findings will form the foundation of the future development of a single-pill triple combination. ClinicalTrials.gov identifier: NCT02899455.

Intensive blood pressure (BP) lowering is important for the treatment of hypertension; however, it has been a challenge to achieve target BP in many patients. The purpose of this study was to explore the optimal dosage of a fixed-dose combination of candesartan cilexetil (CAN) and amlodipine besylate (AML), by examining the tolerability and efficacy of CAN/AML combination therapy compared with those of monotherapy with either drug in patients with essential hypertension. This Phase II multicenter, randomized, double-blind clinical trial enrolled patients aged 19 years or older with essential hypertension, defined as a mean sitting diastolic BP (msDBP) between 95 and 115 mm Hg, and a mean sitting systolic BP (msSBP) of <200 mm Hg after a 2-week placebo run-in period. A total of 635 patients were screened, of whom 439 were randomized to receive treatment; 425 patients were included in the full analysis set (combination therapy, 212; monotherapy, 213). Participants were randomly assigned to receive 1 of 8 treatments: CAN (8 or 16 mg), AML (5 or 10 mg), CAN/AML (8 mg/5 mg, 8 mg/10 mg, 16 mg/5 mg, or 16 mg/10 mg), once daily for 8 weeks. After 8 weeks of treatment, changes in msDBP were significantly greater in the groups receiving CAN/AML combination therapies compared with monotherapies at matched doses, with the exception of CAN 8 mg/AML 10 mg versus AML 10 mg. The response to treatment and the achievement of target BP (both msSBP and msDBP) at week 8 were significantly greater overall in the groups that received combination therapy versus monotherapy. All medications were relatively well tolerated in each group. Eight-week administration of CAN/AML (8 mg/5 mg, 16 mg/5 mg, and 16 mg/10 mg) resulted in a significantly greater BP reduction than that with CAN or AML monotherapy, and was determined to be well tolerated. ClinicalTrials.gov identifier: NCT02944734.

Risk stratification at hospital discharge could be instrumental in guiding postdischarge care. In this study, the risk models for 1-year mortality using machine learning (ML) were evaluated for guiding management of acute myocardial infarction (AMI) patients. From the Korea Acute Myocardial Infarction Registry (KAMIR) dataset, 22,182 AMI patients were selected. The 1-year all-cause mortality was recorded at 12-month follow-up periods. Anomaly detection was conducted for removing outliers; principal component analysis for dimensionality reduction, recursive feature elimination algorithm for feature selection. Model selection and training were conducted with 70% of the dataset after the creation and cross-validation of hundreds of models with decision trees, ensembles, logistic regressions, and deepnets algorithms. The rest of the dataset (30%) was used for comparison between the ML and KAMIR score-based models. The mean age of the AMI patients was 64 years, 71.8% were male, and 56.7% were eventually diagnosed with ST-elevation myocardial infarction. There were 1,332 patients suffering from all-cause mortality (6%) during a median 338 days of follow-up. The ML models for 1-year mortality were well-calibrated (Hosmer-Lemeshow p >0.05) and showed good discrimination (area under the curve for test cohort: 0.918). Compared with the performance of the KAMIR score model, the ML model had a higher area under the curve, net reclassification improvement, and integrated discrimination improvement. The ML model for 1-year mortality was well-calibrated and had excellent discriminatory ability and higher performance. In a comprehensive clinical evaluation process, this model could support risk stratification and management in postdischarge AMI patients.

Background: Therapeutic hypothermia can improve neurological status in cardiac arrest survivors. Objectives: We investigated the association between the timing of inducing therapeutic hypothermia and neurological outcomes in patients who experienced out-of-hospital cardiac arrest. Methods: We evaluated data from 116 patients who were comatose after return of spontaneous circulation and those who received therapeutic hypothermia between January 2013 and April 2017. The primary endpoint was good neurological outcomes during index hospitalization, defined as a cerebral performance category score of 1 or 2. Therapeutic hypothermia timing was defined as the duration from the return of spontaneous circulation to hypothermia initiation. We analyzed the effect of early hypothermia induction on neurological results. Results: In total, 112 patients were enrolled. The median duration to hypothermia initiation was 284 min (25th-75th percentile, 171-418 min). Eighty-two (69.5%) patients underwent hypothermia within 6 h, and 30 (25.4%) had good neurological outcomes. The rates of good neurological outcomes by hypothermia initiation time quartile (shortest to longest) were 28.3%, 34.5%, 14.8%, and 28.6% (p = 0.401). The good neurologic outcomes did not differ between hypothermia patients within 6 h or after (26.5% vs 26.7%, p = 0.986). Short low-flow time and bystander resuscitation were associated with good neurological outcomes (p = 0.044, confidence interval: 0.027-0.955), but the timing of hypothermia initiation was not (p = 0.602, confidence interval: 0.622-1.317). Conclusion: A shorter low-flow time was associated with good neurological outcomes in out-of-hospital cardiac arrest patients who experienced hypothermia. However, inducing hypothermia sooner, even within 6 h, did not improve the neurological outcomes. Thus, as current guidelines recommend, initiating hypothermia within 6 h of recovery of spontaneous circulation is reasonable.

The transradial approach is increasingly used for percutaneous coronary intervention (PCI), and we therefore aimed to compare the clinical outcomes after transradial intervention (TRI) and transfemoral intervention (TFI) in all patients undergoing PCI. Among 6,973 patients enrolled in a nationwide, prospective, multicenter registry (February 2013 to September 2013), 1,860 underwent TRI (n = 1,445, 77.7%) and TFI (n = 415, 22.3%). Bleeding and major adverse cardiac events (MACE; death, myocardial infarction, revascularization, or stent thrombosis) were compared. Bleeding occurred in 42 patients (2.3%) and was significantly less likely in the TRI versus TFI group (overall cohort: 1.5% vs 4.8%, p = 0.001; propensity score–matched: n = 728, 2.7% vs 5.2%, p = 0.048). Multivariate regression revealed that TRI was negatively associated with bleeding (odds ratio 0.42, 95% CI 0.21 to 0.83, p = 0.013). MACE occurred in 152 patients (8.2%). Kaplan–Meier estimates showed higher MACE-free survival rates in the TRI versus TFI group (overall cohort: 93.3% vs 86.7%, log-rank p = 0.026; propensity score–matched: 91.8% vs 86.5%, log-rank p = 0.04). Cox proportional analysis demonstrated that TRI independently predicted improved MACE (hazard ratio 0.64, 95% CI 0.43 to 0.91, p = 0.024). In conclusion, TRI is associated with reduced bleeding rates and better clinical outcomes than TFI in all patients undergoing PCI.

The pill burden of patients with hypertension and dyslipidemia can result in poor medication compliance. This study aimed to evaluate the efficacy and safety of fixed-dose combination (FDC) therapy with olmesartan medoxomil (40 mg) and rosuvastatin (20 mg) in Korean patients with mild to moderate hypertension and dyslipidemia. This multicenter, randomized, double-blind, factorial-design study included patients aged ≥20 years with mild to moderate essential hypertension and dyslipidemia. Patients were randomly assigned to receive FDC therapy (40 mg olmesartan medoxomil, 20 mg rosuvastatin), 40 mg olmesartan medoxomil, 20 mg rosuvastatin, or a placebo. The percentage change from baseline in low-density lipoprotein cholesterol levels was compared between FDC therapy and olmesartan medoxomil, and the change from baseline in diastolic blood pressure was compared between FDC therapy and rosuvastatin 8 weeks after treatment. A total of 162 patients were included. The least square mean percentage change (standard error) from baseline in low-density lipoprotein cholesterol levels 8 weeks after treatment was significantly greater in the FDC than in the olmesartan medoxomil group (-52.3% [2.8%] vs -0.6% [3.5%], P<0.0001), and the difference was -51.7% (4.1%) (95% confidence interval: -59.8% to -43.6%). The least square mean change (standard error) from baseline in diastolic blood pressure 8 weeks after treatment was significantly greater in the FDC group than in the rosuvastatin group (-10.4 [1.2] mmHg vs 0.1 [1.6] mmHg, P<0.0001), and the difference was -10.5 (1.8) mmHg (95% confidence interval: -14.1 to -6.9 mmHg). There were 50 adverse events in 41 patients (22.7%) and eight adverse drug reactions in five patients (2.8%). The study found that FDC therapy with olmesartan medoxomil and rosuvastatin is an effective, safe treatment for patients with hypertension and dyslipidemia. This combination may improve medication compliance in patients with a large pill burden.

Only limited data are available for the recent trend of optimal evidence-based medical therapy at discharge after acute myocardial infarction (AMI) in Asia. We evaluated the predictors for the use of optimal evidence-based medical therapy at discharge and the association between discharge medications and 6-month mortality after AMI. Between November 2005 and January 2008, we evaluated the discharge medications among 9,294 post-MI survivors who did not have any documented contraindications to antiplatelet drugs, β-blockers, angiotensin-converting enzyme inhibitors (ACE-Is)/angiotensin II receptor blockers (ARBs), or statins in the Korea Acute Myocardial Infarction Registry. Optimal evidence-based medical therapy was defined as the use of all 4 indicated medications. Of these patients, 4,684 (50.4%) received all 4 medications at discharge. The discharge prescription rates of antiplatelet drugs, β-blockers, ACE-Is/ARBs, and statins were 99.0%, 72.7%, 81.5%, and 77.2%, respectively. In multivariate analysis, advanced age, lower systolic blood pressure, higher Killip class at admission, left ventricular systolic dysfunction, higher blood creatinine level, lower total cholesterol levels, and coronary artery bypass grafting during hospitalization were independently associated with less use of optimal evidence-based medical therapy. In contrast, patients who underwent percutaneous coronary intervention were more likely to use optimal medications. In Cox proportional hazards model, optimal evidence-based medical therapy was an independent predictor of 6-month mortality after adjusting clinical characteristics and angiographic and procedural data. The optimal evidence-based medical therapy is prescribed at suboptimal rates, particularly in patients with high-risk features. New educational strategies are needed to increase the use of these secondary preventive medical therapies.

Aims Although clinical guidelines advocate the use of the highest tolerated dose of angiotensin‐converting enzyme inhibitors or angiotensin receptor blockers after acute myocardial infarction (MI), the optimal dosing or the risk–benefit profile of different doses have not been fully identified. Methods and results In this multicentre trial, 495 Korean patients with acute ST segment elevation MI and subnormal left ventricular (LV) ejection fraction (<50%) were randomly allocated (2:1) to receive maximal tolerated dose of valsartan (titrated up to 320 mg/day, n = 333) or low‐dose valsartan (80 mg/day, n = 162) treatment. The primary objective was to assess the changes in echocardiographic parameters of LV remodelling from baseline to 12 months after discharge. After treatment, end‐diastolic LV volume (LVEDV) decreased significantly in the low‐dose group, but the difference in LVEDV changes was insignificant between the maximal‐tolerated‐dose and low‐dose groups. End‐systolic LV volume decreased significantly in both groups, to a similar degree between groups. LV ejection fraction rose significantly in both study groups, to a similar degree. Changes in plasma levels of neurohormones were also comparable between the two groups. Drug‐related adverse effects occurred more frequently in the maximal‐tolerated‐dose group than in the low‐dose group (7.96 vs. 0.69%, P < 0.001). Conclusions In the present study, treatment with the maximal tolerated dose of valsartan did not exhibit a superior effect on post‐MI LV remodelling compared with low‐dose treatment and was associated with a greater frequency of adverse effect in Korean patients. Further study with a sufficient number of cases and statistical power is warranted to verify the findings of the present study.

A manufacturer of atorvastatin is seeking marketing approval in Korea of a generic product for adult patients with primary hypercholesterolemia. The objective of this study was to compare the efficacy and tolerability of a new generic formulation of atorvastatin (test) with those of an original formulation of atorvastatin (reference) to satisfy regulatory requirements for marketing of the generic product in Korea. Patients enrolled were aged 20 to 79 years with documented primary hypercholesterolemia who did not respond adequately to therapeutic lifestyle changes and with a LDL-C level >100 mg/dL from a high-risk group of coronary artery disease patients. Eligible patients were randomized to receive 1 of the 2 formulations of atorvastatin 20 mg per day for 8 weeks. The primary end point was the percent change in LDL-C level from baseline to week 8. Secondary end points included the percent change in total cholesterol, triglycerides, HDL-C level, apolipoprotein B:apolipoprotein A-I ratio, LDL:HDL ratio, LDL-C particle size, high-sensitivity C-reactive protein from baseline to week 8, and achievement rate of the LDL-C goal. A total of 298 patients (141 men and 157 women; 149 patients in each group; mean [SD] age, 62.4 [9.2] in the test group vs 60.3 [8.9] years in the reference group) were included. LDL-C levels were significantly decreased from baseline to week 8 in both groups, and there was no significant difference in the percent change in LDL-C level between groups (−44.0% [17.2%] in the test group, −45.4% [16.9%] in the reference group; P = 0.49). The between-group differences in the percent changes in total cholesterol and triglyceride levels were not statistically significant. In addition, there was no significant difference between the 2 groups in percent changes in HDL-C, apolipoprotein B:apolipoprotein A-I ratio, LDL-C:HDL-C ratio, LDL-C particle size, high-sensitivity C-reactive protein, and the achievement rate of the LDL-C goal. Two (1.3%) patients in the reference group (N = 150) experienced treatment-related serious adverse events (AEs): toxic hepatitis and aggravation of chest pain. Common AEs were cough (4.1%), myalgia (2.1%), and indigestion (1.4%) in the test formulation group and cough (5.3%), creatine kinase elevation (2.7%), and edema (0.7%) in the reference formulation group; however, the differences in overall prevalence of AEs between the 2 treatment groups was not significant (P = 0.88). There were no significant differences observed in the efficacy and tolerability between the test and reference formulations of atorvastatin in these Korean adult patients with primary hypercholesterolemia. ClinicalTrials.gov identifier: NCT01285544.