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.

Efficacy and Safety of Adding Omega-3 Fatty Acids in Statin-treated Patients with Residual Hypertriglyceridemia: ROMANTIC (Rosuvastatin-OMAcor iN residual hyperTrIglyCeridemia), a Randomized, Double-blind, and Placebo-controlled Trial.

PURPOSE: The purpose of this study was to examine the efficacy and safety of adding ω-3 fatty acids to rosuvastatin in patients with residual hypertriglyceridemia despite statin treatment. METHODS: This study was a multicenter, randomized, double-blind, placebo-controlled study. After a 4-week run-in period of rosuvastatin treatment, the patients who had residual hypertriglyceridemia were randomized to receive rosuvastatin 20 mg/d plus ω-3 fatty acids 4 g/d (ROSUMEGA group) or rosuvastatin 20 mg/d (rosuvastatin group) with a 1:1 ratio and were prescribed each medication for 8 weeks. FINDINGS: A total of 201 patients were analyzed (mean [SD] age, 58.1 [10.7] years; 62.7% male). After 8 weeks of treatment, the percentage change from baseline in triglycerides (TGs) and non-HDL-C was significantly greater in the ROSUMEGA group than in the rosuvastatin group (TGs: -26.3% vs -11.4%, P < 0.001; non-HDL-C: -10.7% vs -2.2%, P = 0.001). In the linear regression analysis, the lipid-lowering effect of ω-3 fatty acids was greater when baseline TG or non-HDL-C levels were high and body mass index was low. The incidence of adverse events was not significantly different between the 2 groups. IMPLICATIONS: In patients with residual hypertriglyceridemia despite statin treatment, a combination of ω-3 fatty acids and rosuvastatin produced a greater reduction of TGs and non-HDL-C than rosuvastatin alone. Further study is needed to determine whether the advantages of this lipid profile of ω-3 fatty acids actually leads to the prevention of cardiovascular event. ClinicalTrials.gov identifier: NCT03026933.

Anti-platelet effects of epigallocatechin-3-gallate in addition to the concomitant aspirin, clopidogrel or ticagrelor treatment.

BACKGROUND/AIMS: Although epigallocatechin-3-gallate (EGCG), which is found in high contents in the dried leaves of green tea, has been reported to have an anti-platelet effect, synergistic effects of EGCG in addition to current anti-platelet medications remains to be elucidated. METHODS: Blood samples were obtained from 40 participants who took aspirin (ASA, n = 10), clopidogrel (CPD, n = 10), ticagrelor (TCG, n = 10) and no anti-platelet medication (Control, n = 10). Ex vivo platelet aggregation and adhesion under various stimulators were analyzed by multiple electrode aggregometry (MEA) and Impact-R systems. PAC-1 and P-selectin expressions in human platelets were analyzed by flow cytometry. RESULTS: In MEA analysis, adenosine diphosphate (ADP) and thrombin receptor activating peptide (TRAP)-induced platelet aggregations were lower in the CPD and the TCG groups; arachidonic acid (AA)-induced platelet aggregation was lower in the ASA group, whereas collagen (COL)-induced platelet aggregations were comparable among four groups. EGCG significantly reduced ADP- and COL-induced platelet aggregation in dose-dependent manner (ADP, p = 0.04; COL, p < 0.01). There were no additional suppressions of platelet aggregation stimulated by AA in the ASA group, and by ADP in the CPD and TCG groups. Moreover, EGCG suppressed shear stress-induced platelet adhesion on Impact-R, and had no effect on P-selectin and PAC-1 expressions. CONCLUSIONS: Ex vivo treatment of EGCG inhibited platelet adhesion and aggregation without changes in P-selectin and PAC-1 expression. There was no additional suppressions in platelet aggregation stimulated by AA in the ASA group and ADP in the CPD and TCG groups.

Black Raspberry Extract Increased Circulating Endothelial Progenitor Cells and Improved Arterial Stiffness in Patients with Metabolic Syndrome: A Randomized Controlled Trial.

Administration of black raspberry (Rubus occidentalis) is known to improve vascular endothelial function in patients at a high risk for cardiovascular (CV) disease. We investigated short-term effects of black raspberry on circulating endothelial progenitor cells (EPCs) and arterial stiffness in patients with metabolic syndrome. Patients with metabolic syndrome (n = 51) were prospectively randomized into the black raspberry group (n = 26, 750 mg/day) and placebo group (n = 25) during the 12-week follow-up. Central blood pressure, augmentation index, and EPCs, such as CD34/KDR(+), CD34/CD117(+), and CD34/CD133(+), were measured at baseline and at 12-week follow-up. Radial augmentation indexes were significantly decreased in the black raspberry group compared to the placebo group (-5% ± 10% vs. 3% ± 14%, P < .05). CD34/CD133(+) cells at 12-week follow-up were significantly higher in the black raspberry group compared to the placebo group (19 ± 109/µL vs. -28 ± 57/µL, P < .05). Decreases from the baseline in interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) were significantly greater in the black raspberry group compared to the placebo group (-0.5 ± 1.4 pg/mL vs. -0.1 ± 1.1 pg/mL, P < .05 and -5.4 ± 4.5 pg/mL vs. -0.8 ± 4.0 pg/mL, P < .05, respectively). Increases from the baseline in adiponectin levels (2.9 ± 2.1 µg/mL vs. -0.2 ± 2.5 µg/mL, P < .05) were significant in the black raspberry group. The use of black raspberry significantly lowered the augmentation index and increased circulating EPCs, thereby improving CV risks in patients with metabolic syndrome during the 12-week follow-up.

Effects of Rubus occidentalis extract on blood pressure in patients with prehypertension: Randomized, double-blinded, placebo-controlled clinical trial.

OBJECTIVE: Black raspberry (Rubus occidentalis) is known for improving vascular function. However, there has been no study evaluating its effects on 24-h systolic and diastolic blood pressure in prehypertensive patients. The aim of this study was to examine those effects. METHODS: Patients with prehypertension (N = 45) were prospectively randomized into a moderate-dose black raspberry group (n = 15, 1500 mg/d), a high-dose black raspberry group (n = 15, 2500 mg/d), or a placebo group (n = 15) during an 8-wk follow-up period. Raspberries were consumed in the form of a dried powder extract that was fashioned into capsules. The capsules contained 187.5 and 312.5 mg of raspberry powder, which was equivalent to 1500 and 2500 mg raspberries. Ambulatory 24-h blood pressure (BP); central BP; pulse-wave velocity; abdominal visceral fat; serum renin; angiotensin-converting enzyme; and inflammatory cytokines such as interleukin-6, tumor necrosis factor-α, C-reactive protein, soluble intercellular adhesion molecule-1, soluble vascular cell adhesion molecule-1, and plasminogen activator inhibitor-1 were measured at baseline and at 8-wk follow-up. RESULTS: High-dose black raspberry significantly reduced 24-h systolic blood pressure (SBP; 3.3 ± 10 mm Hg versus -6.7 ± 11.8 mm Hg; P < 0.05) and nighttime SBP (5.4 ± 10.6 mm Hg versus -4.5 ± 11.3 mm Hg; P < 0.05) compared with controls during the 8-wk follow-up. Black raspberry powder did not produce any significant changes in most of the parameters other than BP. CONCLUSION: The use of black raspberry significantly lowered 24-h BP in prehypertensive patients during the 8-wk follow-up. Black raspberry used as a dietary supplement could be beneficial in reducing SBP in prehypertensive patients.

Effects of black raspberry on lipid profiles and vascular endothelial function in patients with metabolic syndrome.

Black raspberry (Rubus occidentalis) has been known for its anti-inflammatory and anti-oxidant effects. However, short-term effects of black raspberry on lipid profiles and vascular endothelial function have not been investigated in patients with metabolic syndrome. Patients with metabolic syndrome (n = 77) were prospectively randomized into a group with black raspberry (n = 39, 750 mg/day) and a placebo group (n = 38) during a 12-week follow-up. Lipid profiles, brachial artery flow-mediated dilatation (baFMD), and inflammatory cytokines such as IL-6, TNF-α, C-reactive protein, adiponectin, sICAM-1, and sVCAM-1 were measured at the baseline and at the 12-week follow-up. Decreases from the baseline in the total cholesterol level (-22.8 ± 30.4 mg/dL vs. -1.9 ± 31.8 mg/dL, p < 0.05, respectively) and total cholesterol/HDL ratio (-0.31 ± 0.64 vs. 0.07 ± 0.58, p < 0.05, respectively) were significantly greater in the group with black raspberry than in the placebo group. Increases in baFMD at the 12-week follow-up were significantly greater in the group with black raspberry than in the placebo group (0.33 ± 0.44 mm vs. 0.10 ± 0.35 mm, p < 0.05, respectively). Decreases from the baseline in IL-6 (-0.4 ± 1.5 pg/mL vs. -0.1 ± 1.0 pg/mL, p < 0.05, respectively) and TNF-α (-2.9 ± 4.7 pg/mL vs. 0.1 ± 3.6 pg/mL, p < 0.05, respectively) were significantly greater in the group with black raspberry. The use of black raspberry significantly decreased serum total cholesterol level and inflammatory cytokines, thereby improving vascular endothelial function in patients with metabolic syndrome during the 12-week follow-up.

Red ginseng extract improves coronary flow reserve and increases absolute numbers of various circulating angiogenic cells in patients with first ST-segment elevation acute myocardial infarction.

The effects of red ginseng extract on circulating angiogenic cell mobilization and improvement of microvascular integrity were evaluated in ST-elevation acute myocardial infarction (AMI) patients during 8-month follow-up. AMI patients (n = 50) were randomly assigned to the red ginseng group (3 g/day, n = 25) or the placebo group (n = 25) after coronary stenting. Coronary flow reserve (CFR) was measured at baseline and at 8 months with an intracoronary Doppler wire. Serial changes in the absolute numbers of circulating angiogenic cells such as CD34(+) , CXCR4(+) , CD117(+) , CD133(+) and C-met(+) were measured at baseline, 1 day, 5 days and at 8 months. CFR were similar between the two groups at baseline, and CFR was significantly higher in the red ginseng group than in the placebo group (2.80 ± 0.91 and 2.56 ± 0.77, p < 0.05, respectively) after 8 months of red ginseng administration. The absolute numbers of circulating CD34(+) , CXCR4(+) and CD117(+) cells were significantly higher in the red ginseng group at 1 and 5 days after stenting. Significant positive correlations were found between the numbers of circulating angiogenic cells at day 1 and the changes from baseline in CFR for CD34(+) , CXCR4(+) , CD117(+) and C-met(+) cells. Red ginseng extract increased CD34(+) , CXCR4(+) and CD117(+) circulating angiogenic cell mobilization and decreased inflammation in AMI patients, thereby improving CFR during the 8-month follow-up.