Long-term administration of tolvaptan ameliorates annual decline in estimated glomerular filtration rate in outpatients with chronic heart failure.

Protective effects of tolvaptan against worsening renal function in acute heart failure have been shown. However, long-term effects of its agent on renal function remain to be elucidated. The present study investigated retrospectively whether long-term treatment with tolvaptan exerts renoprotective effects in patients with chronic heart failure, by comparing serial changes in estimated glomerular filtration rate (eGFR) for years before and after tolvaptan administration. From 63 outpatients with chronic heart failure taking diuretics including tolvaptan, 34 patients whose eGFR levels were continuously measured for more than 6 months both before and after administration of tolvaptan (average dose, 7.8 mg/day at the end of the follow-up period) were selected as eligible for the present analyses. All eGFR values were separately plotted before and after the initiation of treatment with tolvaptan (except hospitalization periods) along the time course axis and the slope of the linear regression curve was calculated as an annual change in eGFR. The mean follow-up periods before and after tolvaptan administration were 1197 and 784 days (3.3 and 2.1 years), respectively. Changing rates of eGFR per year were significantly ameliorated after treatment with tolvaptan (mean ± SD, - 8.02 ± 9.35 to - 1.62 ± 5.09 mL/min/1.73m2 /year, P = 0.001). In echocardiographic parameters, inferior vena cava (IVC) diameter significantly decreased after tolvaptan administration, and the decrease in IVC diameter was correlated with the improvement of eGFR decline slope after administration of tolvaptan (P = 0.0075). This longitudinal observational study indicated that long-term treatment with tolvaptan ameliorated annual decline in eGFR in outpatients with chronic heart failure. Our findings suggest that tolvaptan has a protective effect against chronically worsening renal function in heart failure patients.

Usefulness of pre- and post-stent optical frequency domain imaging findings in the prediction of periprocedural cardiac troponin elevation in patients with coronary artery disease.

Cholesterol crystals (CCs) are frequently found in high-risk plaques, such as thin-capped fibroatheromas. The purpose of this study was to investigate the associations of CCs, plaque morphologies, and post-stent optical frequency domain imaging (OFDI) findings with periprocedural cardiac troponin (cTn) elevation in patients treated with percutaneous coronary intervention (PCI). This study consists of 119 patients with stable coronary artery disease (CAD) with normal cTn levels who underwent OFDI-guided PCI. Periprocedural cTn elevation was defined as an elevation of cTn ≥ × 5 times the upper reference limit after PCI. Pre- and post-stent OFDI findings, including fibrous cap thickness (FCT), presence of CCs, and parameters for lipid and calcification were analyzed. A total of 37 (31%) patients were classified into the periprocedural cTn elevation group. Compared with lesions without CCs, lesions exhibiting CCs had thinner FCT, larger lipid arc, and longer lipid length, and were more likely to have irregular protrusion and in-stent thrombus (all p < 0.05). For pre-stent OFDI features, FCT < 82 µm [odds ratio (OR) 4.11; p = 0.003] and CCs (OR 3.23; p = 0.017) were associated with periprocedural cTn elevation. For post-stent OFDI features, in-stent dissection (OR 3.08; p = 0.035) and in-stent thrombus (OR 7.98; p = 0.002) were independent predictors of cTn elevation. The combination of CCs and FCT < 82 µm showed increased risk of periprocedural cTn elevation (OR 7.22; p = 0.002). OFDI-guided PCI provides unique insight into the mechanism for periprocedural cTn elevation in CAD patients.

Ankle-brachial index, arterial stiffness, and biomarkers in the prediction of mortality and outcomes in patients with end-stage kidney disease.

BACKGROUND: Although ankle-brachial index (ABI) and brachial-ankle pulse wave velocity (baPWV) are significant predictors of major adverse cardiovascular event (MACE), their prognostic value in association with biomarkers has not been fully evaluated in patients with end-stage kidney disease (ESKD). HYPOTHESIS: We hypothesized that ABI/baPWV would provide better prognostic value independent of biomarkers in ESKD patients. METHODS: This study included 104 ESKD patients treated with maintenance hemodialysis who underwent ABI and baPWV examinations and laboratory tests, including brain-natriuretic peptide, high-sensitive cardiac troponin T (hs-cTnT), and high-sensitive C-reactive protein (hs-CRP). MACE was defined as a composite event of all-cause death, acute coronary syndrome, and stroke. RESULTS: During a mean follow-up of 3.6 ± 1.7 years, a total of 51 MACE were observed. The independent factors associated with MACE were age >75 years (adjusted hazard ratio [HR], 2.15; P < .05), abnormal ABI (adjusted HR, 2.01; P < .05), left ventricular ejection fraction (LVEF) <50% (adjusted HR, 3.33; P < .001), the upper tertile of hs-cTnT (adjusted HR, 2.77; P < .05), and hs-CRP (HR, 1.96; P < .05). However, baPWV did not remain as an independent predictor of MACE in the entire cohort and also in patients without abnormal ABI. The combination of predictors improves the predictive value of MACE, providing increased HR with 4.00 for abnormal ABI + hs-CRP, 4.42 for abnormal ABI + hs-cTnT, and 7.04 for abnormal ABI + LVEF <50% (all P < .001). CONCLUSION: Abnormal ABI is a robust predictor of MACE independent of biomarkers and their combination provides better risk stratification compared with a single predictor in ESKD patients.

Prognostic significance of renal dysfunction and its change pattern on outcomes in patients with acute coronary syndrome treated with emergent percutaneous coronary intervention.

Renal dysfunction and its change pattern are associated with short- and long-term mortality. However, it remains to be investigated whether or not worsening renal function (WRF) defined by baseline renal function identified from different time points would provide prognostic implication on outcomes in acute coronary syndrome (ACS) patients. This study consists of 334 ACS patients (mean age 68 ± 11 years, 75% male) treated with emergent percutaneous coronary intervention (PCI). Estimated glomerular filtration rate (eGFR) was evaluated on baseline, during hospitalization, at discharge, and at 3-month follow-up. WRF was defined as a relative decrease of eGFR > 20% at 3 months using baseline eGFR identified from different time points. The primary end point was a composite event of major cardiovascular events (MACE), including all-cause death, ACS, and heart failure hospitalization. The associations of chronic kidney disease (CKD), acute kidney injury (AKI), and WRF with MACE were evaluated. During a mean follow-up of 3.3 ± 1.7 years, a total of 64 MACE were observed. Multivariable analysis revealed that CKD (hazard ratio 2.16; p = 0.018) and AKI (hazard ratio 1.95; p = 0.030) were independent predictors of MACE, but WRF did not remain as an independent predictor of MACE (p = 0.208). The highest risk was observed in AKI patients with CKD when stratified by the presence or absence of CKD and AKI. In ACS patients treated with emergent PCI, this study demonstrated that CKD and AKI were independent predictors of MACE, while there was no independent relationship between WRF and MACE.

Associations of sensitive cardiac troponin-I with left ventricular morphology, function and prognosis in end-stage renal disease patients with preserved ejection fraction.

Sensitive cardiac troponin I (cTnI) predicts all-cause and cardiovascular mortality in various clinical settings. However, its clinical significance in hemodialysis (HD) patients with preserved left ventricular ejection fraction (LVEF) has not been fully elucidated. This study investigated the association of cTnI with LV morphology and function, and its long-term outcome in HD patients with preserved LVEF. This prospective study consists of 96 HD patients with preserved LVEF (69 ± 8 years and 63% male) who underwent two-dimensional echocardiographic examination and biomarker tests including cTnI, brain natriuretic peptide, and high-sensitive C-reactive protein. The primary endpoint was all-cause death and secondary endpoint was cardiovascular death. Factors independently associated with cTnI were systolic blood pressure (ß = - 0.239, p = 0.011), heart rate (ß = 0.216, p = 0.021), LV mass index (ß = 0.231, p = 0.020), and E to e' ratio (ß = 0.237, p = 0.016). During a mean follow-up of 3.6 years, primary and secondary endpoints were observed in 23 (24%) and 18 (19%) patients, respectively. In the multivariate Cox proportional hazard analysis, the upper cTnI tertile has significantly increased risk of all-cause mortality [hazard ratio (HR), 2.69; 95% confidence interval (CI), 1.139-6.386; p = 0.024] and that of cardiovascular death (HR, 4.56; 95% CI 2.021-16.968; p = 0.006) independent of echocardiographic measures and other serum biomarkers. In HD patients with preserved LVEF, serum cTnI levels were significantly associated with diastolic function and risk of mortality independent of echocardiographic variables and other biomarkers.

Preventive effect of pravastatin on the development of hypertension in patients with hypercholesterolemia: A post-hoc analysis of the Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese (MEGA) Study.

BACKGROUND: It remains unclear whether treatment of dyslipidemia with 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors (statins) reduces the risk of developing hypertension. OBJECTIVE: In this post-hoc analysis of the Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese (MEGA) Study, a large-scale primary prevention trial with pravastatin, we examined the preventive effect of pravastatin on the future development of hypertension in patients with hypercholesterolemia. METHODS: Of the overall (MEGA) Study population, 3397 nonhypertensive patients at baseline were enrolled in this study. The patients were randomly assigned to either the diet alone group (n = 1722) or the diet plus pravastatin group (n = 1675) and then were followed-up for a median of 36 months to determine new-onset hypertension. RESULTS: During the follow-up period, 1595 patients developed hypertension (49.1% in the diet alone group and 44.7% in the diet plus pravastatin group). After adjusting for multiple covariates, the diet plus pravastatin group showed a 10% reduction in the risk of developing hypertension (hazard ratio 0.90, 95% confidence interval 0.81-0.998), compared with the diet alone group. Subgroup analyses revealed that the preventive effect of pravastatin on the development of hypertension was pronounced in patients aged ≥60 years, men, those with chronic kidney disease or diabetes mellitus and those without obesity. CONCLUSIONS: Pravastatin reduced the risk of developing hypertension in Japanese patients with hypercholesterolemia. The risk reduction of cardiovascular disease with statins could be partly explained by their preventive effect on the development of hypertension.

Consumption of alpha-Linolenic Acid-enriched Diacylglycerol Reduces Visceral Fat Area in Overweight and Obese Subjects: a Randomized, Double-blind Controlled, Parallel-group Designed Trial.

A randomized, double-blind controlled, parallel-group designed trial was performed to investigate the effect of alpha linolenic acid (ALA)-enriched diacylglycerol (DAG) on visceral fat area (VFA) in obese subjects. One hundred eighty-four obese subjects were recruited and randomly allocated to two groups consuming either 2.5 g/d control triacylglycerol (TAG) or ALA-DAG for 12 wk. A 4-wk observation period followed the 12-wk consumption period. One hundred seventy-seven subjects (N=89 in the TAG group, N=88 in the ALA-DAG group) completed the study. The change in VFA at 12-wk from baseline, as the primary outcome, was significantly lower in the ALA-DAG group than in the TAG group. The reduction in VFA was significantly correlated with the baseline VFA. Body weight and waist circumference, as the secondary measures, were also significantly lower in the ALA-DAG group than in the TAG group. The reduction in the VFA was significantly correlated with body weight reduction, suggesting that the VFA reduction was a contributing factor preventing weight gain. Safety parameters and the incidence of adverse events did not differ significantly between groups. In conclusion, ALA-DAG could be useful for reducing VFA and concomitantly suppressing weight gain with no side effects.

Alpha-Linolenic Acid-Enriched Diacylglycerol Oil Suppresses the Postprandial Serum Triglyceride Level-A Randomized, Double-Blind, Placebo-Controlled, Crossover Study.

This study investigated the effect of a single oral ingestion of alpha-linolenic acid-enriched diacylglycerol (ALA-DAG) on postprandial serum triglyceride (TG) levels. A randomized, double-blind, controlled, crossover study was performed in subjects with normal or moderately high fasting serum TG levels. Subjects ingested 0.00 g [control: triacylglycerol; TAG (rapeseed oil)], 1.25 g (1.25-g: mixture of 1.25 g ALA-DAG and 1.25 g TAG), or 2.50 g (2.50 g) of ALA-DAG in random order with a 6-d washout period. Serum TG levels were evaluated in the fasting state, and at 2, 3, 4, and 6 h after the test meal. Thirty-eight subjects completed the study and were defined as the per protocol set. As the primary outcome, postprandial serum TG levels were significantly lower in the 2.50-g treatment compared with the control. The TG level did not differ significantly between the 1.25-g and control. The suppressive effect of ALA-DAG on the serum TG level correlated significantly with the body mass index and fasting insulin level. ALA-DAG at a dose of 2.50 g had greater effects on serum TG and apolipoprotein B levels in subjects with a higher body mass index (≥25 kg/m2) and higher fasting serum insulin levels (>10 µU/mL). Our findings suggest that ingesting 2.50 g ALA-DAG suppresses the postprandial serum TG level in people with normal and moderately high fasting serum TG levels, presumably as a result of poor re-esterification of dietary fat into TG in the intestinal mucosa.

The effect of statin therapy on heart failure events: a collaborative meta-analysis of unpublished data from major randomized trials.

AIMS: The effect of statins on risk of heart failure (HF) hospitalization and HF death remains uncertain. We aimed to establish whether statins reduce major HF events. METHODS AND RESULTS: We searched Medline, EMBASE, and the Cochrane Central Register of Controlled Trials for randomized controlled endpoint statin trials from 1994 to 2014. Collaborating trialists provided unpublished data from adverse event reports. We included primary- and secondary-prevention statin trials with >1000 participants followed for >1 year. Outcomes consisted of first non-fatal HF hospitalization, HF death and a composite of first non-fatal HF hospitalization or HF death. HF events occurring <30 days after within-trial myocardial infarction (MI) were excluded. We calculated risk ratios (RR) with fixed-effects meta-analyses. In up to 17 trials with 132 538 participants conducted over 4.3 [weighted standard deviation (SD) 1.4] years, statin therapy reduced LDL-cholesterol by 0.97 mmol/L (weighted SD 0.38 mmol/L). Statins reduced the numbers of patients experiencing non-fatal HF hospitalization (1344/66 238 vs. 1498/66 330; RR 0.90, 95% confidence interval, CI 0.84-0.97) and the composite HF outcome (1234/57 734 vs. 1344/57 836; RR 0.92, 95% CI 0.85-0.99) but not HF death (213/57 734 vs. 220/57 836; RR 0.97, 95% CI 0.80-1.17). The effect of statins on first non-fatal HF hospitalization was similar whether this was preceded by MI (RR 0.87, 95% CI 0.68-1.11) or not (RR 0.91, 95% CI 0.84-0.98). CONCLUSION: In primary- and secondary-prevention trials, statins modestly reduced the risks of non-fatal HF hospitalization and a composite of non-fatal HF hospitalization and HF death with no demonstrable difference in risk reduction between those who suffered an MI or not.

Cardiovascular and cancer events in hyper-high-density lipoprotein cholesterolemic patients: a post hoc analysis of the MEGA study.

BACKGROUND: The prognosis for hyper-high-density lipoprotein (HDL) cholesterolemic patients has not been fully elucidated. We conducted a post hoc analysis of MEGA study data to investigate prospectively the incidence of cardiovascular events and cancer in hyper-HDL cholesterolemic patients. METHODS: A total of 7832 patients with mild hypercholesterolemia were randomly allocated to either the National Cholesterol Education Program step 1 diet alone (n = 3966) or the diet plus pravastatin (n = 3866) and followed for 5 years. The incidences of coronary heart disease (CHD), CHD plus cerebral infarction (CI), cardiovascular disease (CVD), and cancer were calculated using the Cox proportional hazards model according to the level of HDL cholesterol (HDL-C). RESULTS: CHD incidence was lower in patients with HDL-C >60-90 mg/dL (-52%, p = 0.0018) and HDL-C > 90 mg/dL (-46%, p = 0.4007) than in patients with HDL-C ≤ 60 mg/dL. The incidences of CHD, CHD plus CI, and CVD were significantly lower in patients with HDL-C >60-90 mg/dL than in those with HDL-C ≤ 60 mg/dL in both diet-alone and diet-plus-pravastatin groups. Cancer incidence was not increased in patients with HDL-C >60-90 mg/dL. CONCLUSION: Patients not receiving statin therapy should aim for a target HDL-C of between 60 and 90 mg/dL to achieve a significant reduction in CHD without the occurrence of adverse events. TRIAL REGISTRATION: Clinical trials.gov NCT00211705.

[From the Point of View of Health Evaluation and Promotion (Ningen Dock) Facilities].

Since the direct method of LDL measurement is easy and convenient, many health evaluation and promotion facilities adopted it without sufficient discussion after specific health checkups started in Japan. For the purpose of reliable, specific health checkup data, we must review the methods and standardization of LDL measurement. I hope that medical societies, the Ministry of Health, Labour and Welfare, and reagent manufacturers will collaborate.

Efficacy and effects on lipid metabolism of combination treatment with losartan + hydrochlorothiazide versus losartan + amlodipine: a 48-week prospective, multicenter, randomized, open-label trial.

BACKGROUND: Both combination therapies of an angiotensin II receptor blocker (ARB) with the thiazide diuretic hydrochlorothiazide (HCTZ) and an ARB with a calcium channel blocker (CCB) are recommended to achieve blood pressure (BP) goals in antihypertensive treatment. However, although HCTZ is known to have unfavorable effects on lipid metabolism, the effects of HCTZ in the ARB + HCTZ combination on lipid metabolism have not been fully elucidated. OBJECTIVE: The aim of this study was to compare the effects on lipid metabolism of combination treatment with the ARB losartan + HCTZ and losartan + the CCB amlodipine and to assess the efficacy in BP lowering of these 2 combination therapies. The metabolism of glucose, uric acid (UA), and high-sensitivity C-reactive protein (hs-CRP), an inflammation marker of atherosclerosis, were also assessed in association with lipid metabolism. METHODS: This 48-week, prospective, randomized, open-label trial was conducted at 2 clinics and 2 hospitals in Tokorozawa City (Saitama, Japan) and Shinjuku-ku Ward (Tokyo, Japan). Eligible patients had a systolic BP (SBP) >140 mm Hg and/or diastolic BP (DBP) >90 mm Hg despite a >1-month history of monotherapy with an ARB. Patients were randomly assigned to receive losartan 50 mg/d + HCTZ 12.5 mg/d (LOS + HCTZ) or losartan 50 mg/d + amlodipine 5 mg/d (LOS + CCB) for 48 weeks. Follow-up visits were scheduled at 4, 8, 12, 24, and 48 weeks. Biochemical measurements were centrally measured at a single institute. Tolerability and treatment compliance were assessed by physicians every 4 weeks. RESULTS: A total of 112 patients were enrolled; 26 were excluded from the final analysis, leaving 42 and 44 patients in the LOS + HCTZ and LOS + CCB groups, respectively, included in the final analysis. At 48 weeks, SBP and DBP were significantly decreased in the 2 treatment groups (both, P < 0.0001). The decrease in SBP was significantly greater in the LOS + HCTZ group than in the LOS + CCB group (P < 0.001). The difference in the decrease in DBP between the 2 groups was nonsignificant. There were no significant differences in the changes from baseline (Δ) in any of the lipid parameters between the 2 groups. The decreases at 8 and 12 weeks in LDL-C, TC, and apolipoprotein (apo) B were significantly greater in the LOS + CCB group compared with those in the LOS + HCTZ group. The between-group differences in ΔTG, ΔHDL-C, ΔapoA-1, and ΔapoE throughout the study were nonsignificant. Changes in fasting plasma glucose (FPG), hemoglobin A1c, and hs-CRP were not significantly different between the 2 groups. The between-group difference in ΔUA in men was not significant, but a significant difference was found in women (LOS + HCTZ, 0.74 mg/dL; LOS + CCB, 0.28 mg/dL [P = 0.0017]). No clinically significant adverse events were reported with either treatment throughout the study. CONCLUSIONS: The findings from the present study suggest that LOS + HCTZ was more efficacious in decreasing SBP than was LOS + CCB in the management of hypertension refractory to ARB monotherapy. Unfavorable effects on lipid metabolism were not observed with either combination therapy.

Risk reductions for cardiovascular disease with pravastatin treatment by dyslipidemia phenotype: a post hoc analysis of the MEGA Study.

BACKGROUND: The beneficial effect of statins for cardiovascular disease (CVD) prevention has been well established. However, the effectiveness among different phenotypes of dyslipidemia has not been confirmed. OBJECTIVE: We evaluated the effect of pravastatin on the incidence of CVD in relation to the phenotype of dyslipidemia. METHODS: The MEGA Study evaluated the effect of low-dose pravastatin on primary prevention of CVD in 7832 Japanese patients, who were randomized to diet alone or diet plus pravastatin and followed for more than 5 years. These patients were classified into phenotype IIa (n=5589) and IIb (n=2041) based on the electrophoretic pattern for this post hoc analysis. RESULTS: In the diet group there was no significant difference in the incidence of coronary heart disease (CHD), stroke, CVD, and total mortality between the two phenotypes. Phenotype IIb patients, compared to phenotype IIa, had lower levels of high-density lipoprotein cholesterol (HDL-C) and a significantly higher incidence of CVD in relation to a low HDL-C level (<47.5mg/dL; p=0.02). Furthermore, pravastatin decreased the relative risk for each major endpoint in both type IIa and type IIb dyslipidemia. Significant risk reductions were observed for CHD by 38% (p=0.04) and CVD by 31% (p=0.02) in type IIa dyslipidemia but not in phenotype IIb. CONCLUSION: Pravastatin therapy provided significant risk reductions for CHD and CVD in patients with phenotype IIa dyslipidemia, but not in those with phenotype IIb dyslipidemia.

The effect of low-dose pravastatin in metabolic syndrome for primary prevention of cardiovascular disease in Japan: a post hoc analysis of the MEGA study.

The Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese (MEGA) Study demonstrated the beneficial effect of low-dose pravastatin treatment (10-20 mg/d) on cardiovascular disease (CVD) in Japanese patients with mild-to-moderate hypercholesterolemia. However, it is not known whether mild lipid modification is effective even for patients at high risk. In this study, we evaluated low-dose pravastatin treatment in patients with metabolic syndrome in the MEGA Study. Metabolic syndrome (MetSyn) was defined according to the modified US National Cholesterol Education Program criteria. There were 72 coronary heart disease (CHD) events and 130 CVD events in 2636 patients with MetSyn, and 70 CHD events and 125 CVD events in 5196 patients without MetSyn (hazard ratios 1.85 and 1.90, respectively). No significant risk reduction in CHD was found in the diet plus pravastatin group compared with the diet group patients with MetSyn (hazard ratio .78, P = .29). On the other hand, there was a significant 36% CVD risk reduction (P = .01) in the diet plus pravastatin group compared with the diet group patients with MetSyn, with a small number needed to treat (45). These results indicate that low-dose pravastatin provides a substantial beneficial effect for the prevention of CVD in Japanese patients with MetSyn without known CVD, a population at proportionally high risk in primary prevention.

Statin inhibits hypoxia-induced endothelin-1 via accelerated degradation of HIF-1α in vascular smooth muscle cells.

AIMS: Endothelin-1 (ET-1) contributes to the pathogenesis of cardiovascular diseases with multiple properties such as vasoconstriction. Human ET-1 gene expression is up-regulated by the transcription factor hypoxia-inducible factor-1 (HIF-1) through hypoxia response element (HRE). Although previous studies suggested that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) alter HIF-1-related gene expression, it remained unclear whether statins modulate HIF-1-mediated ET-1 expression. Therefore, we investigated the effect of fluvastatin on hypoxia-induced human ET-1 expression in vascular smooth muscle cells (VSMC). METHODS AND RESULTS: Hypoxia (1% O(2)), compared with the normoxic condition (21% O(2)), significantly induced the expression of preproET-1 mRNA, ET-1 protein, and ET-1 secretion in VSMC. Hypoxia induced a 2.3-fold increase in HRE-dependent ET-1 reporter gene activation. Under concentrations of 1 µmol/L or greater, fluvastatin attenuated the hypoxia-induced ET-1 gene expression through the accelerated ubiquitin/proteasome-dependent degradation of HIF-1α, thus consequently attenuating HIF-1α binding to the HRE of the ET-1 gene. These inhibitory effects of fluvastatin were cancelled by concomitant treatment with mevalonate, farnesyl pyrophosphate, or geranylgeranyl pyrophosphate, but not squalene. CONCLUSION: The present study suggests that fluvastatin attenuates HIF-1-dependent ET-1 gene expression in conjunction with the stimulation of HIF-1α ubiquitin/proteasome-dependent degradation via isoprenoid-dependent mechanisms.

Usefulness of LDL-C-related parameters to predict cardiovascular risk and effect of pravastatin in mild-to-moderate hypercholesterolemia.

AIM: Low-density lipoprotein cholesterol (LDL-C), the ratio of LDL-C to high-density lipoprotein cholesterol (HDL-C; LDL-C/HDL-C), and non-HDL-C were evaluated to determine their ability to predict cardiovascular disease (CVD) risk with pravastatin treatment. METHODS: We conducted a large-scale randomized primary prevention trial in Japan (MEGA Study), in which we randomly allocated 7832 mild hypercholesterolemic patients to diet alone (n= 3966) and diet plus pravastatin groups (n= 3866) and followed them for an average of 5 years. We compared baseline levels and the CVD incidence in the diet alone group, and time-dependent receiver operating characteristic curves in the overall population. To determine the best parameter for predicting the efficacy of pravastatin, the diet plus pravastatin group was divided into tertiles to compare lipid parameters and CVD incidence versus the diet alone group. RESULTS: Significantly graded correlations were found between CVD and LDL-C/HDL-C and non-HDL-C. Significantly more CVD events were associated with non-HDL-C [corrected] > 186 mg/dL and LDL-C/HDL-C > 2.9. Furthermore, LDL-C/HDL-C or non-HDL-C was more predictive than LDL-C. By measuring LDL-C/HDL-C or non-HDL-C, we allocated 32% of the diet plus pravastatin group into a different risk category. The lowest significant incidence of CVD was found in patients with LDL-C 119.8-133.4 mg/dL, LDL-C/HDL-C < 1.9, and non-HDL-C 145.2-160.8 mg/dL. CONCLUSION: Non-HDL-C and LDL-C/HDL-C have a greater ability to predict CVD risk in mild-to-moderate hypercholesterolemic Japanese individuals than LDL-C, and are more useful to evaluate the effect of pravastatin; however, these parameters should be interpreted independently when assessing CVD risk.

Low-dose pravastatin and age-related differences in risk factors for cardiovascular disease in hypercholesterolaemic Japanese: analysis of the management of elevated cholesterol in the primary prevention group of adult Japanese (MEGA study).

BACKGROUND: Limited data are available regarding the relationship between age and the effect of HMG-CoA reductase inhibitor (statin) treatment. OBJECTIVE: The aim of the present analysis was to evaluate the relationships between age, baseline patient characteristics, and pravastatin treatment with respect to the development of cardiovascular disease (CVD) in the Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese (MEGA) study, a large-scale clinical study conducted in Japanese patients with mild or moderate hyperlipidaemia to evaluate the primary preventive effect of pravastatin against coronary heart disease. METHODS: To compare the prevalence of CVD risk factors, the incidence of CVD in relation to each risk factor, and final values and changes in lipid parameters, the 7832 patients were classified into six age groups: <45, 45-49, 50-54, 55-59, 60-64 and ≥65 years. The relationship between pravastatin (10-20 mg/day) treatment efficacy and aging and the incidence of events in relation to the age groups were compared using the multivariable Cox proportional hazards model. RESULTS: The prevalences of diabetes mellitus and hypertension were higher in older men than in younger men, while the prevalences of smoking and obesity were higher in younger men. However, a similar difference in risk factors was not seen in women. High-density lipoprotein cholesterol was higher in women than in men across all age groups. Triglycerides were higher in younger men than in older men and all groups of women. The mean follow-up levels of total cholesterol and low-density lipoprotein cholesterol were lower in older patients than in younger patients. Pravastatin (10-20 mg/day) reduced the risk of CVD by about 30-40% across all age groups, and there was no difference between men and women. Of particular note in this analysis, CVD risk was markedly reduced in older women compared with younger women (53% vs 30% in women aged ≥65 vs ≥45 years). CONCLUSION: A similar satisfactory risk reduction for CVD was achieved with low-dose pravastatin in all men and in older women in particular, despite differences in the prevalence of risk factors. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00211705.

Management of Elevated Cholesterol in the primary prevention Group of Adult Japanese (MEGA) Study assists the view that a fasting plasma glucose level ≥100 mg/dL increases cardiovascular risk.

UNLABELLED: Aims/Introduction: To evaluate the relationship between fasting plasma glucose (FPG) level and cardiovascular disease in patients with hypercholesterolemia, and to evaluate the effect of pravastatin on risk reduction in a post-hoc analysis of the large-scale Management of Elevated Cholesterol in the primary prevention Group of Adult Japanese (MEGA) Study. MATERIALS AND METHODS: A total of 7832 patients were randomized to diet alone or diet plus low-dose pravastatin (10-20 mg/day, average 8.3 mg during follow-up periods) and followed for >5 years. In this analysis, the relationship between FPG and risk of cardiovascular disease events over 5 years were studied in 6673 patients with recorded baseline FPG levels by using the multivariable Cox proportional hazards model with the restricted quadratic spline based on three knots for FPG quartiles. RESULTS: The spline curve showed an obvious sharp increased risk from a FPG of ≥100 mg/dL. The spline curve in the diet plus pravastatin group was consistently lower than in the diet group, regardless of the FPG level. CONCLUSIONS: The risk of cardiovascular disease appears to increase when FPG is ≥100 mg/dL, with a sharp increased risk found above this level in patients with hypercholesterolemia. Statin treatment seems to be beneficial to reduce cardiovascular disease risk in this population. This trial was registered with ClinicalTrials.gov (no. NCT00211705). (J Diabetes Invest, doi: 10.1111/j.2040-1124.2011.00121.x, 2011).