Sustained reduction of serum cholesterol in low-dose 6-year simvastatin treatment with minimum side effects in 51,321 Japanese hypercholesterolemic patients.

The Japan Lipid Intervention Trial (J-LIT) study, a nationwide cohort study utilizing the clinical practice of general physicians, was designed to clarify the relationship between the incidence of coronary heart disease and serum lipid concentrations during simvastatin therapy, as well as the safety of the therapy, in a large number of Japanese hypercholesterolemic patients. All the enrolled patients were treated with simvastatin. The current study analyzed the lipid lowering effect and safety of the low-dose simvastatin therapy used in the J-LIT study. Open-labeled simvastatin was given to 51,321 patients at an initial dose of mostly 5 mg/day. After 6 months of the treatment, the average serum total cholesterol (TC) and low density lipoprotein-cholesterol concentrations in all the patients followed up were reduced by 18.3% and 26.0%, respectively, and that of high density lipoprotein-cholesterol increased 2.3% on average. These concentrations were well maintained throughout the 6-year treatment period. A minority of patients (1.4%) unexpectedly had a remarkable reduction in TC concentration by more than 40%. Hyper-responders, even to low-dose statin, were found for the first time in this large-scale and long-term investigation. Overall adverse drug reactions occurred in 3.3% of subjects during the 6-year treatment, the major events being hepatic and musculoskeletal disorders, of which the incidence was less than 1%. Low-dose simvastatin therapy of 5 mg/day effectively controlled the serum TC concentration by reducing it by approximately 20% on average in hypercholesterolemic Japanese patients, a reduction that corresponds to the effect of simvastatin 20 mg/day in Western studies. In addition, the low incidence of drug-related adverse events in this study may be also related to the low dosage of simvastatin.     

Large scale cohort study of the relationship between serum cholesterol concentration and coronary events with low-dose simvastatin therapy in Japanese patients with hypercholesterolemia.

Hyperlipidemia is a well-established risk factor for primary coronary heart disease (CHD). Although simvastatin is known to lower serum lipid concentrations, the protective effect of such lipid-lowering therapy against primary CHD has not been established in Japanese patients with hypercholesterolemia. The Japan Lipid Intervention Trial was a 6-year, nationwide cohort study of 47,294 patients treated with open-labeled simvastatin (5-10 mg/day) and monitored by physicians under standard clinical conditions. The aim of the study was to determine the relationship between the occurrence of CHD and the serum lipid concentrations during low-dose simvastatin treatment. Simvastatin reduced serum concentrations of total cholesterol (TC), low-density lipoprotein- cholesterol (LDL-C) and triglyceride (TG), by 18.4%, 26.8% and 16.1% on average, respectively, during the treatment period. The risk of coronary events was higher when the average TC concentration was > or =240 mg/dl and the average LDL-C concentration was > or =160 mg/dl. The incidence of coronary events increased in the patients with TG concentration > or =300 mg/dl compared with patients with TG concentration <150 mg/dl. The high-density lipoprotein cholesterol (HDL-C) inversely correlated with the risk of coronary events. The J-curve association was observed between average TC or LDL-C concentrations and total mortality. Malignancy was the most prevalent cause of death. The health of patients should be monitored closely when there is a remarkable decrease in TC and LDL-C concentrations with low-dose statin. A reasonable strategy to prevent coronary events in Japanese hypercholesterolemic patients without prior CHD under low-dose statin treatment might be regulating the serum lipid concentrations to at least <240 mg/dl for TC, <160 mg/dl for LDL-C, <300 mg/dl for TG, and >40 mg/dl for HDL-C.     

Long-term follow-up of medically treated patients with coronary artery disease--I. Incidence of major cardiac events and its risk factors in Japanese with coronary artery disease

In the cooperative, multi-center trial, 491 medically treated patients with coronary artery disease were thoroughly assessed and followed for an average of 49 months. The rate of cardiac death and/or non-fatal myocardial infarction was 9.8%; 64% of cardiac events were fatal. Three factors, such as number of diseased coronary arteries, other diseased organs and the cardiothoracic ratio, contributed significantly to the evolution of cardiac events. The outcome of cardiac events in Japan in the period from 1973 to 1985 in patients with coronary artery disease was more favorable than those reported recently in the United States. The results of this study will serve as a control data base for further studies in Japan.     

Gender differences of low-dose aspirin-associated gastroduodenal ulcer in Japanese patients

AIM:To clarify the gender differences about the clini-cal features and risk factors of low-dose aspirin (LDA) (81-100 mg daily)-associated peptic ulcer in Japanese patients.METHODS: There were 453 patients under treatment with LDA (298 males, 155 females) who underwent esophagogastroduodenoscopy at the Department of Gastroenterology and Hepatology of Hiratsuka City Hospital between January 2003 and December 2007. They had kept taking the LDA or started treatmentduring the study period and kept taking LDA du...     

Cholesterol levels after 3 days of high-dose simvastatin in patients at moderate to high risk for coronary events

BACKGROUND: Elevated levels of low-density lipoprotein cholesterol (LDL-C) impair vascular function by a variety of mechanisms. HMG CoA reductase inhibitors (statins) improve endothelial function by lowering LDL-C and possibly by other "pleiotropic" effects. How rapidly statins can lower LDL-C has not been thoroughly studied. METHODS: We examined the lipid response to 3 days of high-dose simvastatin in a randomized prospective double-blind placebo-controlled crossover study. Twenty-seven subjects at moderate to high risk for coronary heart disease (CHD) received either simvastatin 80 mg/day for 3 days followed by placebo for 3 days or placebo followed by simvastatin. After a washout period of 10 to 14 days, subjects received the opposite treatment. Nonfasting blood lipid levels, including total cholesterol, direct LDL-C, high-density lipoprotein cholesterol (HDL-C), and triglycerides, were obtained before randomization and after each 3-day treatment period. RESULTS: The mean LDL-C level at baseline was 107 mg/dl and decreased 24% in patients receiving simvastatin and 5.6% in patients receiving placebo (P < 0.001). Statistically significant reductions were also achieved in the total cholesterol and cholesterol/HDL-C ratio: 14% and 12%, respectively. Changes in HDL-C and triglyceride levels were not significant. CONCLUSION: Treatment with simvastatin for only 3 days results in a 24% drop in the LDL-C level. As defined by ATPIII, this decrease is comparable to that necessary to lower the LDL-C from one risk level to a lower one and is, therefore, both clinically and statistically significant.     

Ineffective decrease of serum cholesterol by simvastatin in a subgroup of hypercholesterolemic coronary patients

We measured serum cholesterol concentrations and synthesis markers (e.g. serum lathosterol to cholesterol ratio), and absorption markers (e.g. serum campesterol to cholesterol ratio) of cholesterol in 319 good responders (GR; dose 20 mg up to 1 year) and in 115 poor responders (PR; dose increased at 6 weeks to 40 mg) among Finnish participants in the Scandinavian Simvastatin Survival Study at baseline, 6 weeks and 1 year of the simvastatin treatment. The baseline cholesterol level and the ratios of the absorption markers were higher and those of the synthesis markers lower in PR than GR. The ratios of the precursor sterols were negatively related to the baseline cholesterol in GR only (P=0.003). The cholesterol levels, and the ratios of the precursor sterols were decreased and those of the absorption marker sterols increased less consistently in PR than GR by 20 mg, the group differences being only slightly lessened by the dose addition to 40 mg. One-year differences were still frequently significant. The baseline cholesterol concentrations were negatively related to the reduction of the precursor sterol ratios in GR, the change of cholesterol being positively related to those of the synthesis markers and negatively to those of the absorption markers only in PR. Thus, patients needing large statin dose for cholesterol normalization have high absorption and low synthesis of cholesterol, yet baseline synthesis is inversely related to cholesterol level only in GR. The synthesis rate is less markedly reduced by the large than by the small statin dose in the PR, and the reduction is related, in contrast to that in the GR, to lowering of cholesterol.     

Lipoprotein-related coronary risk factors in patients with angiographically defined coronary artery disease: relation to number of stenosed arteries

To determine whether an index estimating antagonism between low density lipoprotein (LDL) and high density lipoprotein (HDL) would improve separation between groups with and without coronary artherosclerosis, patients undergoing coronary catheterization (35 women and 99 men) were analysed for total cholesterol (TC), HDL cholesterol (HDLc), apolipoprotein A (apo A) and apolipoprotein B (apo B). The subjects were categorized as groups 0, 1, 2 or 3 according to the number of stenosed arteries (greater than 75% areal stenosis). Thirty of the patients showed no significant coronary atherosclerosis (group 0). Serum apo B and TC concentrations were directly related to the number of stenosed vessels, whereas the concentrations of apo A and HDLc were negatively correlated with the number of stenosed arteries. An 'atherogenic Index' (ATH index) calculated as the product of serum concentrations of apo B, and TC minus HDLc divided by the product of apo A and HDLc, proved more satisfactory than individual lipoprotein components for discrimination between subjects with and without stenosis. Accordingly, identification of coronary groups may be improved by using the ATH index.     

Risk of coronary events in Japanese patients with both hypercholesterolemia and type 2 diabetes mellitus on low-dose simvastatin therapy: implication from Japan Lipid Intervention Trial (J-LIT)

Hypercholesterolemic patients with type 2 diabetes mellitus are at increased risk of coronary heart disease (CHD); however, direct evidence is very limited in Japanese patients. The J-LIT is the first nationwide study conducted to assess the relationship between serum lipid levels and development of coronary events in Japanese hypercholesterolemic patients. We analyzed the coronary events in the J-LIT study subjects by having type 2 diabetes or not. Of the total 41,801 subjects without prior CHD who received open-label simvastatin, 5mg/day, 6554 (male 40.2%, age 57.8+/-7.8) subjects had type 2 diabetes, while 35,247 (male 30.0%, age 57.8+/-7.9) did not. In this analysis, relative coronary event risks based on a 0.26 mmol/l (10mg/dl) increase in low density lipoprotein-cholesterol (LDL-C), were similar between hypercholesterolemic subjects with and without type 2 diabetes (17.3% versus 19.4%). Although all subjects were treated with simvastatin, the subjects with type 2 diabetes have significantly more coronary events compared to the subjects without type 2 diabetes (1.80/1000 and 0.76/1000 patient-years, respectively). Given the results above, to reduce the risk of coronary events in Japanese patients with both hypercholesterolemia and type 2 diabetes, careful and strict cholesterol management is needed in addition to the control of blood glucose.     

Carotid atherosclerosis in hypercholesterolemic patients: relationship with cardiovascular events.

BACKGROUND AND AIM: Extracranial cerebrovascular atherosclerosis is a common feature of hypercholesterolemia and carotid lesions are good predictors of cardiovascular events in the general population. Factors associated with the carotid damage of hypercholesterolemic patients and their relationships with the occurrence of clinical events are investigated in this study. METHODS AND RESULTS: One hundred and seventeen cardiovascular event-free hypercholesterolemic subjects underwent a complete clinical examination to look for additional risk factors. A blood sample was collected for lipoprotein determination and an ultrasound high resolution B-mode imaging examination of the common carotid arteries was performed. Patients were treated according to the current guidelines during a 4-yr follow-up and all major cardiovascular events were recorded. The prevalence of subjects with increased intima-media thickness and plaque was 21.4% and 29.9% respectively, higher than in normolipidemic controls. Carotid lesions were significantly related to age, hypertension and LDL-cholesterol and HDL-cholesterol levels. The relative risk of developing a major clinical event was 3.92 (95% CI 1.54-9.95, p < 0.004) among categories of carotid status. At multivariate analysis, cardiovascular events were independently related to the diagnosis of familial hypercolesterolemia (FH), baseline carotid score and mean levels of LDL-cholesterol and HDL-cholesterol during the follow-up. CONCLUSIONS: Common risk factors cooperate with plasma lipoprotein levels in increasing the frequency of carotid lesions of hypercholesterolemic patients. Since such lesions are useful predictors of clinical events, B-mode ultrasound evaluation of the carotids should be routinely included in the management of these patients.     

Prevalence of Helicobacter pylori infection and its link to coronary risk factors in Japanese patients with acute myocardial infarction.

The association between Helicobacter pylori (H. pylori) infection and coronary artery disease, as well as the association between H. pylori infection and classic coronary risk factors, is controversial in patients from Western countries. The high prevalence of H. pylori infection in Japanese subjects enables an examination of these associations in a large population, especially in young patients, because coronary risk factors may be more strongly associated with younger individuals than with older individuals. The IgG seropositivity to H. pylori was assessed in 618 cases with acute myocardial infarction (AMI) and in 967 controls. The prevalence of seropositivity to H. pylori was similar between cases and controls, but in subjects younger than 55 years, the rate was significantly higher in cases than in controls (58.7% vs 43.3%, p = 0.009). After adjustment for age, gender, diabetes mellitus, hypertension, smoking, body mass index, total cholesterol, and high density lipoprotein cholesterol, the odds ratio for acute myocardial infarction was 2.97 (95% confidence interval, 1.37-6.41; p = 0.006). Worsening of classic coronary risk factors was not associated with H. pylori infection in subjects younger than 55 years. These results suggest that in younger individuals in Japan, H. pylori infection is significantly associated with AMI independent of the classic coronary risk factors.     

Arcus senilis: its relation to certain attributes and risk factors in patients with coronary heart disease

The frequency and degree of arcus in relation to a number of attributes or risk factors were tested in 534 male patients of all ages with coronary heart disease.     

Vascular risk factors in Japanese non-insulin-dependent diabetic patients with microalbuminuria.

To determine if non-insulin-dependent diabetes mellitus (NIDDM) patients with microalbuminuria would have augmented vascular risk factors, we studied the relationships between blood pressure, serum lipids, plasma fibrinogen, and uric acid concentrations and plasma lipoprotein (a) level in 25 Japanese NIDDM patients with microalbuminuria [albumin excretion rate (AER) 20-200 micrograms/min] and 25 individually pair-matched NIDDM patients with normal urinary albumin excretion (AER less than 20 micrograms/min), matched for age, sex, body mass index, treatment and HbAlc level. Microalbuminuric patients had significantly higher systolic blood pressure (p less than 0.05) and plasma fibrinogen level (p less than 0.05) and lower high-density lipoprotein (HDL) cholesterol concentration (p less than 0.05) as compared with those in normoalbuminuric patients, respectively, while there were no differences in serum triglycerides and uric acid levels between the two groups. Plasma lipoprotein (a) level, assessed in 15 microalbuminuric and 15 normoalbuminuric patients, was comparable in the two groups. The results suggest that some of the vascular risk factors are already present in microalbuminuric NIDDM patients when compared with normoalbuminuric patients.     

41-month follow-up of risk factors correlated with new coronary events in 708 elderly patients

A prospective study correlated coronary risk factors with new coronary events in 192 elderly men and 516 elderly women, mean age 82 +/- 8 years. Follow-up was 41 +/- 6 months (range 24-44). Coronary events (myocardial infarction, primary ventricular fibrillation, and sudden cardiac death) occurred in 64 of 192 men (33%) and in 149 of 516 women (29%), P not significant. Using univariate analysis, significant risk factors for coronary events were antecedent coronary artery disease, cigarette smoking, hypertension, diabetes mellitus, serum total cholesterol (TC) greater than or equal to 200 mg/dL and greater than or equal to 250 mg/dL, serum high-density lipoprotein cholesterol (HDL-C) less than 35 mg/dL, and serum TC/HDL-C greater than or equal to 6.5 in men and women, and obesity in women. Using multivariate analysis, significant risk factors for coronary events were age, antecedent coronary artery disease, cigarette smoking, hypertension, diabetes mellitus, and serum TC in men and women and serum HDL-C and serum triglycerides in women. Using univariate analysis, significant risk factors for coronary events in men and women with antecedent coronary artery disease were cigarette smoking, diabetes mellitus, serum TC greater than or equal to 250 mg/dL, and serum TC/HDL-C greater than or equal to 6.5. Using multivariate analysis, significant risk factors for coronary events in men and women with antecedent coronary artery disease were age, cigarette smoking, diabetes mellitus, serum TC, serum HDL-C, and serum triglycerides.(ABSTRACT TRUNCATED AT 250 WORDS)     

冠状动脉微血管病患者的三支冠状动脉血流储备的差异

目的 :观察冠状动脉 (冠脉 )造影正常而有冠脉微血管病基础者的三支冠脉血流储备 (Coronaryflowreserve ,CFR)之间是否有差异。方法 :临床上有不典型胸闷或胸痛的患者 4 5例 ,冠脉造影及左室射血分数正常 ,按有无冠脉微血管病基础分为甲、乙两组。甲组为冠脉微血管病组 ,共 2 9例 ,男 19例 ,女 10例 ,年龄 37～ 78(5 8±9.9)岁 ,其中心电图有左室肥厚或劳损表现的高血压患者 11例 ,糖尿病 3例 ,肥厚型心肌病 2例 ,长期吸烟者 10例 ,高血脂 8例 ;乙组为无冠脉微血管病组 ,共 16例 ,男 11例 ,女 5例 ,年龄 38～ 5 8(5 1± 8.6 )岁。冠脉造影过程中随机测定冠脉CFR值 (甲组 6 2支 ,左冠脉前降支 2 4支 ,冠脉左旋支 17支 ,右冠脉 2 1支 ;乙组 36支 ,左冠脉前降支13支 ,冠脉左旋支 8支 ,右冠脉 14支 )。结果 :甲组 6 2支冠脉的平均CFR为 2 .32± 0 .6 1,乙组 3.15± 0 .5 5 ,P <0 .0 1。甲组三支冠脉之间的CFR差异有统计学意义 ,P <0 .0 1;乙组三支冠脉的CFR差别无统计学意义P >0 .0 5。甲组前降支的CFR远低于右冠脉与回旋支 (2 .0 4± 0 .5 2∶2 .5 9± 0 .6 5 ,2 .39± 0 .5 5 ,均 P<0 .0 5 ) ;回旋支较右冠脉的CFR低 ,但差异无统计学意义 (2 .39± 0 .5 5∶2 .5 9± 0 .6 5 ,P >0 .0 5 )。结论 :冠脉微血     

Effect of co-administering ezetimibe with on-going simvastatin treatment on LDL-C goal attainment in hypercholesterolemic patients with coronary heart disease

OBJECTIVE: To determine whether co-administering ezetimibe with on-going simvastatin treatment was more effective than placebo plus on-going simvastatin in achieving an LDL-C treatment target of < or = 2.60 mmol/l (100 mg/dl) in hypercholesterolemic patients with coronary heart disease (CHD). METHODS: Men and women (age > or = 18 years) with documented CHD and on a stable dose of simvastatin 10 mg or 20 mg for at least 6 weeks were recruited for this study. After a 4-week simvastatin 10 or 20 mg plus placebo and diet run-in period, patients were eligible for randomization if LDL-C > 2.60 and < or = 4.20 mmol/l and triglycerides (TG) < or = 4.00 mmol/l. Eligible patients were randomized to a double-blind comparative study with ezetimibe 10 mg co-administered with on-going simvastatin 10 mg or 20 mg (n=181) versus placebo to match ezetimibe co-administered with simvastatin 10 mg or 20 mg (n=191) for 6 weeks. RESULTS: At baseline, mean LDL-C was comparable between the ezetimibe (3.14 mmol/l) and placebo (3.19 mmol/l) groups. With the addition of ezetimibe or placebo to on-going simvastatin therapy, the percentage of patients achieving the LDL-C goal of < or = 2.60 mmol/l after 6 weeks of treatment was significantly (p < or = 0.001) greater in the ezetimibe group (74.3%) than in the placebo group (16.7%). The addition of ezetimibe to on-going simvastatin treatment also resulted in a significantly (p < or = 0.001) larger mean percent reduction in LDL-C from baseline (25.2%) compared with placebo (0.9%). Ezetimibe was generally well tolerated compared to placebo when added to on-going simvastatin treatment. CONCLUSIONS: Co-administering ezetimibe with on-going simvastatin 10 or 20 mg treatment allowed more hypercholesterolemic patients with CHD to reach the LDL-C treatment target of < or = 2.60 mmol/l.     

Incidence and risk factors of bleeding-related adverse events in patients with chronic lymphocytic leukemia treated with ibrutinib

Ibrutinib is associated with bleeding-related adverse events of grade ≤2 in severity, and infrequently with grade ≥3 events. To investigate the mechanisms of bleeding and identify patients at risk, we prospectively assessed platelet function and coagulation factors in our investigator-initiated trial of single-agent ibrutinib for chronic lymphocytic leukemia. At a median follow-up of 24 months we recorded grade ≤2 bleeding-related adverse events in 55% of 85 patients. No grade ≥3 events occurred. Median time to event was 49 days. The cumulative incidence of an event plateaued by 6 months, suggesting that the risk of bleeding decreases with continued therapy. At baseline, von Willebrand factor and factor VIII levels were often high and normalized on treatment. Platelet function measured via the platelet function analyzer (PFA-100™) was impaired in 22 patients at baseline and in an additional 19 patients on ibrutinib (often transiently). Collagen and adenosine diphosphate induced platelet aggregation was tested using whole blood aggregometry. Compared to normal controls, response to both agonists was decreased in all patients with chronic lymphocytic leukemia, whether on ibrutinib or not. Compared to untreated chronic lymphocytic leukemia patients, response to collagen showed a mild further decrement on ibrutinib, while response to adenosine diphosphate improved. All parameters associated with a significantly increased risk of bleeding-related events were present at baseline, including prolonged epinephrine closure time (HR 2.74, P=0.012), lower levels of von Willebrand factor activity (HR 2.73, P=0.009) and factor VIII (HR 3.73, P=0.0004). In conclusion, both disease and treatment-related factors influence the risk of bleeding. Patients at greater risk for bleeding of grade ≤2 can be identified by clinical laboratory tests and counseled to avoid aspirin, non-steroidal anti-inflammatory drugs and fish oils. ClinicalTrials.gov identifier {"type":"clinical-trial","attrs":{"text":"NCT01500733","term_id":"NCT01500733"}}NCT01500733