Michal Benderly

Elevated Serum Triglyceride Levels and Long-Term Mortality in Patients With Coronary Heart Disease: The Bezafibrate Infarction Prevention (BIP) Registry

BACKGROUND The association between elevated blood triglyceride levels and subsequent mortality risk in patients with established coronary heart disease (CHD) has been investigated rarely. The aim of the present study was to investigate this association. METHODS AND RESULTS We evaluated mortality over a mean follow-up time of 5. 1 years among 9033 male and 2499 female CHD patients who were screened for participation in the Bezafibrate Infarction Prevention (BIP) Study. A stepwise increase in mortality with increasing serum triglyceride levels was observed in patients with desirable or elevated serum total cholesterol levels and in patients with either desirable or abnormally low HDL cholesterol levels. Multivariate adjustment for factors other than HDL cholesterol yielded a slightly increased adjusted mortality risk with a 1-natural-log-unit elevation of triglyceride levels in men (hazard ratio [HR] 1.14, 95% CI 1.00 to 1.30) and women (HR 1.37, 95% CI 1.04 to 1.88). Excess covariate-adjusted risk was noted among patients with elevated total and LDL cholesterol and in women with HDL cholesterol levels >45 mg/dL. After additional adjustment for HDL cholesterol, the risk of mortality with a 1-natural-log-unit elevation of triglycerides declined in men (HR 1.09, 95% CI 0.94 to 1.26) and in women (HR 1.10, 95% CI 0.80 to 1.50). A trend for increased mortality risk remained in patients with elevated total and LDL cholesterol and in women with HDL cholesterol >45 mg/dL. CONCLUSIONS Elevated triglyceride levels were associated with a small, independent increased mortality risk in CHD patients. This risk may be increased among subgroups of patients with elevated total cholesterol and LDL cholesterol levels.

Effects of Peroxisome Proliferator-Activated Receptor Ligands, Bezafibrate and Fenofibrate, on Adiponectin Level

Objective—Adiponectin is adipose-specific secretory protein and acts as anti-diabetic and anti-atherosclerotic molecule. We previously found peroxisome proliferators response element in adiponectin promoter region, suggesting that peroxisome proliferator-activated receptor (PPAR) ligands elevate adiponectin. Fibrates are known to be PPARα ligands and were shown to reduce risks of diabetes and cardiovascular disease. Effect of fibrates on adiponectin has not been clarified, whereas thiazolidinediones enhance adiponectin. Thus, we explored the possibility and mechanism that fibrates enhance adiponectin in humans, mice, and cells. Methods and Results—Significant increase of serum adiponectin was observed in bezafibrate-treated subjects compared with placebo group in patients enrolled in The Bezafibrate Infarction Prevention study. Higher baseline adiponectin levels were strongly associated with reduced risk of new diabetes. Fibrates, bezafibrate and fenofibrate, significantly elevated adiponectin levels in wild-type mice and 3T3-L1 adipocytes. Such an effect was not observed in PPARα-deficient mice and adipocytes. Fibrates activated adiponectin promoter but failed to enhance its activity when the point mutation occurred in peroxisome proliferators response element site and the endogenous PPARα was knocked down by PPARα-RNAi. Conclusions—Our results suggest that fibrates enhance adiponectin partly through adipose PPARα and measurement of adiponectin might be a useful tool for searching subjects at high risk for diabetes.

C-Reactive Protein as a Predictor of Incident Ischemic Stroke Among Patients With Preexisting Cardiovascular Disease

Background and Purpose— C-reactive protein (CRP) has emerged as an important predictor of cardiovascular disease, but there are few prospective data on its association with risk of ischemic stroke in patients at high risk. Methods— We examined the association between CRP levels and subsequent risk of incident ischemic stroke among 2979 patients with stable coronary heart disease included in a controlled clinical trial (Bezafibrate Infarction Prevention) that assessed the efficacy of bezafibrate, a fibric acid derivative, versus placebo for secondary prevention. CRP was measured by a high-sensitivity assay in plasma samples collected before randomization and again at the second follow-up year of an overall mean follow-up of 6.2 years. Results— Risk of ischemic stroke per 1000 person-years increased from 4.1% for baseline CRP in the lowest tertile (<2.3 mg/L; n=982) to 5.9% for levels at the middle tertile (2.3 to 5.4 mg/L; n=1013) and 10.5% for CRP levels at the upper tertile (>5.4 mg/L; n=984; P<0.001). With adjustment for potential confounders, baseline CRP levels in the top versus bottom tertile were associated with a 2.16-fold increased hazard (95% CI, 1.32 to 3.53) for ischemic stroke, and CRP levels measured after 2 years were associated with a hazard ratio of 2.43 (95% CI, 1.30 to 4.57). The risk of an incident ischemic stroke did not differ between the bezafibrate group compared with the placebo group regardless of baseline CRP levels. Conclusions— These findings, based on a large prospective study, demonstrate the risk prediction for incident ischemic stroke conferred by CRP levels in patients at high risk.

Antihyperglycemic Treatment in Diabetics with Coronary Disease: Increased Metformin-Associated Mortality over a 5-Year Follow-Up

Mortality rates are considerably higher in chronic ischemic heart disease (IHD) patients with non-insulin-dependent diabetes mellitus (NIDDM) than in those who are nondiabetics. The relationship between different types of antihyperglycemic pharmacological therapy and mortality rate in this NIDDM population is uncertain. We aimed to examine the survival in NIDDM patients with IHD using various types of oral antidiabetic treatments over a 5-year follow-up period. The study sample comprised 11,440 patients with a previous myocardial infarction and/or stable anginal syndrome, aged 45–74 years, who were screened, but not included in the Bezafibrate Infarction Prevention study. Among them, 9,045 were nondiabetics and 2,395 diabetics. The diabetic patients were divided into four groups on the basis of their therapeutic regimen at screening: diet alone (n = 990), sulfonylureas (n = 1,041), metformin (n = 78) and a combination of a sulfonylurea and metformin (n = 266). All NIDDM groups were similar with regard to age, gender, hypertension, smoking, heart failure, angina and prior myocardial infarction. Crude mortality rate was lower in the nondiabetic group (11.21 vs. 21.8%; p < 0.001). In the diabetic group, mortality was 18.5% for patients on diet alone, 22.5% for those on sulfonylureas, 25.6% for patients on metformin, and 31.6% for the combined sulfonylurea/metformin group (p < 0.01). When analyzing age-adjusted mortality rate and actuarial survival curves, the lowest mortality was found in patients on diet alone and the highest in patients on metformin (alone or in combination with sulfonylureas). After adjustment for variables connected with long-term prognosis, the use of metformin was associated with increased relative risk (RR) for all-cause mortality of 1.42 (95% CI 1.10–1.85), whereas the use of sulfonylureas alone was not [RR 1.11 (95% CI 0.90–1.36)]. NIDDM patients with IHD using metformin, alone or in combination with sulfonylureas, exhibited a significantly increased mortality. Until the results of problem-oriented prospective studies on oral control of NIDDM will be available, alternative therapeutic approaches should be investigated in these patients.

Relation Between Renal Function and Outcomes in Patients With Non-ST-Segment Elevation Acute Coronary Syndrome Real-World Data From the European Public Health Outcome Research and Indicators Collection Project

BACKGROUND Clinical trials provide limited information about the outcome of patients with acute coronary syndromes (ACSs) and kidney disease (KD) owing to underrepresentation of this population in most studies. METHODS To evaluate the outcome of patients with non-ST-segment elevation ACS (NSTE-ACS) and KD in a real-world setting, we compared the risk of in-hospital and 30-day mortality by the presence of KD (defined as an estimated glomerular filtration rate <60 mL/min/1.73 m(2)) in 13 141 patients with NSTE-ACS enrolled in 3 multinational ACS registries between 2000 and 2006 as part of the European Public Health Outcome Research and Indicators Collection Project. RESULTS Patients with KD (n = 4181) composed 31.8% of the study population and had significantly higher rates of in-hospital (5.4%) and 30-day (7.2%) case fatality compared with patients without KD (1.1% and 1.7%, respectively; P < .001 for both). In multivariate analysis, the presence of KD was independently associated with a significantly higher mortality risk (in-hospital: odds ratio [OR], 2.11; 95% confidence interval [CI], 1.48-3.00; 30-day: OR, 1.95; 95% CI, 1.46-2.61). Patients with KD who underwent coronary angiography experienced a 36% (P = .05) and 40% (P < .001) lower risk of in-hospital and 30-day mortality, respectively, but this high-risk population still exhibited significantly higher case-fatality rates during hospitalization (3.3%) and at 30 days (4.6%) compared with patients without KD who underwent coronary angiography (0.7% and 1.3%, respectively; P < .001 for all). CONCLUSIONS In a real-world setting, KD was present in approximately one-third of patients with NSTE-ACS and is a powerful independent predictor of subsequent mortality. Patients with NSTE-ACS and KD referred for coronary angiography have a significantly lower risk of death, but this high-risk population continues to exhibit increased mortality rates despite intervention procedures.

A prospective study of plasma fibrinogen levels and the risk of stroke among participants in the bezafibrate infarction prevention study.

PURPOSE Plasma fibrinogen has emerged as an important predictor of cardiovascular disease, but few data are available on its association with stroke. We sought to determine if plasma fibrinogen is a marker of increased risk or a direct causative risk factor for stroke. SUBJECTS AND METHODS Patients from the Bezafibrate Infarction Prevention Study, a placebo-controlled, randomized clinical trial of secondary prevention of coronary heart disease by lipid modification with bezafibrate retard (400 mg daily), were studied. Plasma fibrinogen levels were measured at baseline and yearly thereafter. Stroke, a prospectively monitored endpoint, was systematically assessed regarding stroke type, subtype, and functional outcome. RESULTS Mean baseline fibrinogen levels were significantly higher in patients subsequently having a cerebrovascular event (140 strokes, 36 transient ischemic attacks; mean follow-up, 6.2 years) than in patients who did not (375 vs. 349 mg/dL, P <0.0001). Fibrinogen levels did not differ significantly by the type, subtype, or severity of the cerebrovascular event. Risk of ischemic stroke increased from 3.3% in the lowest tertile (baseline fibrinogen <314 mg/dL) to 7.% in the middle tertile (fibrinogen 314 to 373 mg/dL) to 10% in the upper tertile (fibrinogen >373 mg/dL, P <0.001). Adjusting for age, blood pressure, and other covariates, fibrinogen levels in the upper tertile were associated with more than a twofold increase in risk of ischemic stroke compared with in the lowest tertile (hazard ratio = 2.6; 95% confidence interval: 1.5 to 4.3). We did not find fibrinogen change from baseline to be related to subsequent ischemic stroke events. CONCLUSION Plasma fibrinogen is a strong predictor of, rather than a direct causative factor for, subsequent stroke among patients at increased risk owing to manifest coronary heart disease.

Relation of clinical benefit of raising high-density lipoprotein cholesterol to serum levels of low-density lipoprotein cholesterol in patients with coronary heart disease (from the Bezafibrate Infarction Prevention Trial).

Low high-density lipoprotein (HDL) cholesterol is a strong independent predictor of cardiovascular risk. The present study was designed to assess the relation between the clinical response to HDL cholesterol modification and serum levels of low-density lipoprotein (LDL) cholesterol in patients with coronary artery disease (CAD). The risk for a major cardiac event (defined as nonfatal myocardial infarction or cardiac death) during a median 7.9-year follow-up period in 3,020 patients with CAD enrolled in the Bezafibrate Infarction Prevention (BIP) trial was related to changes in lipid levels during the study. Baseline LDL cholesterol levels were categorized according to National Cholesterol Education Program Adult Treatment Panel III criteria. Multivariate analysis demonstrated that the benefit of HDL cholesterol increase was most pronounced in patients with low baseline LDL cholesterol (<or=129 mg/dl; 29% risk reduction per 5 mg/dl increment in HDL cholesterol, p = 0.02), intermediate in patients with intermediate LDL cholesterol (130 to 159 mg/dl; 13% risk reduction per 5 mg/dl increment in HDL cholesterol, p = 0.03), and nonsignificant in patients with high LDL cholesterol (>or=160 mg/dl; hazard ratio 0.94, 95% confidence interval 0.75 to 1.17, p = 0.14). A similar relation was shown for risk reduction-associated triglyceride decrements, whereas the benefit of LDL cholesterol reduction was more pronounced in patients with baseline LDL cholesterol >or=130 mg/dl. In conclusion, these data suggest that the clinical response to HDL cholesterol and triglyceride modification is inversely related to baseline LDL cholesterol levels. Thus, combined assessment of baseline and follow-up lipid levels to direct therapeutic goals in patients with CAD may provide incremental prognostic information to secondary prevention that is based solely on LDL cholesterol modification.

Secondary Prevention With Bezafibrate Therapy for the Treatment of Dyslipidemia: An Extended Follow-Up of the BIP Trial

OBJECTIVES This study was designed to evaluate the long-term cardiovascular benefit of bezafibrate therapy in coronary heart disease patients enrolled in the BIP (Bezafibrate Infarction Prevention) trial. BACKGROUND The BIP trial yielded a nonsignificant 7.3% reduction in the rate of major cardiac events after a mean follow-up period of 6.2 years, possibly owing to an increasing unbalanced usage of nonstudy lipid-lowering drugs (LLDs) during the course of the trial. METHODS The adjusted risk for the combined end point of cardiac death or nonfatal myocardial infarction during an extended mean 8.2-year follow-up period of the BIP trial was assessed in 3,090 patients allocated to the original bezafibrate (n = 1,548) and placebo (n = 1,542) groups of the trial. RESULTS During the extended follow-up period, nonstudy LLDs were administered to a significantly greater proportion of placebo-allocated patients (57%) than bezafibrate-allocated patients (53%; p = 0.02). Interaction-term analysis demonstrated that the benefit of bezafibrate therapy was pronounced (18% risk reduction; p = 0.03) without or before treatment with nonstudy LLDs initiated during follow-up and attenuated (hazard ratio 1.05; p = 0.85) after therapy with nonstudy LLDs initiated during the observation period. Consistent with these findings, treatment with bezafibrate was shown to be associated with a significant 17% risk reduction (p = 0.03) when study patients were censored from the analysis upon initiation of therapy with nonstudy LLDs. CONCLUSIONS The data demonstrate that bezafibrate therapy in the BIP trial was associated with significant long-term cardiovascular protection that was attenuated by an unbalanced usage of nonstudy LLDs during the course of the trial.

Increased prevalence of left ventricular hypertrophy in hypertensive women with type 2 diabetes mellitus.

BackgroundLeft ventricular hypertrophy (LVH) is a powerful independent risk factor for cardiovascular morbidity and mortality among hypertensive patients. Data regarding relationships between diabetes and LVH are controversial and inconclusive, whereas possible gender differences were not specifically investigated. The goal of this work was to investigate whether gender differences in left heart structure and mass are present in hypertensive patients with type 2 diabetes.MethodsFive hundred fifty hypertensive patients with at least one additional cardiovascular risk factor (314 men and 246 women, age 52 to 81, mean 66 ± 6 years), were enrolled in the present analysis. In 200 (36%) of them – 108 men and 92 women – type 2 diabetes mellitus was found upon enrollment. End-diastolic measurements of interventricular septal thickness (IVS), LV internal diameter, and posterior wall thickness were performed employing two-dimensionally guided M-mode echocardiograms. LVH was diagnosed when LV mass index (LVMI) was >134 g/m2 in men and >110 g/m2 in women.ResultsMean LVMI was significantly higher among diabetic vs. nondiabetic women (112.5 ± 29 vs. 105.6 ± 24, p = 0.03). In addition, diabetic women presented a significantly higher prevalence of increased IVS thickness, LVMI and left atrial diameter on intra-gender comparisons. The age adjusted relative risk for increased LVMI in diabetics vs. nondiabetics was 1.47 (95% CI: 1.0–2.2) in females and only 0.8 (0.5–1.3) in males.ConclusionType 2 diabetes mellitus was associated with a significantly higher prevalence of LVH and left atrial enlargement in hypertensive women.

Tilt training: does it have a role in preventing vasovagal syncope?

Background: Vasovagal syncope is one of the most common medical conditions in young adults. Previous trials have shown effectiveness of tilt training in treating this condition. We conducted a prospective, randomized study in order to evaluate the role of tilt‐training in young adults with vasovagal syncope.