Higher testosterone is associated with higher HDL-cholesterol and lower triglyceride concentrations in older women: an observational study.

OBJECTIVE: This study aimed to determine whether concentrations of testosterone and its main precursor after menopause, dehydroepiandrosterone (DHEA), are associated with lipoproteins and other lipids in community-dwelling older women. METHODS: The Sex Hormones in Older Women (SHOW) study was an observational study of 6358 Australian women, aged at least 70 years, with no prior major adverse cardiovascular event who had sex hormones measured by liquid chromatography-tandem mass spectrometry. Associations between hormones and lipids were examined using multilinear regression adjusted for potential confounders. RESULTS: The cross-sectional analyses included 3231 participants, median age 74.0 (interquartile range 71.7-77.9) years. Compared with concentrations in the lowest quartile (Q1), testosterone concentrations in the highest quartiles (Q3 and Q4) were positively associated with high-density lipoprotein cholesterol (HDL-C) (p = 0.002 and p < 0.001, respectively) while Q4 testosterone concentrations were positively associated with total cholesterol (p = 0.038). Q2, Q3 and Q4 testosterone concentrations were significantly inversely associated with triglycerides (TG) (p = 0.024, p = 0.003 and p < 0.001, respectively). For DHEA, Q4 concentrations was positively associated with non-HDL-C (p = 0.024). CONCLUSIONS: In older women, higher endogenous testosterone concentrations are significantly associated with higher HDL-C and lower TG, indicating a less atherogenic profile. These findings suggest a neutral, or potentially protective, cardiovascular disease effect of testosterone in older women.

Compliance-Adjusted Estimates of Aspirin Effects Among Older Persons in the ASPREE Randomized Trial.

The Aspirin in Reducing Events in the Elderly (ASPREE) Trial recruited 19,114 participants across Australia and the United States during 2010-2014. Participants were randomized to receive either 100 mg of aspirin daily or matching placebo, with disability-free survival as the primary outcome. During a median 4.7 years of follow-up, 37% of participants in the aspirin group permanently ceased taking their study medication and 10% commenced open-label aspirin use. In the placebo group, 35% and 11% ceased using study medication and commenced open-label aspirin use, respectively. In order to estimate compliance-adjusted effects of aspirin, we applied rank-preserving structural failure time models. The results for disability-free survival and most secondary endpoints were similar in intention-to-treat and compliance-adjusted analyses. For major hemorrhage, cancer mortality, and all-cause mortality, compliance-adjusted effects of aspirin indicated greater risks than were seen in intention-to-treat analyses. These findings were robust in a range of sensitivity analyses. In accordance with the original trial analyses, compliance-adjusted results showed an absence of benefit with aspirin for primary prevention in older people, along with an elevated risk of clinically significant bleeding.

Estrone, sex hormone binding globulin and lipid profiles in older women: an observational study.

OBJECTIVE: We investigated whether estrone and sex hormone binding globulin (SHBG) concentrations are associated with lipid concentrations in older postmenopausal women. METHODS: This was a cross-sectional study of 6358 Australian women, aged 70-95 years, recruited between 2010 and 2014. Associations between estrone and SHBG and lipid concentrations were examined in participants not using medications that influence estrogen concentrations or lipid-lowering therapy. Linear regression models included age, body mass index, smoking, alcohol consumption, renal function and diabetes, with the lowest quartile (Q1) as the reference for estrone and SHBG. RESULTS: The study included 3231 participants with median age of 74.0 (interquartile range 71.7-77.9) years. Estrone concentration Q3 and Q4 were positively associated with high-density lipoprotein cholesterol (HDL-C) (p = 0.017 and p = 0.046, respectively). Inverse associations were seen for estrone Q4 with total cholesterol (p = 0.018), Q2 and Q4 with non-HDL-C (p = 0.045 and p = 0.002, respectively) and Q3 and Q4 with triglycerides (p = 0.030 and p = 0.001, respectively). For SHBG, Q2, Q3 and Q4 were positively associated with HDL-C (all p < 0.001), and inversely with non-HDL-C (all p = 0.001) and triglycerides (all p < 0.001). CONCLUSIONS: Estrone and SHBG are associated with lipid concentrations in older women. SHBG, but not estrone, may provide additional clinical predictive utility for the assessment of cardiometabolic disease risk in older women.

Common genetic variants do not predict recurrent events in coronary heart disease patients.

BACKGROUND: It is unclear whether genetic variants identified from single nucleotide polymorphisms (SNPs) strongly associated with coronary heart disease (CHD) in genome-wide association studies (GWAS), or a genetic risk score (GRS) derived from them, can help stratify risk of recurrent events in patients with CHD. METHODS: Study subjects were enrolled at the close-out of the LIPID randomised controlled trial of pravastatin vs placebo. Entry to the trial had required a history of acute coronary syndrome 3-36 months previously, and patients were in the trial for a mean of 36 months. Patients who consented to a blood sample were genotyped with a custom designed array chip with SNPs chosen from known CHD-associated loci identified in previous GWAS. We evaluated outcomes in these patients over the following 10 years. RESULTS: Over the 10-year follow-up of the cohort of 4932 patients, 1558 deaths, 898 cardiovascular deaths, 727 CHD deaths and 375 cancer deaths occurred. There were no significant associations between individual SNPs and outcomes before or after adjustment for confounding variables and for multiple testing. A previously validated 27 SNP GRS derived from SNPs with the strongest associations with CHD also did not show any independent association with recurrent major cardiovascular events. CONCLUSIONS: Genetic variants based on individual single nucleotide polymorphisms strongly associated with coronary heart disease in genome wide association studies or an abbreviated genetic risk score derived from them did not help risk profiling in this well-characterised cohort with 10-year follow-up. Other approaches will be needed to incorporate genetic profiling into clinically relevant stratification of long-term risk of recurrent events in CHD patients.

Maximizing efficiency and cost-effectiveness of Type 2 diabetes screening: the AusDiab study.

AIMS: To evaluate how to most efficiently screen populations to detect people at high risk of incident Type 2 diabetes and those with prevalent, but undiagnosed, Type 2 diabetes. METHODS: Data from 5814 adults in the Australian Diabetes, Obesity and Lifestyle study were used to examine four different types of screening strategies. The strategies incorporated various combinations of cut-points of fasting plasma glucose, the non-invasive Australian Type 2 Diabetes Risk Assessment Tool (AUSDRISK1) and a modified version of the tool incorporating fasting plasma glucose (AUSDRISK2). Sensitivity, specificity, positive predictive value, screening costs per case of incident or prevalent undiagnosed diabetes identified and intervention costs per case of diabetes prevented or reverted were compared. RESULTS: Of the four strategies that maximized sensitivity and specificity, use of the non-invasive AUSDRISK1, followed by AUSDRISK2 in those found to be at increased risk on AUSDRISK1, had the highest sensitivity (80.3%; 95% confidence interval 76.6-84.1%), specificity (78.1%; 95% confidence interval 76.9-79.2%) and positive predictive value (22.3%; 95% confidence interval 20.2-24.4%) for identifying people with either prevalent undiagnosed diabetes or future incident diabetes. It required the fewest people (24.1%; 95% confidence interval 23.0-25.2%) to enter lifestyle modification programmes, and also had the lowest intervention costs and combined costs of running screening and intervention programmes per case of diabetes prevented or reverted. CONCLUSIONS: Using a self-assessed diabetes risk score as an initial screening step, followed by a second risk score incorporating fasting plasma glucose, would maximize efficiency of identifying people with undiagnosed Type 2 diabetes and those at high risk of future diabetes.

Clinical effectiveness in everyday practice: improving outcomes for all patients through a national acute coronary syndrome data collaborative.

The management of acute coronary syndromes (ACS) has an extensive and impressive evidence-base with which to guide clinical practice. Despite this, translation to the clinical environment has proved to be challenging and incomplete and can be attributed to patient, provider and system factors. Causes of suboptimal guideline adherence relate to diverse issues, including patient complexity, barriers in knowledge translation of guideline recommendations and a limited capacity within health services. Addressing these factors may enable more effective guideline implementation. In Australia, the infrastructure for clinical data management is fragmented, uncoordinated and often administratively driven, compromising access to important information, which might improve clinical effectiveness. An integrated approach is required to improve clinical effectiveness in ACS care in Australia. Greater access to information both to assist in clinical decision-making and monitoring outcomes may help direct the focus towards understudied populations and improve performance and clinically relevant outcomes. A peer-led initiative based on common datasets, providing rapid feedback, while developing and disseminating a 'toolbox' of proven and sustainable interventions, could improve clinical effectiveness in the Australian management of ACS and provides a rationale for a national ACS registry.

HOMA insulin sensitivity index and the risk of all-cause mortality and cardiovascular disease events in the general population: the Australian Diabetes, Obesity and Lifestyle Study (AusDiab) study.

AIMS/HYPOTHESIS: We assessed whether the relationships between insulin sensitivity and all-cause mortality as well as fatal or non-fatal cardiovascular disease (CVD) events are independent of elevated blood glucose, high blood pressure, dyslipidaemia and body composition in individuals without diagnosed diabetes. METHODS: Between 1999 and 2000, baseline fasting insulin, glucose and lipids, 2 h plasma glucose, HbA(1c), anthropometrics, blood pressure, medication use, smoking and history of CVD were collected from 8,533 adults aged >35 years from the population-based Australian Diabetes, Obesity and Lifestyle study. Insulin sensitivity was estimated by HOMA of insulin sensitivity (HOMA-%S). Deaths and fatal or non-fatal CVD events were ascertained through linkage to the National Death Index and medical records adjudication. RESULTS: After a median of 5.0 years there were 277 deaths and 225 CVD events. HOMA-%S was not associated with all-cause mortality. Compared with the most insulin-sensitive quintile, the combined fatal or non-fatal CVD HR (95% CI) for quintiles of decreasing HOMA-%S were 1.1 (0.6-1.9), 1.4 (0.9-2.3), 1.6 (1.0-2.5) and 2.0 (1.3-3.1), adjusting for age and sex. Smoking, CVD history, hypertension, lipid-lowering medication, total cholesterol and waist-to-hip ratio moderately attenuated this relationship. However, the association was rendered non-significant by adding HDL. Fasting plasma glucose, but not HOMA-%S significantly improved the prediction of CVD, beyond that seen with other risk factors. CONCLUSIONS/INTERPRETATION: In this cohort, HOMA-%S showed no association with all-cause mortality and only a modest association with CVD events, largely explained by its association with HDL. Fasting plasma glucose was a better predictor of CVD than HOMA-%S.

Continuous relationships between non-diabetic hyperglycaemia and both cardiovascular disease and all-cause mortality: the Australian Diabetes, Obesity, and Lifestyle (AusDiab) study.

AIMS/HYPOTHESIS: Hyperglycaemia is a risk factor for cardiovascular disease (CVD) and all-cause mortality in individuals without diabetes. We investigated: (1) whether the risk of all-cause and CVD mortality extended continuously throughout the range of fasting plasma glucose (FPG), 2 h plasma glucose (2hPG) and HbA(1c) values; and (2) the ability of these measures to improve risk prediction for mortality. METHODS: Data on 10,026 people aged >or=25 years without diagnosed diabetes were obtained from the population-based Australian Diabetes, Obesity and Lifestyle study. Between 1999 and 2000, FPG, 2hPG and HbA(1c) were assessed and all-cause (332 deaths) and CVD (88 deaths) mortality were obtained after 7 years. RESULTS: Both 2hPG and HbA(1c) exhibited linear relationships with all-cause and CVD mortality, whereas FPG showed J-shaped relationships. The adjusted HR (95% CI) for all-cause mortality per SD increase was 1.2 (1.1-1.3) for 2hPG and 1.1 (1.0-1.2) for HbA(1c). The HR for FPG <5.1 mmol/l (per SD decrease) was 2.0 (1.3-3.0); for FPG >or=5.1 mmol/l (per SD increase) the HR was 1.1 (1.0-1.2). Corresponding HRs for CVD mortality were 1.2 (1.0-1.4), 1.2 (1.0-1.3), 4.0 (2.1-7.6) and 1.3 (1.1-1.4). The discriminative ability of each measure was similar; no measure substantially improved individual risk identification over traditional risk factors. CONCLUSIONS/INTERPRETATION: In individuals without diagnosed diabetes, 2hPG and FPG, but not HbA(1c) were significant predictors of all-cause mortality, whereas all measures were significant predictors of CVD mortality. However, these glucose measures did not substantially improve individual risk identification.

Leptin, but not adiponectin, is a predictor of recurrent cardiovascular events in men: results from the LIPID study.

OBJECTIVE: To investigate the relationships between plasma leptin and adiponectin levels and recurrent cardiovascular events (cardiovascular death, nonfatal myocardial infarction and stroke) in men with earlier acute coronary syndromes. DESIGN, SUBJECTS AND MEASUREMENTS: A nested case-control study examined circulating leptin and adiponectin levels in plasma obtained 4-6 years after entry into the Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) trial. Plasma was assayed from 184 men who suffered recurrent events within 4.4 years after blood collection and 184 matched controls who remained free of further events. The association between cardiovascular events and the explanatory variables was examined by conditional logistic regression analysis. RESULTS: Relative risk (RR) increased across increasing leptin quartiles; the highest quartile compared with the lowest quartile was related to the highest risk (P for trend=0.002); the increased risk remained after adjustment for risk factors (P=0.018) or for obesity (P=0.038), but in the final model (adjusted for randomized treatment, other drugs, LIPID risk score, age and body mass index), the risk was attenuated (RR=1.61, 95% CI: 0.72-3.57, P for trend=0.34). Adiponectin did not predict cardiovascular events. Subjects randomly allocated to pravastatin had 6% lower leptin levels (P=0.04) than those allocated to placebo. CONCLUSION: Plasma leptin was a significant and independent predictor of recurrent cardiovascular events (cardiovascular death, nonfatal myocardial infarction and stroke) in men with earlier acute coronary syndromes.

Validity of self-reported cardiovascular disease events in comparison to medical record adjudication and a statewide hospital morbidity database: the AusDiab study.

Epidemiological studies often rely on self-reported cardiovascular disease (CVD) information, but this may be inaccurate. We investigated the accuracy of self-reported CVD (myocardial infarction, stroke, coronary artery bypass surgery and coronary artery angioplasty) during the follow up of the Australian Diabetes, Obesity and Lifestyle (AusDiab) study. Self-reported CVD events, including the date of the event and hospital admission details, were collected with an interviewer-administered questionnaire. Of the 276 self-reported CVD events, 188 (68.1%) were verified by adjudication of medical records. Furthermore, linkage to the statewide Western Australian Hospital Morbidity Database (WAHMD) showed that CVD events were unlikely to be missed, with only 0.2% of those denying any CVD event being recorded as having had an event on the WAHMD. The adjudication of medical records was as accurate as record linkage to the WAHMD for validation of self-reported CVD, but combining the results from both methods of ascertainment improved CVD event identification.

The metabolic syndrome as a tool for predicting future diabetes: the AusDiab study.

OBJECTIVE: To compare the ability of the metabolic syndrome (MetS), a diabetes prediction model (DPM), a noninvasive risk questionnaire and individual glucose measurements to predict future diabetes. DESIGN: Five-year longitudinal cohort study. Tools tested included MetS definitions [World Health Organization, International Diabetes Federation, ATPIII and European Group for the study of Insulin Resistance (EGIR)], the FINnish Diabetes RIsk SCore risk questionnaire, the DPM, fasting and 2-h post load plasma glucose. SETTING: Adult Australian population. SUBJECTS: A total of 5842 men and women without diabetes > or =25 years. Response 58%. A total of 224 incident cases of diabetes. RESULTS: In receiver operating characteristic curve analysis, the MetS was not a better predictor of incident diabetes than the DPM or measurement of glucose. The risk for diabetes among those with prediabetes but not MetS was almost triple that of those with MetS but not prediabetes (9.0% vs. 3.4%). Adjusted for component parts, the MetS was not a significant predictor of incident diabetes, except for EGIR in men [OR 2.1 (95% CI 1.2-3.7)]. CONCLUSIONS: A single fasting glucose measurement may be more effective and efficient than published definitions of the MetS or other risk constructs in predicting incident diabetes. Diagnosis of the MetS did not confer increased risk for incident diabetes independent of its individual components, with an exception for EGIR in men. Given these results, debate surrounding the public health utility of a MetS diagnosis, at least for identification of incident diabetes, is required.

Effect of pravastatin on coronary disease events in subgroups defined by coronary risk factors: the Prospective Pravastatin Pooling Project.

BACKGROUND: Previous trials have had insufficient numbers of coronary events to address definitively the effect of lipid-modifying therapy on coronary heart disease in subgroups of patients with varying baseline characteristics. METHODS AND RESULTS: The data from 3 large randomized trials with pravastatin 40 mg were pooled and analyzed with the use of a prospectively defined protocol. Included were 19 768 patients, 102 559 person-years of follow-up, 2194 primary end points (coronary death or nonfatal myocardial infarction), and 3717 expanded end points (primary end point, CABG, or PTCA). Pravastatin significantly reduced relative risk in younger (<65 years) and older (>/=65 years) patients, men and women, smokers and nonsmokers, and patients with or without diabetes or hypertension. The relative effect was smaller, but absolute risk reduction was similar in patients with hypertension compared with those without hypertension. Relative risk reduction was significant in predefined categories of baseline lipid concentrations. Tests for interaction were not significant between relative risk reduction and baseline total cholesterol (5% to 95% range 177 to 297 mg/dL, 4.6 to 7.7 mmol/L), HDL cholesterol (27 to 58 mg/dL, 0.7 to 1.5 mmol/L), and triglyceride (74 to 302 mg/dL, 0.8 to 3.4 mmol/L) concentrations, analyzed as continuous variables. However, for LDL cholesterol, the probability values for interaction were 0.068 for the prespecified primary end point and 0.019 for the expanded end point. Relative risk reduction was similar throughout most of the baseline LDL cholesterol range (125 to 212 mg/dL, 3.2 to 5.5 mmol/L) with the possible exception of the lowest quintile of CARE/LIPID (<125 mg/dL) (relative risk reduction 5%, 95% CI 19% to -12%). CONCLUSIONS: Pravastatin treatment is effective in reducing coronary heart disease events in patients with high or low risk factor status and across a wide range of pretreatment lipid concentrations.

Comparison of dobutamine echocardiography and positron emission tomography in patients with chronic ischemic left ventricular dysfunction.

OBJECTIVES: The aim of this study was to correlate dobutamine-induced contractile reserve as detected by echocardiography with findings on positron emission tomography in patients with chronic ischemic left ventricular dysfunction. BACKGROUND: Contractile reserve induced by low dose dobutamine infusion has been proposed as a marker of myocardial viability. METHODS: Sixty patients with stable coronary artery disease and left ventricular dysfunction (mean ejection fraction [+/- SD] 29 +/- 10%) underwent transthoracic echocardiography with dobutamine infusion (up to 10 micrograms/kg body weight per min) and positron emission tomography with nitrogen-13 ammonia and fluorine-18 (F-18) fluorodeoxyglucose as a perfusion and a metabolic tracer, respectively. Regional wall motion, perfusion and metabolism were analyzed semiquantitatively by using a 16-segment model. Segments with F-18 fluorodeoxyglucose uptake > 50% were considered viable on positron emission tomography. RESULTS: After dobutamine infusion, hemodynamic variables changed significantly, and myocardial ischemia was evident in 17 patients. All 60 patients had dysfunctional myocardium considered viable on positron emission tomography (8 +/- 4 segments/patient), whereas 52 patients had dysfunctional myocardium with contractile enhancement by dobutamine echocardiography (4 +/- 2 segments/patient, p = 0.01). The extent of dysfunctional myocardium with contractile reserve appeared to correlate less closely with the total extent of viable dysfunctional myocardium identified by positron emission tomography than with the number of such segments associated with a pattern of perfusion-metabolism mismatch. CONCLUSIONS: In patients with chronic ischemic left ventricular dysfunction, echocardiography can be used to identify enhancement in the contractile function of viable dysfunctional myocardium after infusion of low dose dobutamine. In this study, the presence and extent of such enhancement were relatively less than the values obtained from positron emission tomography.

Importance of electrode design, lead configuration and impedance for successful low energy transcatheter atrial defibrillation in dogs.

OBJECTIVES: We assessed the feasibility of low energy endocardial defibrillation in a canine model of atrial fibrillation, comparing catheters with large surface area electrodes and standard electrode catheters, and evaluated the effects of lead configuration and circuit impedance on defibrillation energy requirements. BACKGROUND: Although recent animal studies have demonstrated the feasibility of low energy endocardial atrial defibrillation, their results have been conflicting with regard to important methodologic aspects. METHODS: In 14 anesthetized greyhounds, atrial fibrillation was induced by rapid atrial pacing and maintained by vagal stimulation. Two large surface area braided electrode catheters and two standard electrode catheters were introduced percutaneously, one of each, in the right atrial appendage and right ventricular apex. A cutaneous patch electrode was placed on the left thorax. Biphasic shocks synchronized to the ventricular electrogram were used to terminate atrial fibrillation. Seven configurations were evaluated. Three used standard electrodes: proximal atrial cathode to distal atrial, ventricular or cutaneous anode. Four used braided electrodes: three with atrial cathode to ventricular, cutaneous or combined anode; one with ventricular cathode to atrial anode. RESULTS: Defibrillation with standard electrode catheters was associated with high impedance (576 +/- 112 omega) and low success rates for all configurations (28% success at < or = 40 J, no successes at 10 J). Low energy defibrillation was readily achieved with the braided electrodes with significantly lower impedance (75 +/- 13 omega, p < 0.0001). Ventricular fibrillation did not occur. The success rate of cardioversion increased in a dose-response manner, allowing fitting of a sigmoid curve and calculation of energy associated with 50% (ED50) and 90% (ED90) success. The most successful configuration was ventricular cathode/atrial anode (ED50 1.5 +/- 0.4 J), and the least successful was atrial anode/cutaneous patch (ED50 6.5 +/- 3.2 J, p = 0.0001). CONCLUSIONS: Low energy atrial defibrillation is feasible using large surface area electrodes but not with standard electrode catheters owing to high impedance. An intracardiac anode provides lower impedance and higher success rates than are provided by a cutaneous anode.

Passive ventricular constraint amends the course of heart failure: a study in an ovine model of dilated cardiomyopathy.

OBJECTIVE: Dilated cardiomyopathy (DCM) is associated with a progressive deterioration in cardiac function. We hypothesised that some of the deleterious effects of DCM could be reduced by mechanically limiting the degree of cardiac dilatation. METHODS: A Transonic 20A cardiac output (CO) flow-probe was implanted in the pulmonary artery of 12 adult (52 +/- 4 kg) sheep. Early heart failure was created by rapid right ventricular (RV) pacing for 21 days at a rate which resulted in an initial 10% decrease in CO (to a maximum of 190 bpm). A custom polyester jacket (Acorn Cardiovascular, St Paul, MN) was then placed, via a partial lower sternotomy, on the ventricular epicardium of all sheep. Animals were randomised either to jacket retention (wrap) or removal (sham). Pacing was recommenced at a higher rate (that initiated a further 10% decrease in CO) for 28 days. Haemodynamic and echocardiographic parameters were determined at baseline, implant and at termination. RESULTS: At termination, the left ventricular fractional shortening was significantly higher (p = 0.03), the degree of mitral valve regurgitation lower (scaled 0-3) (p = 0.03) and the left ventricular long axis area smaller (p = 0.02) in the wrap animals compared with sham. CONCLUSIONS: In this model of heart failure, ventricular constraint with a polyester jacket diminished the deterioration in cardiac function associated with progressive dilated cardiomyopathy. These results suggest that maintainance of a more normal cardiac size and shape may be beneficial in patients with dilated cardiomyopathy.

Adverse effects of low-dose aspirin in a healthy elderly population.

The adverse effects of low-dose aspirin (100 mg daily) in the elderly were studied over a 12-month period in a double-blind, randomized, placebo-controlled trial of 400 subjects who were 70 years of age or older and had no preexisting major vascular diseases at the time of entry. Subjects were randomized so that 200 subjects received low-dose enteric-coated aspirin (100 mg daily) and 200 subjects received placebo. Compliance with medication, assessed by pill count, was 86%. Gastrointestinal symptoms were reported by 18% (n = 36) of participants receiving aspirin and 13% (n = 26) of those receiving placebo. Clinically evident gastrointestinal bleeding occurred in 3% (n = 6) of subjects receiving aspirin and none receiving placebo. Aspirin-treated subjects had a significant decrease in mean hemoglobin levels of 0.33 gm/dl during the 12-month study period, which was significantly greater than the decrease in the placebo-treated group (0.11 gm/dl; p < 0.05). These rates of unwanted symptoms are comparable with previous studies that used higher doses of aspirin. Until the risk-benefit trade-off from the use of low-dose aspirin in the elderly is established with an appropriate clinical trial, caution should be exercised when this compound is used for primary prevention of cardiovascular disease in this age group.

Management of the Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) study after the Scandinavian Simvastatin Survival Study (4S).

The Long-term Intervention with Pravastatin in Ischaemic Disease (LIPID) study was designed when considerable disagreement existed as to relative benefits and risks of cholesterol reduction. Between June 1990 and December 1992, 9,014 patients aged 31-75 years were randomized to receive either pravastatin 40 mg once daily or placebo. These patients had experienced either acute myocardial infarction or unstable angina within the preceding 3 months to 3 years and had total cholesterol levels of 155-271 mg/dl (4.0-7.0 mmol/liter). All patients received dietary advice. The LIPID study is projected for conclusion in 1997, after a follow-up period of at least 5 years. The primary study endpoint is mortality due to coronary artery disease (CAD). The Scandinavian Simvastatin Survival Study (4S) is the first secondary prevention trial to show a reduction in total mortality with lipid-lowering therapy. However, the LIPID study should continue for the following reasons: (1) important differences exist between the LIPID study and 4S cohorts. Overall, > 80% of the LIPID patients could not have been included in 4S on the basis of their cholesterol level, age, or history of CAD; (2) the LIPID study will also provide important information on noncoronary mortality and on other groups, such as women and diabetic patients, who have been underrepresented in previous trials; (3) the LIPID study design allows for clinical management, including lipid-lowering therapy, to be at the discretion of the physician managing a trial patient. The 4S results have been brought to the attention of all LIPID investigators, Institutional Ethics Committees, the physicians of the individual patients, and the patients themselves.(ABSTRACT TRUNCATED AT 250 WORDS)

Evidence that patent foramen ovale is not a risk factor for cerebral ischemia in the elderly.

Patent foramen ovale (PFO) may be a risk factor for ischemic stroke in young patients. The aim of this study was to assess the importance of PFO in subjects with a wider age range using patient-control methodology. Transesophageal contrast echocardiography and carotid imaging were performed in 220 consecutive patients with cerebral ischemia (mean age 66 +/- 13 years) and in 202 community-based control subjects (mean age 64 +/- 11 years). Of patients with stroke, 35 (16%) had PFO compared with 31 control subjects (15%) (p = 0.98). Analysis of PFO prevalence by age did not show a significant difference between patients and controls subjects in the age groups < 50 years (27% vs 11%; p = 0.33), 50 to 69 years (17% vs 15%; p = 0.78), and > or = 70 years (12% vs 17%; p = 0.43). However, the group aged < 50 years was relatively small (26 cases, 19 controls). No significant difference in PFO prevalence was detected between patients with cryptogenic stroke (20%), noncryptogenic stroke (14%), and control subjects (15%). These results suggest that PFO is not a risk factor for cerebral ischemia in subjects aged > 50 years, which would have major implications for the investigation and management of stroke patients in this age group. Longitudinal studies are now required to assess the incidence of stroke in symptom-free patients with PFO.

Atrial fibrillation with left atrial spontaneous contrast detected by transesophageal echocardiography is a potent risk factor for stroke.

Nonrheumatic atrial fibrillation (AF) frequently coexists with other risk factors for cerebral ischemia. This study was originally designed to determine which combinations of clinical and echocardiographic abnormalities were most closely associated with the risk of cerebral ischemic events. Patients with cerebral ischemic events (n = 214) and community-based control subjects (n = 201) underwent transesophageal echocardiography and carotid artery imaging. Adjusted odds ratios (ORs) were determined using multiple logistic regression analysis. Independent risk factors for cerebral ischemia included diabetes, carotid stenosis, aortic sclerosis, left ventricular dysfunction, left ventricular hypertrophy, left atrial (LA) spontaneous contrast, and proximal aortic atheroma. Nonrheumatic AF in combination with LA spontaneous contrast and LA enlargement showed a strong association with cerebral ischemic events (OR 33.7 [95% confidence interval 4.53 to 251]). In subjects with sinus rhythm or nonrheumatic AF, LA enlargement was not associated with an increased risk of cerebral ischemic events in the absence of LA spontaneous contrast. However, only 2 patients and 1 control subject had nonrheumatic AF without LA spontaneous contrast or LA enlargement. Therefore, study of a larger number of subjects is required to address the issue of whether nonrheumatic AF itself carries increased risk. The combination of nonrheumatic AF with LA spontaneous contrast is a potent risk factor for cerebral ischemia. Ascertaining the risk factor in nonrheumatic AF requires adequate examination for underlying cardiac, aortic, and carotid vascular disease. Transesophageal echocardiography may contribute to this assessment.