Risk Of Nonfatal Myocardial Infarction Research Articles

Effect of Sibutramine on Cardiovascular Outcomes in Overweight and Obese Subjects

The long-term effects of sibutramine treatment on the rates of cardiovascular events and cardiovascular death among subjects at high cardiovascular risk have not been established. We enrolled in our study 10,744 overweight or obese subjects, 55 years of age or older, with preexisting cardiovascular disease, type 2 diabetes mellitus, or both to assess the cardiovascular consequences of weight management with and without sibutramine in subjects at high risk for cardiovascular events. All the subjects received sibutramine in addition to participating in a weight-management program during a 6-week, single-blind, lead-in period, after which 9804 subjects underwent random assignment in a double-blind fashion to sibutramine (4906 subjects) or placebo (4898 subjects). The primary end point was the time from randomization to the first occurrence of a primary outcome event (nonfatal myocardial infarction, nonfatal stroke, resuscitation after cardiac arrest, or cardiovascular death). The mean duration of treatment was 3.4 years. The mean weight loss during the lead-in period was 2.6 kg; after randomization, the subjects in the sibutramine group achieved and maintained further weight reduction (mean, 1.7 kg). The mean blood pressure decreased in both groups, with greater reductions in the placebo group than in the sibutramine group (mean difference, 1.2/1.4 mm Hg). The risk of a primary outcome event was 11.4% in the sibutramine group as compared with 10.0% in the placebo group (hazard ratio, 1.16; 95% confidence interval [CI], 1.03 to 1.31; P=0.02). The rates of nonfatal myocardial infarction and nonfatal stroke were 4.1% and 2.6% in the sibutramine group and 3.2% and 1.9% in the placebo group, respectively (hazard ratio for nonfatal myocardial infarction, 1.28; 95% CI, 1.04 to 1.57; P=0.02; hazard ratio for nonfatal stroke, 1.36; 95% CI, 1.04 to 1.77; P=0.03). The rates of cardiovascular death and death from any cause were not increased. Subjects with preexisting cardiovascular conditions who were receiving long-term sibutramine treatment had an increased risk of nonfatal myocardial infarction and nonfatal stroke but not of cardiovascular death or death from any cause. (Funded by Abbott; ClinicalTrials.gov number, NCT00234832.)

Alcohol consumption and the risk of sudden cardiac death in women: An evaluation from the Nurses' Health Study

The impact of alcohol consumption on total and cardiovascular mortality is well studied and often discussed in lay publications. Alcohol consumption is associated with decreased all-cause mortality and cardiovascular disease in a J-shaped or U-shaped curve. 1–3 Patients who do not consume alcohol or consume excessive amounts have higher mortality and prevalence of cardiovascular disease compared with those who drink alcohol in moderate amounts. As with many other cardiovascular risk factors and therapeutic interventions, gender differences are noted. Decreased hypertension, coronary heart disease (CHD), stroke, and mortality have been associated with moderate alcohol use in women. 4–6 Studies have also demonstrated a high risk of sudden cardiac death (SCD) and cardiac arrhythmias with heavy drinking but less SCD with moderate alcohol use 7–10 ; these studies had limited inclusion of women. Women also can develop alcohol-related medical problems at lower levels of consumption than men, 11 and although this may reflect lower body weight, it could also represent gender differences in alcohol metabolism or effects on postmenopausal estrogen levels. The study by Chiuve et al 12 in this issue of Heart Rhythm addresses the association of alcohol consumption and SCD in 121,700 women ages 30 to 55 years from the Nurses’ Health Study. In this ambitious, prospective cohort study participants were surveyed every 4 years to document the amount and type of alcohol consumption. Because other medical comorbidities or illness can cause patients to cease alcohol consumption and introduce bias, nondrinkers were separated into lifetime abstainers and former drinkers. After excluding women with a baseline diagnosis of cancer or cardiovascular disease or incomplete information on alcohol intake and dietary data, the study population comprised 85,067 subjects. Studied end points included SCD, other fatal CHD, and nonfatal myocardial infarction. Extensive efforts to increase the accuracy of SCD classification included obtaining death certificates, interviewing family members, and obtaining hospital records. These efforts at accurate classification were appropriate, as proper diagnosis of SCD remains a major challenge in studies. The authors hypothesized that the greatest association of CHD to alcohol consumption would be the most recent intake, and this intake amount was used to estimate risk in the subsequent 4-year period. Results were adjusted for age, diet, cardiovascular disease risk factors, and caloric intake. Women who consumed 5.0 to 14.9 g alcohol daily (approximately ½ to 1 drink/day) accounted for 50% of the study population and had the lowest risk of SCD in a U-shaped association (P .0003) over 26 years of follow-up. There was no significant difference in risk of SCD between abstainers and women who had higher amounts of alcohol intake. No differences in results were observed when probable but not definite SCD cases were excluded. Moreover, there were no differences in light to moderate consumption of different types of alcohol (wine, beer, or liquor) on the observed association with less SCD (RR 0.78 for beer, 0.84 for wine, 0.77 for liquor). Alcohol consumption was also associated with lower risk of nonfatal myocardial infarction or fatal CHD, but this was a linear and inverse relationship. A study of this size evaluating the association of alcohol consumption and SCD in women has not been performed previously. This study has a high number of study participants followed up over an extended time as well as a significant number of SCD and CHD events. Such an analysis generally has several significant challenges. First, correct classification of SCD events can be difficult. SCD is defined as death that occurs within 1 hour or less of symptom onset or during sleep in a person without a condition that would seem fatal, 13 but some methods of SCD identification used in previous studies are not accurate. Every et al 14 demonstrated that SCD classification on death certificates can be a sensitive but not specific method of identifying SCD events. In addition, the general public often confuses SCD and myocardial infarction. Although the authors of the present study made extensive efforts to properly classify SCD, accurate identification of such events remains a weakness in most studies of SCD. Addressing multiple comorbidities in a high number of patients can be quite complicated. Risk of SCD in this study was controlled for over 15 potentially confounding vari

Aspirin in the secondary prevention of cardiovascular disease: an update of the APTC meta‐analysis

We updated the 2002 Antiplatelet Trialists' Collaboration meta-analysis of antiplatelet therapy to assess the effects of aspirin alone in the secondary prevention of different types of thrombotic arterial disease. Results of randomized, placebo-controlled trials of aspirin in patients with confirmed cardiovascular disease were abstracted and synthesized by the Mantel-Haenszel method. We defined three cardiovascular disease groups according to the qualifying disease at entry: coronary artery disease (CAD), cerebrovascular disease (CRVD), and peripheral arterial disease (PAD). Results are given as odds ratios (OR) and 95% confidence intervals (95% CI). Compared with placebo, aspirin decreased significantly the risk of all-cause death in CAD and CRVD (OR = 0.80, 95% CI 0.75-0.86 and 0.91, 95% CI 0.85-0.98, respectively), and of vascular events in CAD, CRVD, and PAD (OR = 0.71, 95% CI 0.67-0.76, 0.87, 95% CI 0.82-0.93, and 0.50, 95% CI 0.29-0.88, respectively). The risk of non-fatal stroke was decreased in the CAD, CRVD, and PAD (OR = 0.64, 95% CI 0.50-0.83, 0.81, 95% CI 0.74-0.89, and 0.26, 95% CI 0.07-0.94, respectively). The risk of non-fatal myocardial infarction was decreased significantly in the CAD and CRVD (OR = 0.59, 95% CI 0.53-0.67, and 0.63, 95% CI 0.48-0.84, respectively), but not in the PAD (OR = 0.43, 95% CI 0.15-1.25). Aspirin nearly doubled the risk of major bleeds (OR = 1.87, 95% CI 1.51-2.32 for all clinical conditions). This meta-analysis confirms that aspirin decreases the risk of thrombotic events in patients with confirmed disease of the coronary, cerebrovascular, or peripheral artery beds.

Inclusion of Stroke as an Outcome and Risk Equivalent in Risk Scores for Primary and Secondary Prevention of Vascular Disease

Current guideline statements for primary and secondary prevention of cardiovascular disease (CVD) rely on estimates of absolute risk of coronary events. For example, the American Heart Association guidelines on primary prevention state that persons with ≥10% risk over 10 years of myocardial infarction (MI) or coronary death should be considered for antiplatelet therapy with aspirin.1 Similarly, the National Cholesterol Education Program Adult Treatment Panel III (ATP III) guidelines2 state that target low-density lipoprotein level should be based on projected absolute risk of future coronary events rather than on presence or absence of specific risk factors. These guidelines state that patients at high risk of MI and coronary death, defined as an absolute 10-year risk of ≥20%, should have a target low-density lipoprotein level <100 mg/dL and should receive statin therapy if needed to achieve this goal. Stroke, however, is not included as one of the outcomes contributing to these absolute risk levels. Included in the group of patients with elevated risk, moreover, are those who already have ischemic heart disease, as well as patients deemed to be “coronary heart disease (CHD) risk equivalents,” indicating those at the same elevated risk as patients with ischemic heart disease. CHD risk equivalents include patients with diabetes mellitus, those with multiple risk factors that put them at elevated risk based on calculation of their Framingham Score, and patients with “other forms of symptomatic atherosclerotic disease.” The latter group is further defined to include those with peripheral arterial disease (PAD), abdominal aortic aneurysm (AAA), and carotid artery disease. The category of “risk equivalents” in the ATP III guidelines, however, does not include the vast majority (≈80%3) of ischemic stroke patients without carotid artery disease as cause of their stroke. Ischemic stroke is therefore notably excluded from the list of outcomes contributing to …

SHA 75. The missed essence: Holistic nursing care

Individuals with both type 1 and type 2 diabetes mellitus (DM) are known to be at high risk for developing coronary artery disease (CAD). The risk is two to three times greater in those with DM compared with those without, and is especially high in women with DM. An additional problem in individuals with DM is that, even with severe underlying CAD, many individuals may have atypical symptoms or be totally asymptomatic, a condition referred to as silent or asymptomatic myocardial ischemia. Asymptomatic myocardial ischemia is frequently found in individuals with known CAD, even in individuals without DM, and is associated with a poorer long term prognosis. The Asymptomatic Cardiac Ischemia Pilot Study demonstrated that asymptomatic ischemia was associated with three times the risk of nonfatal myocardial infarction and six times the risk of myocardial infarction or death. However, asymptomatic myocardial infarction also occurs in a substantial number of individuals without known CAD, particularly those with DM. These individuals have not been diagnosed with CAD and do not have the benefit of anti-anginal therapies or aggressive CAD risk reduction. In the recent Detection of Ischemia in Asymptomatic Diabetics (DIAD) study, 21.6% of older adults with type 2 DM, none of whom had any clinical evidence of CAD, had evidence of myocardial ischemia on single photon emission computed tomography (SPECT) myocardial perfusion imaging. This finding was consistent with earlier studies in the population with type 2 DM. In asymptomatic patients with either type 1 or type 2 DM, asymptomatic myocardial ischemia is also associated with major cardiac events. Importantly, the presence of cardiac autonomic neuropathy, long theorized to have a role in asymptomatic CAD, substantially increases the risk of subsequent cardiac events, with those individuals with both asymptomatic myocardial ischemia and cardiac autonomic neuropathy, being at highest risk.

SHA 74. Silent ischemia in patients with diabetes

Individuals with both type 1 and type 2 diabetes mellitus (DM) are known to be at high risk for developing coronary artery disease (CAD). The risk is two to three times greater in those with DM compared with those without, and is especially high in women with DM. An additional problem in individuals with DM is that, even with severe underlying CAD, many individuals may have atypical symptoms or be totally asymptomatic, a condition referred to as silent or asymptomatic myocardial ischemia. Asymptomatic myocardial ischemia is frequently found in individuals with known CAD, even in individuals without DM, and is associated with a poorer long term prognosis. The Asymptomatic Cardiac Ischemia Pilot Study demonstrated that asymptomatic ischemia was associated with three times the risk of nonfatal myocardial infarction and six times the risk of myocardial infarction or death. However, asymptomatic myocardial infarction also occurs in a substantial number of individuals without known CAD, particularly those with DM. These individuals have not been diagnosed with CAD and do not have the benefit of anti-anginal therapies or aggressive CAD risk reduction. In the recent Detection of Ischemia in Asymptomatic Diabetics (DIAD) study, 21.6% of older adults with type 2 DM, none of whom had any clinical evidence of CAD, had evidence of myocardial ischemia on single photon emission computed tomography (SPECT) myocardial perfusion imaging. This finding was consistent with earlier studies in the population with type 2 DM. In asymptomatic patients with either type 1 or type 2 DM, asymptomatic myocardial ischemia is also associated with major cardiac events. Importantly, the presence of cardiac autonomic neuropathy, long theorized to have a role in asymptomatic CAD, substantially increases the risk of subsequent cardiac events, with those individuals with both asymptomatic myocardial ischemia and cardiac autonomic neuropathy, being at highest risk.

Polymorphisms in the platelet-specific collagen receptor GP6 are associated with risk of nonfatal myocardial infarction in Caucasians

Background and aims Glycoprotein 6 (GP6) is a platelet-specific collagen receptor implicated in the thrombotic pathway to acute myocardial infarction (AMI), but a possible genetic relationship between GP6 and AMI is poorly understood. We tested for the genetic association between AMI and single nucleotide polymorphisms (SNPs) in 24 loci, including GP6. Methods and results We conducted a case-control study of AMI and GP6 in a community-based population ( n = 652 cases, 625 controls). We also examined men and women separately and stratified the latter by use of hormone replacement therapy (HRT). Among both sexes, the strongest association was for a protective missense polymorphism (rs1163662) in the GP6 gene (OR = 0.70; Bonferroni-adjusted p < 0.05). SNPs in GP6 were also strongly associated with AMI among women who reported ever taking HRT, but not among women who never took HRT. Haplotype analyses were consistent with the single-SNP findings. Conclusions In this sample of white non-Hispanic men and women, several SNPs in GP6 were significantly related to risk of AMI. Development of pharmacologic therapy directed towards platelet activity and thrombosis may reduce the incidence of AMI among at-risk groups.

The effect of intensive glucose control on all-cause and cardiovascular mortality, myocardial infarction and stroke in persons with type 2 diabetes mellitus: a systematic review and meta-analysis

We performed a meta-analysis of studies evaluating the effect of intensive glucose control on major adverse cardiovascular events in patients with type 2 diabetes from 1990 to 2009. A search of the published literature and the Cochran Central Register for Controlled Trials was performed using pre-specified inclusion criteria consisting of randomised controlled trials evaluating intensive glycaemic control and reporting the individual endpoints of all-cause mortality, non-fatal myocardial infarction, and non-fatal stroke. Incident rate ratios for these endpoints were calculated using standard meta-analytic techniques of pooled data from eligible trials. Six reports from four randomised trials including 27,544 patients met the pre-specified inclusion criteria. Mean follow-up was 5.4 years; haemoglobin A(1C) at study end was 6.6% vs. 7.4% in patients randomised to intensive compared with conventional glucose control. Intensive glucose control did not affect the incident rate ratio for all-cause mortality (1.01, 95% confidence interval 0.86-1.18, p=0.54) or stroke (1.02, 95% confidence interval 0.88-1.20, p=0.62). However, there was a statistically significant 14% reduction in non-fatal myocardial infarction in patients randomised to intensive glucose control (0.86, 95% confidence interval 0.77-0.97, p=0.015). Although intensification of glucose control did not affect mortality or non-fatal stroke, the risk for non-fatal myocardial infarction was significantly reduced in patients with type 2 diabetes.

Hemostasis, Inflammation, and Fatal and Nonfatal Coronary Heart Disease

Objective— This study examines the hypothesis that chronic inflammation is associated with a higher risk of cardiac death compared to the risk of nonfatal myocardial infarction. Methods and Results— Cardiac death and nonfatal MI events were identified in the ARIC cohort during follow-up from 1987 through 2001. Markers of inflammation and hemostasis were determined at baseline using standardized procedures. Cox proportional hazard regression and polytomous logistic regression were used to estimate associations. We observed a positive gradient in incidence of sudden cardiac death (SCD), nonsudden cardiac death (NSCD), and nonfatal MI in association with decreasing levels of albumin and increasing levels of white blood cell count and of markers of hemostasis (fibrinogen, von Willebrand factor, factor VIIIc). Associations for von Willebrand factor were stronger for fatal relative to nonfatal events (3rd versus 1st tertile hazard ratios: SCD 3.11 [95% CI 2.10, 4.59], NSCD 2.12 [95% CI 1.28, 3.49], nonfatal MI 1.42 [95% CI 1.19, 1.70]). For factor VIIIc those associations were strongest for sudden cardiac death: SCD 3.16 (95% CI 2.18, 4.58), NSCD 1.44 (95% CI 0.93, 2.24), nonfatal MI 1.54 (95% CI 1.29, 1.84). Gradients of association for fibrinogen and white blood cell count, examined over tertiles of distribution and per one SD increase, were similar for the 3 end points. All associations were independent of smoking status. Conclusion— von Willebrand factor and factor VIIIc are associated with an increased risk of cardiac death as compared to the risk of nonfatal MI.

Usefulness of Pregnancy-Associated Plasma Protein A in Patients With Acute Coronary Syndrome

To investigate whether pregnancy-associated plasma protein-A (PAPP-A) is a prognostic marker in patients admitted with high-risk acute coronary syndrome. In patients admitted with high-risk non-ST-segment elevation acute coronary syndrome (NSTE-ACS) and ST-segment elevation myocardial infarction (STEMI), risk stratification is primarily determined by the markers of myocardial necrosis and known demographic risk profiles. However, it has recently been proposed that the presence and extent of vulnerable plaques might influence the prognosis significantly. A marker for the vulnerable plaque could identify patients at high risk who would potentially benefit from intensive treatment and surveillance. Two populations of consecutive patients admitted with high-risk NSTE-ACS (n = 123) and STEMI (n = 314) were evaluated with serial measurements of PAPP-A. The incidence of mortality and nonfatal myocardial infarction was prospectively registered for 2.66 to 3.47 years. In the patients with high-risk NSTE-ACS, PAPP-A was related to the risk of nonfatal myocardial infarction (p = 0.02) and death (p = 0.03). This result was consistent on multivariate analysis of the combination of mortality or nonfatal myocardial infarction (odds ratio 2.65, 95% confidence interval 1.40 to 5.03) but not for mortality alone (p = NS). In patients with STEMI, PAPP-A was related to the risk of death (p = 0.01) but not the composite outcome of myocardial infarction and death. This was also true after adjustment for other univariate predictors of death (odds ratio 2.19, 95% confidence interval 1.16 to 4.16). In conclusion, PAPP-A seems to be valuable in predicting the outcomes of patients admitted with high-risk NSTE-ACS or STEMI.

Optimal body weight for the prevention of coronary heart disease in normal-weight physically active men.

Although 36% of US men are normal weight (BMI <25 kg/m(2)), the health benefits of greater leanness in normal-weight individuals are seldom acknowledged. To assess the optimal body weight with respect to minimizing coronary heart disease (CHD) risk, we applied Cox proportional hazard analyses of 20,525 nonsmoking, nondiabetic, normal-weight men followed prospectively for 7.7 years, including 20,301 who provided follow-up questionnaires. Two-hundred and forty two men reported coronary artery bypass graph (CABG) or percutaneous transluminal coronary angioplasty (PTCA) and 82 reported physician-diagnosed incident myocardial infarction (267 total). The National Death Index identified 40 additional ischemic heart disease deaths. In these normal-weight men, each kg/m(2) decrement in baseline BMI was associated with 11.2% lower risk for total CHD (P = 0.005), 13.2% lower risk for nonfatal CHD (P = 0.002), 19.0% lower risk for nonfatal myocardial infarction (P = 0.01), and 12.2% lower risk for PTCA or CABG (P = 0.007). Compared to men with BMI between 22.5 and 25 kg/m(2), those <22.5 kg/m(2) had 24.1% lower total CHD risk (P = 0.01), 27.9% lower nonfatal CHD risk (P = 0.01), 37.8% lower nonfatal myocardial infarction risk (P = 0.05), and 27.8% lower PTCA or CABG risk (P = 0.02). In nonabdominally obese men (waist circumference <102 cm), CHD risk declined linearly with declining waist circumference. CHD risk was unrelated to change in waist circumference between 18 years old and baseline except as it contributed to baseline circumference. These results suggest that the optimal BMI for minimizing CHD risk lies somewhere <22.5 kg/m(2), as suggested from our previous analyses of incident diabetes, hypertension, and hypercholesterolemia in these men.

Prognostic implications of vascular complications following PCI

To evaluate the effect of vascular complications (VC) on the adjusted risk of nonfatal myocardial infarction (MI) or death following percutaneous coronary intervention (PCI) at 1 year in a large contemporary cohort. Peri-procedural bleeding increases the risk of adverse clinical outcomes at 1 year. Whether access site VC's identify patients at high risk or independently alter the risk of adverse clinical outcomes at 1 year, however, is uncertain. 3,931 PCI procedures performed via a femoral access at a single site (WFUBMC) were evaluated. Access and nonaccess site post procedural bleeding were assessed. The adjusted risk of access site VC's association with 1-year clinical outcomes was evaluated by Cox proportional hazards modeling. Any VC occurred in 1.7%, and any TIMI bleeding in 6.7% after PCI. The hazard ratio (HR) adjusted for baseline and procedural covariates for any VC of nonfatal MI or all cause death at 1 year was 1.68 (1.00-2.81), P = 0.049 and 1.69 (0.92-3.09), P = 0.088 for all cause death alone. However, after adjusting for any TIMI bleeding, the HR for nonfatal MI or death was 0.84 (0.49-1.45), P = 0.527, and for death alone 0.75 (0.39-1.41), P = 0.369. The occurrence of VC following PCI was an independent predictor of nonfatal MI or death at 1 year, but only if accompanied by TIMI major or minor bleeding. A vascular complication without TIMI bleeding did not alter prognosis at 1 year.

Growth-Differentiation Factor-15 for Risk Stratification in Patients With Stable and Unstable Coronary Heart Disease

Background— Growth-differentiation factor-15 (GDF-15) is a stress-responsive transforming growth factor-β-related cytokine that has emerged as a prognostic biomarker in acute coronary syndrome trial populations. Its predictive role in stable coronary heart disease (CHD) has never been assessed. Methods and Results— The circulating levels of GDF-15 were measured by immunoradiometric assay in patients with stable angina pectoris (n=1352) or acute coronary syndrome (n=877) who were followed up for a median of 3.6 years. Stable angina pectoris patients presenting with normal (&lt;1200 ng/L), moderately elevated (1200 to 1800 ng/L), or markedly elevated (&gt;1800 ng/L) GDF-15 levels had 3.6-year CHD mortality rates of 1.4%, 2.7%, and 15.0%, respectively ( P &lt;0.001). By backward stepwise Cox-regression analysis, which adjusted for age and gender, clinical variables, the number of diseased vessels, renal function, the levels of C-reactive protein, cardiac troponin I, and N-terminal pro-B-type natriuretic peptide, GDF-15 remained an independent predictor of CHD mortality ( P &lt;0.001). Addition of GDF-15 improved the prognostic accuracy of a clinical risk prediction model concerning CHD mortality (c-statistic, 0.84 versus 0.74; P =0.005). Analysis of the acute coronary syndrome part of the study population confirmed GDF-15 as an independent predictor of CHD mortality ( P &lt;0.001). The circulating levels of GDF-15 did not predict the future risk of nonfatal myocardial infarction in patients with stable angina pectoris or acute coronary syndrome. Conclusion— This study identifies GDF-15 as a strong and independent predictor of CHD mortality across the broad spectrum of patients with stable and unstable CHD.

Cardiac safety profile of rosiglitazone: A comprehensive meta-analysis of randomized clinical trials

Background Some meta-analyses of randomized clinical trials suggested that rosiglitazone could be associated with increased risk for myocardial infarction (MI). Available meta-analyses, based on studies sponsored by GlaxoSmithKline (GSK), failed to include all trials performed with rosiglitazone. Aim of this analysis is the assessment of the cardiovascular risk with rosiglitazone, using a comprehensive data set. Methods Results of 164 trials with duration > 4 weeks were retrieved from http://ctr.gsk.co.uk/welcome.asp and from Medline, while unpublished studies were identified from www.clinicaltrials.gov. A total of 164 trials (42,922 and 45,483 patient⁎years for rosiglitazone and comparators, respectively) were included in the analysis. Results The OR for all-cause and cardiovascular mortality with rosiglitazone was 0.93[0.76;1.14] and 0.94[0.68;1.29], respectively; rosiglitazone-associated risk for nonfatal MI and heart failure was 1.14[0.90;1.45] and 1.69[1.21;2.36], respectively. The risk of heart failure was higher (2.20[1.28;3.78]) when rosiglitazone was administered as add-on therapy to insulin. Conclusions Figures for rosiglitazone-associated risk for myocardial infarction could be lower than those previously reported on the basis of a smaller number of clinical trials. No increase of all-cause or cardiovascular mortality were observed with rosiglitazone. Conversely, treatment with rosiglitazone is associated with a relevant increase in the risk of heart failure, particularly in insulin-treated patients.

Traffic-Generated Air Pollution and Myocardial Infarction

Although long-term air pollution exposure has been linked to cardiovascular mortality, data on incidence and nonfatal coronary disease are limited and inconclusive. The aim of this study was to investigate the association between long-term residential exposure to air pollution from traffic and the risk of nonfatal and fatal myocardial infarction. The records of all individuals aged 15 to 79 with a first event of myocardial infarction in Stockholm County during 1985 to 1996 were retrieved from a registry. Population controls were randomly selected from the study base stratified by age, sex, and calendar year. Individual socioeconomic data and home addresses were obtained from population censuses 1970 to 1995. Annual air pollution exposure was assessed by dispersion modeling at the home addresses of 24,347 cases and 276,926 controls. Five-year average traffic-generated air pollution exposure corresponding to a difference in nitrogen dioxide from the fifth to the 95th percentile (31 microg/m) was associated with an odds ratio for fatal myocardial infarction adjusted for age, sex, calendar year, and socioeconomic status of 1.23 (95% confidence interval [CI] = 1.15-1.32). The corresponding odds ratio was 2.54 (1.96-3.29) among those with least expected misclassification of true individual exposure (those who did not move between censuses). Different time-windows and analyses of other pollutants including carbon monoxide and particles less than 10 mum in diameter (PM10) produced weaker associations. There was no increased risk for nonfatal myocardial infarction (ORs 0.94-0.98). Long-term exposure to traffic-generated air pollution is associated with fatal myocardial infarction but not with nonfatal infarction.

Fibrates in the prevention of cardiovascular disease in patients with type 2 diabetes mellitus – A pooled meta-analysis of randomized placebo-controlled clinical trials

Objective Fibrates are thought to be useful anti-dyslipidemic agents particularly in patients with diabetes mellitus and dyslipidemia characterized by high triglyceride (TG) and low high-density lipoprotein cholesterol (HDL-C) levels. We conducted a systematic review and meta-analysis of long-term randomized controlled trials to evaluate the role of fibrates in the prevention of cardiovascular events in patients with type 2 diabetes mellitus. Data sources English-language journals indexed in Index Medicus/MEDLINE and the Cochrane Collaboration databases (through December 2007), unpublished data from selected clinical trials. Data extraction and analysis A total of 11,590 patients from 6 published randomized placebo-controlled trials were analyzed using pooled meta-analysis techniques. Relative risks were computed for various cardiovascular outcomes and mortality, and statistical significance was tested using the z-test statistic (two-sided alpha error < 0.05). Results The use of fibrates did not significantly affect the risk of all-cause mortality or cardiac mortality, and also did not affect the risk of stroke, unstable angina, or invasive coronary revascularization. However, the relative risk of non-fatal myocardial infarction was significantly reduced by about 21% (pooled relative risk 0.79, p = 0.006) with the use of fibrates. Conclusions Long-term use of fibrates in patients with type 2 diabetes mellitus significantly reduces the risk of non-fatal myocardial infarction, but has no significant effect on mortality or on other adverse cardiovascular outcomes.

Therapy and clinical trials: management of diabetic dyslipidemia

Therapy and clinical trials: management of diabetic dyslipidemia

Interaction between the Gly460Trp α-adducin gene variant and diuretics on the risk of myocardial infarction

The Gly460Trp variant of the alpha-adducin gene has been associated with the salt-sensitive and diuretic responsive form of hypertension. The aim of the study was to determine whether the alpha-adducin 460Trp variant allele modifies the risk-lowering effect of diuretics on myocardial infarction (MI). In a population-based registry of pharmacy records linked to hospital discharge records (PHARMO), we used a nested case-control design. We selected patients hospitalized for MI as cases if they had at least one prescription for antihypertensive drugs in the 3 months prior to their first MI and were registered in PHARMO for at least 1 year. Controls that were matched on age, sex, region and calendar date, met the same eligibility criteria as the patients, but were not hospitalized for MI. Only current users of antihypertensive drugs in whom the Gly460Trp polymorphism was genotyped were included for this study. Logistic regression analysis was used to calculate odds ratio (OR), synergy indices, 95% confidence intervals (CIs) and to adjust for the potential confounding factors high cholesterol, smoking, BMI, diabetes, physical activity, alcohol use, use of loop diuretics, coumarins, antiplatelet drugs, ischemic heart disease and number of antihypertensive drugs. The study included 613 patients and 3627 controls. Compared with users of other antihypertensives, the risk of MI was significantly lower among users of thiazide diuretics (OR 0.71, 95% CI 0.55-0.92). Among patients with the adducin variant the risk of MI was similar among thiazide users as compared with users of other antihypertensives (OR 0.88, 95% CI 0.58-1.33), whereas among wild-type carriers this risk was significantly lower (OR 0.62, 95% CI 0.44-0.87). The interaction between current use of diuretics and the alpha-adducin polymorphism was not statistically significantly increased on the multiplicative scale (synergy index 1.41, 95% CI 0.91-2.17). In sensitivity analyses, we found a nonsignificant trend towards a difference between patients who used potassium-sparing diuretics (synergy index 0.98, 95% CI 0.45-2.12) and patients who did not use potassium-sparing diuretics (synergy index 1.60, 95% CI 0.98-2.60) and a statistically significant difference between patients on monotherapy (synergy index 0.69, 95% CI 0.30-1.59) and those on combination therapy (synergy index 1.90, 95% CI 1.04-3.47). This study suggests that the alpha-adducin gene does not play an important role in modifying the risk of nonfatal MI associated with the use of thiazide diuretics.

Inhaled anticholinergics and the long-term treatment of chronic obstructive pulmonary disease: Weighing benefits and risks

A meta-analysis recently published in the Journal of the American Medical Association found an increased risk of nonfatal myocardial infarction, stroke, and cardiovascular death associated with inhaled anticholinergic use in patients with chronic obstructive pulmonary disease (COPD); however, inherent limitations in the meta-analysis and contradictory results from other studies cast uncertainty onto its conclusions. For example, the Understanding Potential Long-term Impacts on Function with Tiotropium trial, a large, prospective, 4-year outcome study in nearly 6000 patients with COPD, did not demonstrate an increase in cardiovascular events with anticholinergic therapy. Until more data are available, clinicians should always carefully weigh safety and efficacy data and help patients make informed decisions about their COPD care.

Meta-Analysis of the Relationship Between Non–High-Density Lipoprotein Cholesterol Reduction and Coronary Heart Disease Risk

To determine the relationship between non-high-density lipoprotein cholesterol (HDL-C) lowering and coronary heart disease (CHD) risk reduction for various lipid-modifying therapies. Non-HDL-C is the second lipid target of therapy after low-density lipoprotein cholesterol (LDL-C). Randomized placebo or active-controlled trials were evaluated. The effect of mean non-HDL-C reduction on the relative risk of nonfatal myocardial infarction and CHD death was estimated using Bayesian random-effects meta-analysis models adjusted for study duration. Cochrane's Q was used to test for heterogeneity. Inclusion criteria were met by 14 statin (n = 100,827), 7 fibrate (n = 21,647), and 6 niacin (n = 4,445) trials, and 1 trial each of a bile acid sequestrant (n = 3,806), diet (n = 458), and ileal bypass surgery (n = 838). For statins, each 1% decrease in non-HDL-C resulted in an estimated 4.5-year CHD relative risk of 0.99 (95% Bayesian confidence interval: 0.98 to 1.00). The fibrate model did not differ from the statin model (Bayes factor K = 0.49) with no evidence of heterogeneity. The niacin model was moderately different from the statin model (K = 7.43), with heterogeneity among the trials (Q = 11.8, 5 df; p = 0.038). The only niacin monotherapy trial (n = 3,908) had a 1:1 relationship between non-HDL-C and risk reduction. No consistent relationships were apparent for the 5 small trials of niacin in combination. The 95% confidence intervals for the single trials of diet, bile acid sequestrants, and surgery also included the 1:1 relationship. Non-HDL-C is an important target of therapy for CHD prevention. Most lipid-modifying drugs used as monotherapy have an approximately 1:1 relationship between percent non-HDL-C lowering and CHD reduction.