Cardiovascular Disease Endpoints Research Articles

On-Treatment Non–High-Density Lipoprotein Cholesterol, Apolipoprotein B, Triglycerides, and Lipid Ratios in Relation to Residual Vascular Risk After Treatment With Potent Statin Therapy: JUPITER (Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin)

The goal of this study was to determine whether residual risk after high-dose statin therapy for primary prevention individuals with reduced levels of low-density lipoprotein cholesterol (LDL-C) is related to on-treatment apolipoprotein B, non-high-density lipoprotein cholesterol (non-HDL-C), trigylcerides, or lipid ratios, and how they compare with on-treatment LDL-C.Guidelines focus on LDL-C as the primary target of therapy, yet residual risk for cardiovascular disease (CVD) among statin-treated individuals remains high and not fully explained.Participants in the randomized placebo-controlled JUPITER (Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin) trial were adults without diabetes or CVD, with baseline LDL-C levels <130 mg/dl, high-sensitivity C-reactive protein levels ≥2 mg/l, and triglyceride concentrations <500 mg/dl. Individuals allocated to receive rosuvastatin 20 mg daily with baseline and on-treatment lipids and lipoproteins were examined in relation to the primary endpoint of incident CVD (nonfatal myocardial infarction or stroke, hospitalization for unstable angina, arterial revascularization, or cardiovascular death).Using separate multivariate Cox models, statistically significant associations of a similar magnitude with residual risk of CVD were found for on-treatment LDL-C, non-HDL-C, apolipoprotein B, total cholesterol/HDL-C, LDL-C/HDL-C, and apolipoprotein B/A-I. The respective adjusted standardized hazard ratios (95% confidence intervals) for each of these measures were 1.31 (1.09 to 1.56), 1.25 (1.04 to 1.50), 1.27 (1.06 to 1.53), 1.22 (1.03 to 1.44), 1.29 (1.09 to 1.52), and 1.27 (1.09 to 1.49). The overall residual risk and the risk associated with these measures decreased among participants achieving on-treatment LDL-C ≤70 mg/dl, on-treatment non-HDL-C ≤100 mg/dl, or on-treatment apolipoprotein B ≤80 mg/dl. In contrast, on-treatment triglycerides showed no association with CVD.In this primary prevention trial of nondiabetic individuals with low LDL-C and elevated high-sensitivity C-reactive protein, on-treatment LDL-C was as valuable as non-HDL-C, apolipoprotein B, or ratios in predicting residual risk. (JUPITER-Crestor 20mg Versus Placebo in Prevention of Cardiovascular [CV] Events; NCT00239681).

Association of adult-onset asthma with specific cardiovascular conditions

While asthma is known to be associated with cardiovascular disease (CVD), the relation to specific manifestations of CVD has not been previously described. Our objective was to explore the relation of child and adult-onset asthma with specific CVD conditions. We examined data from 16,943 (projected 178 million) U.S. adults aged 18-90 years old with relevant information on asthma and CVD. The study was a cross-sectional analysis of the National Health and Nutrition Examination Survey 1999-2006. We determined the prevalence of CVD risk factors and likelihood of CVD conditions according to gender and asthma status using multiple logistic regression adjusted for age, gender and other CVD risk factors. The proportions of subjects with child and adult-onset asthma were 4.8% (n=702) and 3.3% (n=534), respectively. Adult-onset asthma was significantly associated with total CVD (OR=2.07, CI=1.2-3.7), but child-onset asthma was not associated with any CVD conditions. Of the four specific CVD endpoints, adult-onset asthma overall was only associated with coronary heart disease (CHD) (OR=2.26, CI=1.2-4.2) in the total population. Our data suggests that CHD is the major cardiovascular condition associated with asthma; a prospective study must be done to confirm a causal relationship.

A Meta-Analysis of Spurious Associations between Type D Personality and Cardiovascular Disease Endpoints

Denollet et al. claim that high social inhibition and negative affectivity, termed type D personality, predict negative cardiovascular disease outcomes, and notably mortality [1]. Our group noted that almost all research testing this hypothesis came from small studies from Denollet’s group at Tilburg University that for mortality had 4, 6, 8, 12, and 47 deaths to explain. We conducted the largest study of mortality to date, with 192 deaths being explained, recruited patients from some of the same hospitals used by the Tilburg group, but found no association between type D personality and mortality [2]. Our primary analyses retained the component social inhibition and negative affectivity as continuous variables and tested their interaction. Secondary analyses relied upon Denollet’s preferred method of dichotomizing social inhibition and negative affectivity, creating a 2 × 2 cross-tabulation, and then comparing the high/high type D quadrant to the other three. Our results were still null but we drew on our own work [3] and other sources [4] to caution that Denollet’s strategy was inappropriate and likely to produce spurious results, as did an accompanying editorial [5]. We provided data from our study to Grande et al. for inclusion in their meta-analyses [6]. Consistent with what they had done in all but one of their past and forthcoming studies, Grande et al. relied on Denollet’s strategy of data reduction and analysis, disregarding our caution that type D personality data is frequently inappropriately analyzed in this manner is insufficient reason for continuing to do so. In a further meta-analysis, Grande et al. combined multivariate analyses from Denollet et al. that consistently exceeded the number of allowable covariates, making spurious results likely. Problems in the credibility and generalizability of such overfit regression equations [7] are not overcome by simply integrating their results. Grande et al. found substantial heterogeneity and evidence of publication bias in their meta-analysis and should have further pursued that this was due to what they termed a striking rift between “very large effects in small studies and low or null effects from the largest studies,” [6] which were conducted outside the Tilburg group. The rate of positive findings in the Tilburg studies is considerably beyond what would have been predicted by a power analysis based on events being explained. Figure 3 in the meta-analysis article is misleading and obscures this problem, but the pattern is readily apparent in an examination of the meta-analysis' other forest plots and tables. Only after presenting their analyses, do Grande et al. concede “Our review cannot overcome some serious methodological shortcomings in Type D research,” Grande et al. then cataloged many of the criticisms of this research that we [2] had previously noted. Yet, they neither refuted these criticisms nor allowed them to influence how they conducted their meta-analysis. Instead, they ended with a declaration of the “urgency” for better studies of type D personality. Our assessment is that this literature is indeed ailing, but we believe that pulling the plug is better than keeping it on life support. There simply is no encouragement from adequately powered studies conducted outside the Tilburg group to continue this line of research. This would be apparent in a meta-analysis that used an appropriate statistical approach in calculating type D and accurately pointed to the source of the publication bias in studies sharing some characteristics: positive results from small samples, inappropriate statistics, and having been conducted by a single investigator group.

Abstract MP090: “Life’s Simple 7” and Risk of Incident CHD in the REasons for Geographic And Racial Differences (REGARDS) Study

The American Heart Association’s “Life’s Simple 7” (LS7) is a tool intended to encourage improvements in cardiovascular health. It is not clear whether LS7 scores are associated with similar risks for fatal and nonfatal acute coronary heart disease (CHD) events across race-sex groups in the 21st century. REGARDS is following 30,239 community-dwellers age &gt;45 years recruited between 2003-7 from the contiguous US states. Recruitment was designed to balance race and sex; the final sample was 55% female and 41% black. Participants were telephoned every 6 months for cardiovascular disease endpoints, with retrieval of medical records, death certificates, interviews with next-of-kin or proxies, and expert adjudication of endpoints following national consensus recommendations. Acute CHD was defined as definite or probable myocardial infarction (MI) not resulting in death within 28 days (nonfatal acute CHD) or fatal acute CHD. Among participants free of CHD at baseline, we used Cox models to examine hazard ratios for incident overall acute CHD, and, separately, fatal and nonfatal acute CHD for white and black men and women through 2008, examining associations with LS7 score (blood pressure, cholesterol, glucose, body mass index, smoking, physical activity, and diet), each scored as poor (1 point), intermediate (2 points) or ideal (3 points). The score ranged from 7-21 with 21 being the best cardiovascular health. The study sample numbered 24,431 with mean age 64.1 (SD+9.3) years. Mean follow-up over 3.4 (maximum 5.9) years resulted in 515 incident acute CHD events (355 nonfatal, 160 fatal). Race-sex specific hazard ratios for incident acute CHD and incident nonfatal acute CHD per point higher LS7 score are shown in the table. The AHA’s goal of improving cardiovascular health by 20% by 2020 as assessed by LS7 could have major impact on improving CHD outcomes among black and white Americans.

How Accurate Are 3 Risk Prediction Models in US Women?

Cardiovascular disease (CVD) is the leading cause of death for US women, and nearly two thirds who died suddenly of CVD had no previous symptoms.1 Therefore, it is of great importance to identify “at-risk” women early, so that effective primary prevention strategies can be instituted. A universal recommendation of prevention guidelines is that all asymptomatic women should undergo a global risk assessment.2 Article see p 1748 The Adult Treatment Panel III (ATP-III) of the National Cholesterol Education Program set thresholds for lipid treatment based on one's predicted 10-year risk for a hard coronary heart disease (CHD) event (myocardial infarction or CHD death) using a modified Framingham risk score (FRS).3 There are limitations, however, with use of the ATP-III model for CVD prediction in women. The ATP-III version predicts “hard” CHD events but not angina or revascularizations, even if such revascularizations are performed to manage an acute coronary syndrome. Yet women are more likely to experience “soft” CHD events or strokes than men. Moreover, a single laboratory measurement does not reflect lipid values over a woman's lifetime. The FRS does not take into account family history of premature CHD, a well-established independent risk factor for CHD events.4 Also, because stroke accounts for a higher proportion of CVD events than CHD in women before age 75 years,1 we believe that total CVD risk should be the outcome for prediction and preventive strategies. Indeed, that is the conclusion of the 2011 American Heart Association CVD prevention guidelines for women.5 Furthermore, the FRS only predicts 10-year risk, whereas for women, the issue is most often “lifetime” risk. The Third National Health and Nutrition Examination Survey found that among women without a history of CHD or diabetes, 92% of those aged 60 to 69 years and >98% aged <59 …

Effects of fenofibrate on cardiovascular events in patients with diabetes, with and without prior cardiovascular disease: The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study

In the FIELD study, comparison of the effect of fenofibrate on cardiovascular disease (CVD) between those with prior CVD and without was a prespecified subgroup analysis. The effects of fenofibrate on total CVD events and its components in patients who did (n = 2,131) and did not (n = 7,664) have a history of CVD were computed by Cox proportional hazards modeling and compared by testing for treatment-by-subgroup interaction. The analyses were adjusted for commencement of statins, use of other CVD medications, and baseline covariates. Effects on other CVD end points were explored. Patients with prior CVD were more likely than those without to be male, to be older (by 3.3 years), to have had a history of diabetes for 2 years longer at baseline, and to have diabetic complications, hypertension, and higher rates of use of insulin and CVD medications. Discontinuation of fenofibrate was similar between the subgroups, but more patients with prior CVD than without, and also more placebo than fenofibrate-assigned patients, commenced statin therapy. The borderline difference in the effects of fenofibrate between those who did (hazard ratio [HR] 1.02, 95% CI 0.86-1.20) and did not have prior CVD (HR 0.81, 95% CI 0.70-0.94; heterogeneity P = .045) became nonsignificant after adjustment for baseline covariates and other CVD medications (HR 0.96, 95% CI 0.81-1.14 vs HR 0.78, 95% CI 0.67-0.90) (heterogeneity P = .06). Our findings do not support treating patients with fenofibrate differently based on any history of CVD, in line with evidence from other trials.

Mipomersen

Mipomersen is an antisense oligonucleotide inhibitor of apolipoprotein (apo) B-100 currently in phase 3 of development for the treatment of hyperlipidemia in patients with a high risk for cardiovascular disease. The drug acts by inhibiting the production of apoB-100, which is the structural core for all atherogenic lipids, including low-density lipoprotein cholesterol (LDL-C). The agent has been shown to produce significant reductions in LDL-C from baseline values compared with placebos. Clinical trials have demonstrated that mipomersen reduces LDL-C up to 44% in patients with familial hypercholesterolemia and patients with significantly elevated LDL despite taking maximum doses of statins. Unlike other medications that target apoB-100, such as microsomal triglyceride transfer proteins, mipomersen does not cause hepatic steatosis or intestinal steatosis and does not affect dietary fat absorption. Adverse side effects encountered with mipomersen include flu-like symptoms, injection site reactions, and elevated liver transaminases. If future studies continue to show such promising results, mipomersen would likely be a viable additional lipid-lowering therapy for patients who are at high cardiovascular risk, intolerant to statins, and/or not at target lipid levels despite maximum doses of statin therapy. Clinical outcome studies looking at cardiovascular disease end points still need to be done.

Targeting S100A1 in heart failure

Heart failure (HF) is the common endpoint of many cardiovascular diseases with a 1-year survival rate of about 50% in advanced stages. Despite increasing survival rates in the past years, current standard therapeutic strategies are far away from being optimal. For this reason, the concept of cardiac gene therapy for the treatment of HF holds great potential to improve disease progression, as it specifically targets key pathologies of diseased cardiomyocytes (CM). The small calcium (Ca(2+))-binding protein S100A1 presents a promising target for cardiac gene therapy, as it has been identified as a central regulator of cardiac performance and the Ca(2+)-driven network within CM. S100A1 was shown to regulate sarcoplasmic reticulum, sarcomere and mitochondrial function by modulating target protein activity. Furthermore, deranged S100A1 expression has been linked to HF in human ischemic and dilated cardiomyopathies as well as in various HF animal models. Proof-of-concept studies in small and large animal models as wells as in human failing CM could demonstrate feasibility and efficacy of S100A1 genetically targeted therapy. This review summarizes the developmental steps of S100A1 gene therapy for the implementation into first human clinical trials.

Anabolic Steroids and Cardiovascular Risk

Recent reports from needle exchange programmes and other public health initiatives have suggested growing use of anabolic steroids (AS) in the UK and other countries. Data indicate that AS use is not confined to body-builders or high-level sportsmen. Use has spread to professionals working in emergency services, casual fitness enthusiasts and subelite sportsmen and women. Although the precise health consequences of AS use is largely undefined, AS use represents a growing public health concern. Data regarding the consequences of AS use on cardiovascular health are limited to case studies and a modest number of small cohort studies. Numerous case studies have linked AS use with a variety of cardiovascular disease (CVD) events or endpoints, including myocardial infarction, stroke and death. Large-scale epidemiological studies to support these links are absent. Consequently, the impact of AS use upon known CVD risk factors has been studied in relatively small, case-series studies. Data relating AS use to elevated blood pressure, altered lipid profiles and ECG abnormalities have been reported, but are often limited in scope, and other studies have often produced equivocal outcomes. The use of AS has been linked to the appearance of concentric left ventricular hypertrophy as well as endothelial dysfunction but the data again remains controversial. The mechanisms responsible for the negative effect of AS on cardiovascular health are poorly understood, especially in humans. Possibilities include direct effects on myocytes and endothelial cells, reduced intracellular Ca2+ levels, increased release of apoptogenic factors, as well as increased collagen crosslinks between myocytes. New data relating AS use to cardiovascular health risks are emerging, as novel technologies are developed (especially in non-invasive imaging) that can assess physiological structure and function. Continued efforts to fully document the cardiovascular health consequences of AS use is important to provide a clear, accurate, public health message to the many groups now using AS for performance and image enhancement.

Evidence on the Human Health Effects of Low-Level Methylmercury Exposure

Background: Methylmercury (MeHg) is a known neuro-toxicant. Emerging evidence indicates it may have adverse effects on the neuro-logic and other body systems at common low levels of exposure. Impacts of MeHg exposure could vary by individual susceptibility or be confounded by bene-ficial nutrients in fish containing MeHg. Despite its global relevance, synthesis of the available literature on low-level MeHg exposure has been limited.Objectives: We undertook a synthesis of the current knowledge on the human health effects of low-level MeHg exposure to provide a basis for future research efforts, risk assessment, and exposure remediation policies worldwide.Data sources and extraction: We reviewed the published literature for original human epidemio-logic research articles that reported a direct biomarker of mercury exposure. To focus on high-quality studies and those specifically on low mercury exposure, we excluded case series, as well as studies of populations with unusually high fish consumption (e.g., the Seychelles), marine mammal consumption (e.g., the Faroe Islands, circumpolar, and other indigenous populations), or consumption of highly contaminated fish (e.g., gold-mining regions in the Amazon).Data synthesis: Recent evidence raises the possibility of effects of low-level MeHg exposure on fetal growth among susceptible subgroups and on infant growth in the first 2 years of life. Low-level effects of MeHg on neuro-logic outcomes may differ by age, sex, and timing of exposure. No clear pattern has been observed for cardio-vascular disease (CVD) risk across populations or for specific CVD end points. For the few studies evaluating immunologic effects associated with MeHg, results have been inconsistent.Conclusions: Studies targeted at identifying potential mechanisms of low-level MeHg effects and characterizing individual susceptibility, sexual dimorphism, and non-linearity in dose response would help guide future prevention, policy, and regulatory efforts surrounding MeHg exposure.

Abstract 17392: High-Sensitivity Troponin T Predicts Recurrent Cardiovascular Disease Events in Stable Coronary Heart Disease Patients: 8-Year Follow-Up of the KAROLA Study

Purpose: The clinical relevance of only slightly elevated circulating troponin levels in patients with stable coronary heart disease (CHD) several weeks after an acute event has not been fully evaluated. We aimed to assess the predictive value of a new high-sensitivity troponin T assay (hsTnT) for recurrent cardiovascular disease (CVD) events in stable CHD patients, simultaneously controlling for a large number of potential confounders. Methods: Plasma concentrations of hsTnT (Roche Elecsys 2010) were measured at baseline in a cohort of 1,050 patients aged 30-70 years with CHD. The Cox proportional hazards model was used to determine the prognostic value of hsTnT on a combined CVD endpoint after adjustment for covariates. Results: The median hsTnT level was 10.9 ng/L (IQR 5.1-18.9). Elevated hsTnT levels were associated with higher age, history of hypertension, history of diabetes, a higher number of affected vessels, initial management of CHD, and left-ventricular dysfunction. In addition as determined by 12-lead routine ECG, rhythm disorders, and anterior wall infarction were associated with higher hsTnT levels. Furthermore, hsTnT was highly correlated with NT-proBNP and cystatin C (R=0.61 and R=0.32, respectively, both p-values &lt;0.0001). During a median follow-up of 8.1 years, 150 patients (21.0%) experienced a fatal- or non-fatal secondary CVD event. In a multivariate model, hsTnT was associated with a hazard ratio (HR) for secondary CVD events of 2.83 (95% CI, 1.68-4.79) when extreme quartiles were compared. Further adjustment for cystatin C, NT-proBNP, and CRP attenuated the association only slightly (2.27; 95% CI, 1.31-3.95), p for trend &lt;0.002). ROC analysis of a clinical model which included hsTnT to a baseline model showed a modest improvement in the AUC (0.69 vs 0.67). Conclusions: Slightly elevated hsTnT levels in stable CHD patients are associated with a number of CVD disorders and predict long-term CVD events in these patients.

Abstract 16978: Midregional Pro-Atrial Natriuretic Peptide and Risk of Recurrent Cardiovascular Disease Events in Patients with Stable Coronary Heart Disease Followed Over 8 Years

Aim: Natriuretic peptides provide valuble information about cardiac dysfunction. The clinical relevance of elevated circulating midregional pro-atrial natriuretic peptide (MR-proANP) in patients with stable coronary heart disease (CHD) several weeks after an acute event has not been fully evaluated. We aimed to assess the predictive value of MR-proANP for recurrent cardiovascular disease (CVD) events in stable CHD patients, simultaneously controlling for a large number of potential confounders. Methods: Plasma concentrations of MR-proANP (BRAHMS) were measured at baseline in a cohort of 1,048 patients aged 30-70 years with CHD. The Cox proportional hazards model was used to determine the prognostic value of MR-proANP on a combined CVD endpoint after adjustment for covariates. Results: The median MR-proANP level was 135.2 pmol/L (interquartile range 95.2-185.8). Elevated MR-proANP levels were associated with higher age, obesity, history of hypertension, diabetes, and heart failure, higher number of affected vessels, initial management of CHD, and left-ventricular dysfunction in a statistically significant way. Furthermore, after adjustment for age and gender MR-proANP was correlated with CRP (correlation coefficient (R=0.21), NT-proBNP (R=0.72), creatinine clearance (R= -0.32), cystatin C (R=0.43), hsTnT (R= 0.51) respectively (all p-values &lt;0.0001). During a median follow-up of 8.1 years, 150 patients (21.1%) experienced a fatal- or non-fatal secondary CVD event. In a multivariate model MR-proANP was associated with a hazard ratio (HR) of secondary CVD events of 3.00 (95% confidence interval (CI), 1.70-5.28) when extreme quartiles were compared. Further adjustment for NT-proBNP attenuated the association only slightly (HR 2.67; 95% CI, 1.48-4.79). Conclusions: Elevated MR-proANP levels in stable CHD patients are associated with several CVD disorders and predict long-term CVD events in these patients.

Biomarkers and Heart Disease

This review will focus on the evaluation of biomarkers and surrogate endpoints in chronic disease risk with a focus on cardiovascular disease. It provides an example of how identification of relevant biomarkers might be useful in sleep research and clinical care. Much of this review is derived from work performed by the Institute of Medicine (IOM) Committee on Qualification of Biomarkers and Surrogate Endpoints in Chronic Disease (see footnote in the Acknowledgments). This discussion will review the committee charge, definitions of biomarkers and other endpoints, biomarker evaluation framework, case studies of representative biomarkers, recommendations, and conclusions.

P1-284 Variation in estimated ten-year cardiovascular risk across four risk scoring tools in both a general population sample and an occupational setting

IntroductionSeveral screening tools are now available to estimate 10-year risk of cardiovascular disease (CVD). This study aimed to quantify the differences in CVD risk estimates derived from four widely-used risk...

Predictors of heart rate variability and its prognostic significance in chronic kidney disease

Heart rate variability (HRV), a noninvasive measure of autonomic dysfunction and a risk factor for cardiovascular disease (CVD), has not been systematically studied in nondialysis chronic kidney disease (CKD). HRV was assessed using 24-h Holter monitoring in 305 subjects from the Renal Research Institute-CKD Study, a four-center prospective cohort of CKD (Stages 3-5). Multiple linear regression was used to assess predictors of HRV (both time and frequency domain) and Cox regression used to predict outcomes of CVD, composite of CVD/death and end-stage renal disease (ESRD). A total of 47 CVD, 67 ESRD and 24 death events occurred over a median follow-up of 2.7 years. Lower HRV was significantly associated with older age, female gender, diabetes, higher heart rate, C-reactive protein and phosphorus, lower serum albumin and Stage 5 CKD. Lower HRV (mostly frequency domain) was significantly associated with higher risk of CVD and the composite end point of CVD or death. Significantly, lower HRV (frequency domain) was associated with higher risk of progression to ESRD, although this effect was relatively weaker. This study draws attention to the importance of HRV as a relatively under recognized predictor of adverse cardiovascular and renal outcomes in patients with nondialysis CKD. Whether interventions that improve HRV will improve these outcomes in this high-risk population deserves further study.

Defining Left Ventricular Hypertrophy in Children on Peritoneal Dialysis

Left ventricular hypertrophy (LVH) is an important end point of dialysis-associated cardiovascular disease. The objective of this study was to evaluate the effect of different pediatric reference systems on the estimated prevalence of LVH in children on chronic peritoneal dialysis (CPD). Echocardiographic studies in 507 pediatric CPD patients from neonatal age to 19 years were collected in 55 pediatric dialysis units around the globe. We compared the prevalence of LVH on the basis of the traditional cutoff of left ventricular mass (LVM) index (>38.5 g/m(2.7)) with three novel definitions of LVH that were recently established in healthy pediatric cohorts. Application of the new reference systems eliminated the apparently increased prevalence of LVH in young children obtained by the traditional fixed LVM index cutoff currently still recommended by consensus guidelines. However, substantial differences of LVM distribution between the new reference charts resulted in a marked discrepancy in estimated LVH prevalence ranging between 27.4% and 51.7%. Although our understanding of the anthropometric determinants of heart size during childhood is improving, more consistent normative echocardiographic data from large populations of healthy children are required for cardiovascular diagnostics and research.

Lipid control in patients with diabetes mellitus

Patients with diabetes mellitus are at increased risk of cardiovascular disease (CVD). Dyslipidemia, an important component of the insulin resistance syndrome and type 2 diabetes, is strongly related to CVD risk and is open to therapeutic intervention. Statins have proved to be safe, very-well tolerated, and highly effective in reducing the levels of LDL cholesterol and apolipoprotein B. Primary and secondary CVD prevention trials have shown that use of statins leads to highly significant reductions in the incidence of major CVD events. A wealth of data on the outcomes of statin therapy is now available to guide clinical practice in the population of patients with type 2 diabetes. Statin therapy in patients with type 1 diabetes seems to have a similar benefit to that seen in patients with type 2 diabetes. However, despite statin therapy, high CVD risk persists in these populations. More-intensive statin therapy produces greater reduction in the incidence of CVD events, but a more-global approach to lipid management is likely to result in further risk reduction. After reductions in the levels of LDL cholesterol and apolipoprotein B, the next target of lipid-lowering therapy is to increase HDL-cholesterol levels, which tend to be low in patients with type 2 diabetes. The most effective HDL-cholesterol-raising agent currently available for use in clinical practice is niacin. Trials with surrogate end points have pointed to the cardiovascular benefit of adding niacin to statin therapy. Large CVD end point trials, which include many patients with diabetes, are underway to test the combination of a statin and niacin versus a statin alone.

Promotional Tone in Reviews of Menopausal Hormone Therapy After the Women's Health Initiative: An Analysis of Published Articles

Even after the Women's Health Initiative (WHI) found that the risks of menopausal hormone therapy (hormone therapy) outweighed benefit for asymptomatic women, about half of gynecologists in the United States continued to believe that hormones benefited women's health. The pharmaceutical industry has supported publication of articles in medical journals for marketing purposes. It is unknown whether author relationships with industry affect promotional tone in articles on hormone therapy. The goal of this study was to determine whether promotional tone could be identified in narrative review articles regarding menopausal hormone therapy and whether articles identified as promotional were more likely to have been authored by those with conflicts of interest with manufacturers of menopausal hormone therapy. We analyzed tone in opinion pieces on hormone therapy published in the four years after the estrogen-progestin arm of the WHI was stopped. First, we identified the ten authors with four or more MEDLINE-indexed reviews, editorials, comments, or letters on hormone replacement therapy or menopausal hormone therapy published between July 2002 and June 2006. Next, we conducted an additional search using the names of these authors to identify other relevant articles. Finally, after author names and affiliations were removed, 50 articles were evaluated by three readers for scientific accuracy and for tone. Scientific accuracy was assessed based on whether or not the findings of the WHI were accurately reported using two criteria: (1) Acknowledgment or lack of denial of the risk of breast cancer diagnosis associated with hormone therapy, and (2) acknowledgment that hormone therapy did not benefit cardiovascular disease endpoints. Determination of promotional tone was based on the assessment by each reader of whether the article appeared to promote hormone therapy. Analysis of inter-rater consistency found moderate agreement for scientific accuracy (κ=0.57) and substantial agreement for promotional tone (κ=0.65). After discussion, readers found 86% of the articles to be scientifically accurate and 64% to be promotional in tone. Themes that were common in articles considered promotional included attacks on the methodology of the WHI, arguments that clinical trial results should not guide treatment for individuals, and arguments that observational studies are as good as or better than randomized clinical trials for guiding clinical decisions. The promotional articles we identified also implied that the risks associated with hormone therapy have been exaggerated and that the benefits of hormone therapy have been or will be proven. Of the ten authors studied, eight were found to have declared payment for speaking or consulting on behalf of menopausal hormone manufacturers or for research support (seven of these eight were speakers or consultants). Thirty of 32 articles (90%) evaluated as promoting hormone therapy were authored by those with potential financial conflicts of interest, compared to 11 of 18 articles (61%) by those without such conflicts (p=0.0025). Articles promoting the use of menopausal hormone therapy were 2.41 times (95% confidence interval 1.49-4.93) as likely to have been authored by authors with conflicts of interest as by authors without conflicts of interest. In articles from three authors with conflicts of interest some of the same text was repeated word-for-word in different articles. There may be a connection between receiving industry funding for speaking, consulting, or research and the publication of promotional opinion pieces on menopausal hormone therapy.

Chlorthalidone Versus Hydrochlorothiazide as the Preferred Diuretic

See related article, pp 689–694 In this issue of Hypertension , the retrospective observational cohort analysis of the Multiple Risk Factor Intervention Trial by Dorsch et al1 adds to the growing body of evidence supporting the superiority of chlorthalidone over hydrochlorothiazide (HCTZ) as the preferred diuretic in the treatment of hypertension. In the absence of a randomized, controlled clinical end point trial directly comparing chlorthalidone and HCTZ, the data from observational cohort analysis of Dorsch et al1 is another important and convincing piece of the available data repository; this report is the first analysis of the relative impact of chlorthalidone and HCTZ on pressure-related cardiovascular disease (CVD) end points available in the published literature. Importantly, they reported a highly significant 21% lower risk of CVD among those taking chlorthalidone compared with those taking HCTZ over a median follow-up of 6 years. Although not a randomized trial, these investigators made a very credible effort to delineate the unbiased relative effect of these 2 diuretics on pressure-related CVD end points. They also examined the relative effects of chlorthalidone and HCTZ on several secondary end points, total and low-density lipoprotein cholesterol, potassium, uric acid, and glucose, with proven links to CVD. The chlorthalidone group had lower blood pressure (BP) throughout most of the study, as well as lower total and low-density lipoprotein cholesterol; however, potassium levels were lower and uric acid levels were higher in those taking chlorthalidone. Thus, some of these trends in secondary end points …

Cocoa Consumption, Cocoa Flavonoids, and Effects on Cardiovascular Risk Factors: An Evidence-Based Review

There has been considerable interest in the health effects of cocoa products. Cocoa flavonoids have especially been associated with cardiovascular disease (CVD) risk factors. We summarize the effects of total flavonoid and cocoa flavonoid consumption on CVD endpoints in observational studies and intermediate risk factors in experimental designs. From an evidence-based review, there is strong evidence that high cocoa intake lowers blood pressure, improves vascular endothelial function, and potentially increases insulin sensitivity. However, evidence does not support effects on blood lipids and body weight. Total flavonoid intake, and potentially cocoa flavonoid intake, is associated with coronary heart disease mortality in observational studies; however, there is conflicting evidence regarding the dose at which cocoa flavonoids are beneficial. Moreover, because chocolate is often nutritionally energy dense and with added sugar, considerations must be given to caloric balance and body weight. Overall, combining the multiple lines of evidence from experimental and observational studies on the effects of cocoa flavonoids and cocoa intake on cardiovascular risk factors, there is rather strong evidence supporting and demonstrating that cocoa consumption improves several important cardiovascular risk factors and likely reduces the risk of CVD, although more research is needed to further examine etiological mechanisms, demonstrate efficacy on hard clinical CVD endpoints in large-scale randomized trials, as well as carefully estimate attributable disease burden. More importantly, as intake of cocoa is inextricably linked with increased calories in chocolate consumption, further careful risk-benefit analysis is needed to assess whether consuming cocoa in the form of energy-dense chocolate products may yield a net benefit on cardiovascular risks.