Cardiovascular Disease Prevention Trials Research Articles

The Effect of Clonal Hematopoiesis of Indeterminate Potential (CHIP) and Aspirin on Clinical Outcomes in the Healthy Elderly: A Sub-Study of the Aspirin in Reducing Events in the Elderly (ASPREE) Randomized Controlled Trial

Background Clonal hematopoiesis of indeterminate potential (CHIP) increases with age and is a risk factor for blood cancer, cardiovascular disease (CVD) and other diseases. Recent experimental evidence suggests a causal link between CHIP and CVD, however it is not known whether individuals with CHIP are more likely to benefit from preventive interventions for CVD, such as low-dose aspirin. ASPREE was a double-blind, randomized, placebo-controlled trial comparing 100mg aspirin with placebo on disability-free survival (DFS, composed of death, dementia and physical disability) in initially healthy participants aged ≥70y (≥65y for US minorities of Black and Hispanic background). We measured CHIP in serial blood samples of 11,298 ASPREE participants at baseline and/or year 3 (Y3), and assessed incidence of CHIP and its association with various clinical outcomes. We also examined whether randomization to aspirin had a differential effect on clinical outcomes according to the presence of CHIP at study entry. Methods CHIP was measured in 19 CHIP-associated genes using a custom targeted amplicon-based NGS assay, designed to have a sensitivity of 0.5-2% variant allele fraction (VAF). CHIP was defined as a VAF ≥ 2%. We evaluated the association of CHIP at baseline and Y3, defined as a categorical variable (VAF< 2%, VAF 2-10%, VAF >10%), with clinical outcomes, including DFS, all-cause mortality, cancer and major adverse cardiovascular events (MACE, composed of fatal coronary heart disease, non-fatal myocardial infarction and ischemic stroke) using Y3-landmark Cox proportional hazards models. Risk factors for incident CHIP at Y3 were identified using multivariable logistic regression. Treatment heterogeneity of aspirin was assessed in CHIP subgroups overall and by the most common genes. Results CHIP was present in 3,345/9,926 (34%) participants at baseline and in 3,685/9,812 (39%) at Y3. Of the 5,612 participants without CHIP at baseline who had a Y3 sample, 1,195 (25%) developed CHIP by Y3 (incidence 7% per year). Risk factors for incident CHIP included cancer history (odds ratio [OR] (95% CI) 1.20 [1.02-1.41] P=0.031), and family history of blood cancer (OR 1.50 [1.16-1.93] P=0.002). With regards to clinical outcomes, the presence of CHIP at >10% VAF at baseline (but not VAF 2-10%) was associated with increased all-cause mortality (adjusted [aHR] [95% CI] 1.53 [1.23-1.90] P<0.001). This increased risk appeared to be driven by increased cancer-related mortality (baseline aHR 1.62, [1.19-2.22] p=0.002) more than cardiovascular-related mortality (baseline aHR 1.34 [0.84-2.12] p=0.21). CHIP at >10% at baseline and Y3 was also associated with increased risk of blood cancer (HR 2.48 [1.59-3.88] and 3.24 [1.98-5.30], both P<0.001) and other cancers at Y3 (HR 1.31 [1.02-1.68] P=0.033). After adjustment for potential confounders, this association remained significant for blood cancers (aHR 2.29 [1.44-3.62] p<0.001) but not non-blood cancers (aHR 1.21 [0.98 -1.48] P=0.07). There was no evidence of an association between CHIP at 2-10% and >10% with MACE (aHR 0.91 [0.74-1.11] P=0.34 and aHR 0.73 [0.50-1.07] P=0.11, respectively). There was no evidence of a differential effect of aspirin on DFS according to presence of CHIP at study entry (CHIP HR 0.91 [0.77-1.07], no-CHIP HR 0.88 [0.70-1.10], test for heterogeneity P=0.83) or on MACE (CHIP HR 1.23 [0.85-1.80], no-CHIP HR 0.80 [0.62-1.03] heterogeneity P=0.06) - Figure 1. There was no subgroup difference for the effect of aspirin on incident cancer or cancer-related mortality. Participants with detectable JAK2V617F (VAF > 0.5%, n=123) had worse outcomes if randomized to aspirin, including the primary outcome of DFS (Fig 1). There was no differential effect of aspirin in the JAK2V617F subgroup for MACE (Fig 1). Conclusions This is the largest primary CVD prevention trial to evaluate the intervention effect according to presence of CHIP in healthy elderly. We found CHIP at >10% VAF was associated with increased all-cause mortality, which appeared to be driven largely by increased cancer-related mortality. There was no evidence that participants with CHIP were more likely to benefit from aspirin, including for MACE. Furthermore, aspirin appeared to reduce DFS for individuals with JAK2V617F mutation, although sub-group numbers were small. Our results suggest aspirin should not be used for primary prevention in older individuals with CHIP, including JAK2V617F. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Effects of aspirin on cardiovascular outcomes in patients with chronic kidney disease

Patients with chronic kidney disease (CKD) carry a high cardiovascular (CV) risk. Since whether this risk is reduced by aspirin is unclear, we examined if the effect of aspirin on cardiovascular outcomes varied by baseline kidney function in a primary cardiovascular disease prevention trial. The International Polycap Study-3 (TIPS-3) trial had randomized people without previous cardiovascular disease to aspirin (75 mg daily) or placebo. We now examined aspirin versus placebo on cardiovascular events in participants grouped by estimated glomerular filtration rate (eGFR), using a threshold of 60 ml/min/1.73 m2, and by using tertiles of eGFR. The primary outcome was a composite of non-fatal myocardial infarction, non-fatal stroke or cardiovascular death. A total of 5712 participants were randomized with a mean follow-up of 4.6 years. Of these, 983 (17.2%) had an eGFR under 60 ml/min/1.73 m2 (mean eGFR 49 ml/min/1.73 m2) and 4,729 over 60 ml/min/1.73 m2 (mean 84 ml/min/1.73 m2). In participants with an eGFR under 60 ml/min/1.73 m2 there were 26 primary outcomes in 502 participants on aspirin and 39/481 on placebo (hazard ratio 0.57; 95% confidence interval 0.34-0.94). In participants with an eGFR over 60 ml/min/1.73 m2 there were 90 primary outcomes in 2357 participants on aspirin and 95/2372 on placebo (0.95; 0.71-1.27). With tertiles of eGFR under 70, 70-90, and over 90 ml/min/1.73 m2, risk reductions with aspirin for the primary outcome were larger at lower eGFR levels (0.62; 0.43-0.91) for the lowest tertile, (0.96; 0.62-1.49) for the middle, and (1.30; 0.77-2.18) for the highest tertile. Thus, our findings support aspirin may reduce cardiovascular events in people with moderate to advanced stage CKD.

Asymptomatic SARS-CoV-2 Infection Is Common Among ART-Treated People With HIV.

Limited data are available regarding asymptomatic COVID-19 among people with HIV (PWH). Data on a representative subset of PWH enrolled in Randomized Trial to Prevent Vascular Events in HIV, a global clinical trial, are presented here. Randomized Trial to Prevent Vascular Events in HIV is an atherosclerotic cardiovascular disease prevention trial among 7770 PWH on antiretroviral therapy. Beginning April 2020, targeted data on coronavirus disease 2019 (COVID-19) diagnosis and symptoms were collected during routine trial visits. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection was defined as either COVID-19 clinical diagnosis or presence of SARS-CoV-2 Immunoglobulin G (IgG) or Immunoglobulin A (IgA) receptor binding domain protein (antispike) antibodies in the absence of prior COVID-19 vaccine. The group (N = 2464) had a median age 53 years, 35% female sex, 47% Black or African American race, median CD4 count 649 c/mm 3 , and 97% with HIV VL <400 cp/m. SARS-CoV-2 infection occurred in 318 persons (13%): 58 with clinical diagnosis and 260 with detectable antibodies. Of these PWH, 304 completed symptom questionnaires: 121 (40%) reported symptoms, but 183 (60%) were asymptomatic. PWH with asymptomatic SARS-CoV-2 infection were more likely to be from low-income or middle-income regions, of Black or African American race, older in age, and with higher atherosclerotic cardiovascular disease risk score. Symptomatic COVID was more common with obesity, metabolic syndrome, and low HDL levels. CD4 counts and HIV viral suppression rates were similar among PWH with symptomatic vs. asymptomatic COVID. Asymptomatic SARS-CoV-2 infection is common among antiretroviral therapy-treated PWH globally. We determined that 60% of infections in PWH were asymptomatic. HIV clinicians must remain vigilant about COVID-19 testing among PWH to identify asymptomatic cases.

Strategies to alter the trajectory of atherosclerotic cardiovascular disease.

Cardiovascular disease prevention trials of lipid lowering with statins have shown unexpected long-term benefits after the formal randomized treatment stopped. This finding needs further exploration because it raises the possibility that the trajectory of the disease can be modified. Extended follow up data are now available from further major primary prevention studies and from meta-analyses of the legacy effect of statin trials. New outcome studies have been proposed and launched to test the ability of early intervention to slow or regress atherosclerosis. Legacy effects are apparent in trials of LDL lowering in hypercholesterolemic and hypertensive patient cohorts. Over follow up periods of decades, both cardiovascular mortality and all-cause mortality are reduced in individuals who received 3 to 5 years of statin therapy. The phenomenon is observed also in studies of intensive glycemic control suggesting that it is possible to impact plaque development with long-term beneficial consequences. Novel strategies for primary prevention are being devised that include the early use of both prolonged-moderate and short-term aggressive LDL lowering.

Rationale and design of a nurse-led intervention to extend the HIV treatment cascade for cardiovascular disease prevention trial (EXTRA-CVD)

Persons living with human immunodeficiency virus (PLHIV) are at increased risk of atherosclerotic cardiovascular disease (ASCVD). In spite of this, uptake of evidence-based clinical interventions for ASCVD risk reduction in the HIV clinic setting is sub-optimal. METHODS: EXTRA-CVD is a 12-month randomized clinical effectiveness trial that will assess the efficacy of a multi-component nurse-led intervention in reducing ASCVD risk among PLHIV. Three hundred high ASCVD risk PLHIV across three sites will be randomized 1:1 to usual care with generic prevention education or the study intervention. The study intervention will consist of four evidence-based components: (1) nurse-led care coordination, (2) nurse-managed medication protocols and adherence support (3) home BP monitoring, and (4) electronic health records support tools. The primary outcome will be change in systolic blood pressure and secondary outcome will be change in non-HDL cholesterol over the course of the intervention. Tertiary outcomes will include change in the proportion of participants in the following extended cascade categories: (1) appropriately diagnosed with hypertension and hyperlipidemia (2) appropriately managed; (3) at treatment goal (systolic blood pressure <130 mm Hg and non-HDL cholesterol < National Lipid Association targets). CONCLUSIONS: The EXTRA-CVD trial will provide evidence appraising the potential impact of nurse-led interventions in reducing ASCVD risk among PLHIV, an essential extension of the HIV care continuum beyond HIV viral suppression.

The Modern Randomized Clinical Trial: Is it Time to Sharpen a Blunt Instrument?

Abstract In spite of the obvious differences in the diseases under study, designs of trials of prevention of HIV and cardiovascular disease share some common features. A trial of prevention should identify a population at risk for the disease; it should have a clearly defined, clinically important, outcome; it should be large enough to have sufficient power to detect an effect of public health importance; and participants should be followed long enough for the effect of the intervention to become manifest (but the trial should not take so long as to render the intervention no longer of interest). Many cardiovascular prevention studies have been large, simple, randomized trials leading to easily interpretable results. This paper urges that designers of trials of HIV prevention should consider mimicking the strategies used in cardiovascular disease prevention trials: focus on a clear inferential path to the question being asked while limiting unnecessary data collection, auditing, and complexity. Finally, showing benefit in a trial is only the first step in reducing the burden of disease: aggressive, effective efforts at educating the population at risk so they will implement the intervention is essential to improvement in public health.

Abstract MP42: Association of Taste Perception for Sweet, Salt, Sour, Bitter and Umami With Fruit and Vegetable Intake Among Community-dwelling Men and Women in the PREDIMED-PLUS Trial

Introduction: Emerging evidence suggests that differences in the ability to perceive individual tastes; sweet, salt, sour, bitter and umami, may influence food intake - amount and variety, thereby influencing diet quality, energy balance and cardiometabolic disorders. Objective: To explore the relationship between perception of each taste and intake of different categories of fruits and vegetables. We hypothesized that greater perception of each taste will be inversely associated with amount consumed. Methods: A cross-sectional analysis was performed on baseline data from participants (N=379) in the University of Valencia center of the PREDIMED-PLUS Clinical Trial; a multi-center weight-loss primary prevention trial of cardiovascular disease, among community-dwelling adults in Spain aged 55-75y diagnosed with metabolic syndrome. Taste perception was determined by challenging subjects with solutions of standard tastants representing sweet, salt, sour, bitter, and umami (400 mM sucrose, 200 mM NaCl, 34 mM citric acid, 5.6 mM phenylthiocarbamide [PTC], 200 mM monopotassium glutamate, respectively). Taste perception intensities were evaluated on a 0-5 scale. Food intake was assessed using a validated food frequency questionnaire. Outcomes included fruit and vegetable intake (servings/week), total and sub-groups (citrus and non-citrus fruits; cruciferous and non-cruciferous vegetables). Multivariable linear regression models were used to assess relationships between perception of each tastant and number of servings/week consumed, for total and square root-transformed sub-groups. Results: In the fully-adjusted models, controlling for sex, age, diabetes, smoking status, daily physical activity and weekly energy intake, there were inverse associations between sweet perception and intake of citrus fruit (β=-0.5; p&lt;0.01) and total vegetables (β=-1.1; 95% CI [-2.0, -0.2]), particularly non-cruciferous vegetables (β=-1.0; p=0.02); and positive associations between salt perception and intake of total fruit (β=0.9; 95% CI [0.02, 1.7]), particularly non-citrus fruit (β=0.6; p=0.03), sour perception and intake of cruciferous vegetables (β=0.1; p=0.04) and umami perception and intake of non-cruciferous vegetables (β=0.7; p=0.04). No significant associations were observed between bitter taste perception and fruit or vegetable intake. Conclusion: This marks the first exploration of taste perception as a determinant of fruit and vegetable intake among community-dwelling adults. Perception for each tastant differentially affected the amount and type of fruits and vegetables consumed, with sweet, salt, sour and umami perception emerging as significant predictors. These findings support a role of taste perception in guiding the amount and type of foods consumed, albeit in a more complex manner than originally hypothesized.

Follow YOUR Heart: development of an evidence-based campaign empowering older women with HIV to participate in a large-scale cardiovascular disease prevention trial

Background: Women’s under-representation in HIV and cardiovascular disease (CVD) research suggests a need for novel strategies to ensure robust representation of women in HIV-associated CVD research.Objective: To elicit perspectives on CVD research participation among a community-sample of women with or at risk for HIV, and to apply acquired insights toward the development of an evidence-based campaign empowering older women with HIV to participate in a large-scale CVD prevention trial.Methods: In a community-based setting, we surveyed 40 women with or at risk for HIV about factors which might facilitate or impede engagement in CVD research. We applied insights derived from these surveys into the development of the Follow YOUR Heart campaign, educating women about HIV-associated CVD and empowering them to learn more about a multi-site HIV-associated CVD prevention trial: REPRIEVE.Results: Endorsed best methods for learning about a CVD research study included peer-to-peer communication (54%), provider communication (46%) and video-based communication (39%). Top endorsed non-monetary reasons for participating in research related to gaining information (63%) and helping others (47%). Top endorsed reasons for not participating related to lack of knowledge about studies (29%) and lack of request to participate (29%). Based on survey results, the REPRIEVE Follow YOUR Heart campaign was developed. Interwoven campaign components (print materials, video, web presence) offer provider-based information/knowledge, peer-to-peer communication, and empowerment to learn more. Campaign components reflect women’s self-identified motivations for research participation – education and altruism.Conclusions: Investigation of factors influencing women’s participation in HIV-associated CVD research may be usefully applied to develop evidence-based strategies for enhancing women’s enrollment in disease-specific large-scale trials. If proven efficacious, such strategies may enhance conduct of large-scale research studies across disciplines.

Aspirin for the Prevention of Cancer Incidence and Mortality: Systematic Evidence Reviews for the U.S. Preventive Services Task Force.

Cancer is the second leading cause of death in the United States. To conduct systematic reviews of aspirin and 1) total cancer mortality and incidence in persons eligible for primary prevention of cardiovascular disease (CVD) and 2) colorectal cancer (CRC) mortality and incidence in persons at average CRC risk. MEDLINE, PubMed, and the Cochrane Central Register of Controlled Trials through January 2015 and relevant references from other reviews. Trials comparing oral aspirin versus placebo or no treatment in adults aged 40 years or older were included. Two investigators independently reviewed abstracts and articles against inclusion and quality criteria. Data from 20 good- or fair-quality trials were abstracted by one reviewer and checked by another. In CVD primary prevention trials, cancer mortality (relative risk [RR], 0.96 [95% CI, 0.87 to 1.06]) (10 trials; n= 103787) and incidence (RR, 0.98 [CI, 0.93 to 1.04]) (6 trials; n= 72926) were similar in aspirin and control groups over 3.6 to 10.1 years. In CVD primary and secondary prevention trials, 20-year CRC mortality was reduced among persons assigned to aspirin therapy (RR, 0.67 [CI, 0.52 to 0.86]) (4 trials; n= 14033). Aspirin appeared to reduce CRC incidence beginning 10 to 19 years after initiation (RR, 0.60 [CI, 0.47 to 0.76]) (3 trials; n= 47464). Most data were from clinically and methodologically heterogeneous CVD prevention trials. Outcome assessment and follow-up length varied across studies. Data on non-CRC cancer types and subgroups were limited. In CVD primary prevention populations, aspirin's effect on total cancer mortality and incidence was not clearly established. Evidence from CVD primary and secondary prevention studies suggested that aspirin therapy reduces CRC incidence and perhaps mortality approximately 10 years after initiation. Agency for Healthcare Research and Quality.

Effect of long-term supplementation with folic acid and B vitamins on risk of depression in older women.

Homocysteine-lowering nutrients may have preventive/ameliorative roles in depression. To test whether long-term B-vitamin/folate supplementation reduces depression risk. Participants were 4331 women (mean age 63.6 years), without prior depression, from the Women's Antioxidant and Folic Acid Cardiovascular Study - a randomised controlled trial of cardiovascular disease prevention among 5442 women. Participants were randomly assigned to receive a combination of folic acid (2.5 mg/d), vitamin B6 (50 mg/d) and vitamin B12 (1 mg/d) or a matching placebo. Average treatment duration was 7 years. The outcome was incident depression, defined as self-reported physician/clinician-diagnosed depression or clinically significant depressive symptoms. There were 524 incident cases. There was no difference between active v. placebo groups in depression risk (adjusted relative risk 1.02, 95% CI 0.86-1.21, P = 0.81), despite significant homocysteine level reduction. Long-term, high-dose, daily supplementation with folic acid and vitamins B6 and B12 did not reduce overall depression risk in mid-life and older women.

Factors influencing participation in a vascular disease prevention lifestyle program among participants in a cluster randomized trial

BackgroundPrevious research suggests that lifestyle intervention for the prevention of diabetes and cardiovascular disease (CVD) are effective, however little is known about factors affecting participation in such programs. This study aims to explore factors influencing levels of participation in a lifestyle modification program conducted as part of a cluster randomized controlled trial of CVD prevention in primary care.MethodsThis concurrent mixed methods study used data from the intervention arm of a cluster RCT which recruited 30 practices through two rural and three urban primary care organizations. Practices were randomly allocated to intervention (n = 16) and control (n = 14) groups. In each practice up to 160 eligible patients aged between 40 and 64 years old, were invited to participate. Intervention practice staff were trained in lifestyle assessment and counseling and referred high risk patients to a lifestyle modification program (LMP) consisting of two individual and six group sessions over a nine month period. Data included a patient survey, clinical audit, practice survey on capacity for preventive care, referral and attendance records at the LMP and qualitative interviews with Intervention Officers facilitating the LMP. Multi-level logistic regression modelling was used to examine independent predictors of attendance at the LMP, supplemented with qualitative data from interviews with Intervention Officers facilitating the program.ResultsA total of 197 individuals were referred to the LMP (63% of those eligible). Over a third of patients (36.5%) referred to the LMP did not attend any sessions, with 59.4% attending at least half of the planned sessions. The only independent predictors of attendance at the program were employment status - not working (OR: 2.39 95% CI 1.15-4.94) and having high psychological distress (OR: 2.17 95% CI: 1.10-4.30). Qualitative data revealed that physical access to the program was a barrier, while GP/practice endorsement of the program and flexibility in program delivery facilitated attendance.ConclusionBarriers to attendance at a LMP for CVD prevention related mainly to external factors including work commitments and poor physical access to the programs rather than an individuals’ health risk profile or readiness to change. Improving physical access and offering flexibility in program delivery may enhance future attendance. Finally, associations between psychological distress and attendance rates warrant further investigation.Trial registrationACTRN12607000423415

Vascular Protection in People with Diabetes

Vascular Protection in People with Diabetes

Does early intensive multifactorial treatment reduce total cardiovascular burden in individuals with screen-detected diabetes? Findings from the ADDITION-Europe cluster-randomized trial.

AimsTo describe the total cardiovascular burden (cardiovascular morbidity or mortality, revascularization or non-traumatic amputation) in individuals with screen-detected diabetes in the ADDITION-Europe trial and to quantify the impact of the intervention on multiple cardiovascular events over 5 years.MethodsIn a pragmatic, cluster-randomized, parallel-group trial in four centres (Denmark; Cambridge, UK; the Netherlands; and Leicester, UK), 343 general practices were randomized to screening plus routine care (n = 1379 patients), or screening and promotion of target-driven, intensive treatment of multiple risk factors (n = 1678). We estimated the effect of the intervention on multiple cardiovascular events after diagnosis of diabetes using the Wei, Lin and Weissfeld method.ResultsOver 5.3 years, 167 individuals had exactly one cardiovascular event, 53 exactly two events, and 18 three or more events. The incidence rates (95% CI) of first events and any event per 1000 person-years were 14.6 (12.8–16.6) and 20.4 (18.2–22.6), respectively. There were non-significant reductions in the risk of a first (hazard ratio 0.83, 95% CI 0.65–1.05) and second primary endpoint (hazard ratio 0.70, 95% CI 0.43–1.12). The overall average hazard ratio for any event was 0.77 (95% CI 0.58–1.02).ConclusionsEarly intensive multifactorial treatment was not associated with a significant reduction in total cardiovascular burden at 5 years. Focusing on first events in cardiovascular disease prevention trials underestimates the total cardiovascular burden to patients and the health service.

Aspirin in the Chemoprevention of Colorectal Neoplasia: An Overview

Considerable evidence supports the effectiveness of aspirin for chemoprevention of colorectal cancer (CRC) in addition to its well-established benefits in the prevention of vascular disease. Epidemiologic studies have consistently observed an inverse association between aspirin use and risk of CRC. A recent pooled analysis of a long-term posttrial follow-up of nearly 14,000 patients from four randomized, cardiovascular disease prevention trials showed that daily aspirin treatment for about five years was associated with a 34% reduction in 20-year CRC mortality. A separate metaanalysis of nearly 3,000 patients with a history of colorectal adenoma or cancer in four randomized adenoma prevention trials showed that aspirin reduced the occurrence of advanced adenomas by 28% and any adenoma by 17%. Aspirin has also been shown to be beneficial in a clinical trial of patients with Lynch syndrome, a hereditary CRC syndrome; in those treated with aspirin for at least two years, there was a 50% or more reduction in the risk of CRC commencing five years after randomization and after aspirin had been discontinued. A few observational studies have shown an increase in survival among patients with CRC who use aspirin. Taken together, these findings strengthen the case for consideration of long-term aspirin use in CRC prevention. Despite these compelling data, there is a lack of consensus about the balance of risks and benefits associated with long-term aspirin use, particularly in low-risk populations. The optimal dose to use for cancer prevention and the precise mechanism underlying aspirin's anticancer effect require further investigation.

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.

Dysglycemia and Cardiovascular Risk in the General Population

Diabetes is a metabolic disorder that is diagnosed when the fasting and/or postload glucose level rises above well-established thresholds. These thresholds were chosen because they identified people at particularly high risk for retinopathy based on epidemiological data. These data also have shown that people with diabetes and poorly controlled glucose levels have higher risks of retinopathy than people with diabetes and well-controlled glucose levels.1,2 Moreover, recent studies have shown that the relationship between chronically elevated glucose levels (as measured by A1c) and retinal disease is not confined to people with diabetes and is apparent (although less marked) in people with high glucose levels that are below the diabetes cutoffs such as those with impaired glucose tolerance and/or impaired fasting glucose.3–5 Thus, there is a progressive relationship between glycemia and retinopathy that extends below glucose thresholds for diabetes. Article p 812 Clearly, diabetes also is a risk factor for many other serious chronic diseases, including cardiovascular disease.6 Indeed, a recent meta-analysis of large prospective studies comprising 450 000 people showed that men and women with diabetes are 2 and 3 times more likely, respectively, to die of coronary heart disease than men and women without diabetes.7 Other studies have shown that the degree of glucose elevation measured by A1c, fasting glucose, or postload glucose is progressively related to the incidence of cardiovascular outcomes in people with established diabetes and in people without diabetes after adjustment for age and varying numbers of other risk factors.8–15 Moreover, several studies that recruited people from both ambulatory and hospitalized settings suggest that there may be a stronger relationship between glycemia and incident cardiovascular outcomes in people without diabetes than in people with diabetes.8,9,15–17 Such a discrepancy may occur because in people with established diabetes, markers of …

Thiazide-type diuretics and beta-adrenergic blockers as first-line drug treatments for hypertension.

Systemic arterial hypertension affects 72 million US adults and an additional hundreds of millions of persons worldwide.1,2 Most of these are candidates for pharmacological treatment to reduce risk of cardiovascular disease (CVD) events, based primarily on a very large body of epidemiological and intervention research in humans. Because of this high prevalence and the cardiovascular consequences of untreated or inadequately treated hypertension, the selection of drugs for initial and continuing, long-term treatment has large public health and economic implications. Fortunately, such decisions and the expert recommendations that seek to guide them can call on evidence from 4 decades of randomized multicenter clinical trials evaluating effects of treatment on clinical CVD. We summarize that evidence in this article, in approximate chronological order, and we comment on the related treatment guidelines. We close with some of the major clinical questions yet to be resolved. Response by Messerli et al p 2705 Before the current era beginning in the early 1990s of emphasis on positive-control trials, which directly compare different drug regimens, there were 3 decades of trials that compared an active regimen with placebo or, in a few cases, “usual care.” For most of this period, the mainstay of treatment was generally a thiazide-type diuretic (hereinafter called thiazides) or, to a lesser extent, a β-adrenergic blocker (termed β-blockers). With few exceptions, these trials, especially those with high statistical power and thiazide-based regimens, showed benefit for CVD outcomes.3–8 This evidence, which provided a basis for recommending thiazides or β-blockers as first-step drugs in most editions of US guidelines through 1997,9 needs to continue to be given due weight in practice and practice guidelines. The largest and most consistent benefits from the earlier trials were for stroke and (where reported) heart failure. Benefits for coronary heart disease (CHD) were less clear, …

Rationale, design, and baseline characteristics for a large international trial of cardiovascular disease prevention in people with dysglycemia: The ORIGIN Trial (Outcome Reduction with an Initial Glargine Intervention)

Impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and diabetes arise due to insufficient insulin secretion and are risk factors for cardiovascular (CV) events. Thus, targeting normal fasting glucose levels with insulin may reduce CV events. Previous studies suggest that omega-3 fatty acid supplements may reduce CV death; however, their effect in high-risk dysglycemic individuals is not known. People aged > or = 50 years with evidence of CV disease and with IFG, IGT, newly detected or established diabetes (on 0 or 1 oral agent), and a local glycated hemoglobin < 150% of the upper limit of normal for that assay were recruited and allocated to (a) either 1 daily injection of insulin glargine with the dose titrated to achieve a fasting plasma glucose < or = 5.3 mmol/L (95 mg/dL), or standard glycemic care; and (b) either omega-3-acid ethyl esters 90 (1 g consisting of EPA 465 mg and DHA 375 mg) or identical placebo, according to a 2 x 2 factorial design. The 2 different primary outcomes for the insulin and omega-3 fatty acid arms are CV events and CV death, respectively. A total of 12,612 (mean age 64, 35% women) people in 40 countries were randomized during a 2-year period ending December 2005. Eighty-two percent had established diabetes, 6% had new diabetes, and 12% had IGT or IFG; the mean fasting plasma glucose was 7.3 mmol/L (131 mg/dL). The ORIGIN trial will determine whether or not either or both of these interventions can reduce CV events.

Primary prevention of cardiovascular diseases among hypercholesterolemic Japanese with a low dose of pravastatin

The MEGA Study was Japan's first primary prevention trial of cardiovascular disease (CVD) by cholesterol lowering with low-dose pravastatin. Included were postmenopausal women aged < or =70 years and men aged 40-70 years with mildly elevated total cholesterol (TC) level 220-270 mg/dL. In all, 8214 outpatients were randomly assigned to receive diet alone or diet plus pravastatin 10-20mg/day for an average follow-up of 5.3 years. The primary endpoint was a composite of fatal and nonfatal MI, angina, cardiac and sudden death, and coronary revascularization. TC was reduced by 11.5% in the diet plus pravastatin group versus 2.1% in the diet alone group. LDL-C was reduced by 18% and 3.2% in the two groups, respectively. TC was reduced to <220 mg/dL and LDL-C to <130 mg/dL in patients in the diet plus pravastatin group. There was a significant 33% reduction of the primary endpoint in the diet plus pravastatin group compared with the diet alone group. Notable findings of the MEGA Study included the observation that despite pravastatin's modest LDL-C reductions in this low-risk population, a 33% reduction of CHD events was achieved. Even though 68% of patients were women, who have been traditionally considered at less risk than men, significant CHD risk reduction was observed across all groups.

Identifying and Attaining LDL-C Goals: Mission Accomplished? Next Target: New Therapeutic Options to Raise HDL-C Levels

Currently, low density lipoprotein cholesterol (LDL-C) levels are the main, if not the only, lipid target in the effort to reduce cardiovascular disease (CVD) morbidity and mortality. Several primary and secondary CVD prevention trials with statins shaped current guidelines and provided detailed targets across a range of CVD risk categories. These targets can be attained using effective statins or combination therapy. However, the net benefit in CVD risk reduction may be improved if we address other lipid risk factors. High density lipoprotein cholesterol (HDL-C) emerges from epidemiological studies as the most promising target. This review links the increase in HDL-C levels with clinical benefit from "old" (e.g. sustained release niacin) and new treatment options. Synthetically produced recombined apolipoprotein A-I Milano administered intravenously seems to have a marked effect in reducing the atheroma burden. The anti-cholesterol ester transfer protein (CETP) vaccine (CETi-1) produces auto-antibodies against CETP thus increasing the cholesterol ester content in HDL particles. CETP inhibitors (e.g. JTT-705 and torcetrapib) seem to be the most promising regimen to increase HDL-C levels. Torcetrapib (already in phase IIIa studies) can substantially increase HDL-C levels (up to 106%), alone or in combination with atorvastatin. HDL-C strategies, in combination with effective statins, are a new drug target aimed at a further reduction in CVD morbidity and mortality compared with statin monotherapy.