Aggressive lipid management for cardiovascular prevention: evidence from clinical trials

Epidemiologic evidence shows that elevated serum cholesterol, specifically low-density lipoprotein cholesterol (LDL-C), increases the risk of coronary heart disease (CHD). Moreover, large-scale intervention trials demonstrate that treatment with HMG-CoA reductase inhibitors (statins), the most effective drug class for lowering LDL-C, significantly reduces the risk of CHD events. Unfortunately, only a moderate percentage of hypercholesterolemic patients are achieving LDL-C targets specified by the National Cholesterol Education Program (NCEP), in part because clinicians are not effectively titrating medications as needed to achieve LDL-C goals. Recent evidence suggests that more aggressive LDL-C lowering may provide greater clinical benefit, even in individuals with moderately elevated serum cholesterol levels. Furthermore, recent studies suggest that statins have cardioprotective effects in many high-risk individuals, including those with baseline LDL-C <100 mg/dl. High-density lipoprotein cholesterol (HDL-C) was recognized by the NCEP-Adult Treatment Panel II (ATP II) as a negative risk factor for CHD. The NCEP-ATP III guidelines have also reaffirmed the importance of HDL-C by increasing the low HDL-C designation from <35 to <40 mg/dl as a major risk factor for CHD. Similarly, triglyceride control will play a larger role in dyslipidemia management. As more clinicians effectively treat adverse lipid and lipoprotein cardiovascular risk factors, patients will likely benefit from reductions in cardiovascular events.     

Risk factor control in secondary prevention of cardiovascular disease: results from the multi-ethnic HELIUS study

Objective

To evaluate the quality of contemporary secondary prevention of cardiovascular disease (CVD), and the differences between six ethnic groups in a large, observational cohort.

Design

We included participants with a self-reported history of CVD from the HEalthy LIfe in an Urban Setting (HELIUS) study, which investigates inequalities in health between six ethnic groups living in Amsterdam, the Netherlands. We quantified the proportions of patients who were at the preventive treatment goal according to the guidelines of the European Society of Cardiology for six risk factors: hypertension, dyslipidaemia, smoking, overweight, physical inactivity and diabetes mellitus, and the use preventive medication.

Results

Of 22,165 participants, 1163 (5%) reported a history of CVD. Mean age was 54 years. Overall, 69% had a systolic blood pressure of <140?mm?Hg, and 42% had a low-density lipoprotein (LDL) cholesterol of <2.5?mmol/l. Non-smoking was found in 67%. Body mass index (BMI) <25?kg/m² was found in 24%, and 54% reported adequate physical activity. The mean number of risk factors per patient was three (±1.1) out of six, and only 2% had all risk factors on target. Across the ethnic groups, non-smoking was more prevalent in the Ghanaian and Moroccan groups than in the Dutch (p < 0.001 and p = 0.001, respectively); BMI <25?kg/m² and adequate physical activity were less prevalent among all ethnic minority groups compared with the Dutch group.

Conclusion

We found large treatment gaps in secondary prevention of CVD. Ethnic differences in risk factors were found; however, strategies to improve overall risk factor management may be mandated before designing ethnic-specific strategies.

     

The role of folic acid in the prevention of cardiovascular disease

Coronary heart disease is the leading cause of death in the developed world. Current surgical and pharmacological interventions are essentially palliative and interest in preventive strategies, particularly through nutrition and avoidance of tobacco has increased in recent years. Basic scientific, clinical and epidemiological evidence indicates a positive association between the plasma level of the amino acid homocysteine and vascular disease. Homocysteine levels are inversely related to both intake and plasma levels of folate. Less strong evidence indicates an inverse relationship between folate intake and coronary heart disease risk. It is likely that current estimates of dietary folate requirements are lower than optimal. Folic acid supplementation reliably reduces homocysteine levels, and may also modify endothelial function independent of this effect on homocysteine. Such treatment is cheap and appears to be essentially free of risk. However, until present randomised control trials are complete, it will not be known definitively whether or not increasing folate intake reduces cardiovascular risk.     

Naturopathic medicine for the prevention of cardiovascular disease: a randomized clinical trial

Background:Although cardiovascular disease may be partially preventable through dietary and lifestyle-based interventions, few individuals at risk receive intensive dietary and lifestyle counselling. We performed a randomized controlled trial to evaluate the effectiveness of naturopathic care in reducing the risk of cardiovascular disease.Methods:We performed a multisite randomized controlled trial of enhanced usual care (usual care plus biometric measurement; control) compared with enhanced usual care plus naturopathic care (hereafter called naturopathic care). Postal workers aged 25–65 years in Toronto, Vancouver and Edmonton, Canada, with an increased risk of cardiovascular disease were invited to participate. Participants in both groups received care by their family physicians. Those in the naturopathic group also received individualized care (health promotion counselling, nutritional medicine or dietary supplementation) at 7 preset times in work-site clinics by licensed naturopathic doctors. The body weight, waist circumference, lipid profile, fasting glucose levels and blood pressure of participants in both groups were measured 3 times during a 1-year period. Our primary outcomes were the 10-year risk of having a cardiovascular event (based on the Framingham risk algorithm) and the prevalence of metabolic syndrome (based on the Adult Treatment Panel III diagnostic criteria).Results:Of 246 participants randomly assigned to a study group, 207 completed the study. The characteristics of participants in both groups were similar at baseline. Compared with participants in the control group, at 52 weeks those in the naturopathic group had a reduced adjusted 10-year cardiovascular risk (control: 10.81%; naturopathic group: 7.74%; risk reduction −3.07% [95% confidence interval (CI) −4.35% to −1.78%], p < 0.001) and a lower adjusted frequency of metabolic syndrome (control group: 48.48%; naturopathic care: 31.58%; risk reduction −16.90% [95% CI −29.55% to −4.25%], p = 0.002).Interpretation:Our findings support the hypothesis that the addition of naturopathic care to enhanced usual care may reduce the risk of cardiovascular disease among those at high risk. Trial registration: ClinicalTrials.gov, no. NCT0071879.Cardiovascular disease is the second leading cause of death in Canada.¹ Observational studies, including a large international case–control study, have shown that several modifiable behavioural factors contribute to the risk of cardiovascular disease.² Metabolic syndrome, a cluster of modifiable risk factors for atherosclerotic cardiovascular disease, is strongly associated with increased risk of cardiovascular-related mortality.^3,4 Guidelines by the American Heart Association and the United States Preventive Services Task Force recommend lifestyle interventions as an important part of cardiovascular disease prevention.^5,6 Although the importance of lifestyle intervention is widely recognized, few individuals with, or at risk of, cardiovascular disease receive intensive dietary and lifestyle counselling.^7,8A variety of health care practitioners routinely deliver diet and health promotion advice to patients at risk of cardiovascular disease. Naturopathic doctors in North America are trained and regulated practitioners who emphasize this form of self-directed care. Several retrospective analyses have suggested that patients at risk of cardiovascular disease receive lifestyle counselling routinely as part of naturopathic care.^9–11 However, no rigorous studies have examined the effectiveness of these approaches. To evaluate the effectiveness of representative naturopathic approaches to reducing the risk of cardiovascular disease, we conducted a randomized clinical trial of a multimodality nutritional and physical activity intervention in a workplace setting.     

Biventricular pacing in heart failure: update on results from clinical trials

Biventricular pacing or resynchronisation therapy is a non-pharmacological therapy for patients with chronic heart failure. Since being originally described in 1994, biventricular pacing has become a subject of intense interest and investigation. This review analyses the results reported in observational series and randomised trials, and seeks to answer two questions. If it works, why does it work? Which heart failure patients will it benefit?     

Limited accessibility to designs and results of Japanese large-scale clinical trials for cardiovascular diseases

Background

We aimed to make individual patient data from the International Stroke Trial (IST), one of the largest randomised trials ever conducted in acute stroke, available for public use, to facilitate the planning of future trials and to permit additional secondary analyses.

Methods

For each randomised patient, we have extracted data on the variables assessed at randomisation, at the early outcome point (14-days after randomisation or prior discharge) and at 6-months and provide them as an analysable database.

Results

The IST dataset includes data on 19 435 patients with acute stroke, with 99% complete follow-up. Over 26.4% patients were aged over 80 years at study entry. Background stroke care was limited and none of the patients received thrombolytic therapy.

Conclusions

The IST dataset provides a source of primary data which could be used for planning further trials, for sample size calculations and for novel secondary analyses. Given the age distribution and nature of the background treatment given, the data may be of value in planning trials in older patients and in resource-poor settings.     

Relapse prevention in schizophrenia: evidence from longterm, randomized, double-blind clinical trials

Fourteen long-term (duration at least 26 months) double-blind, randomized studies comparing second-generation antipsychotics (SGAs) with placebo, conventional antipsychotics, or two or more SGAs, published after 2002 have been reviewed and are summarized in this chapter. Methodological problems and factors influencing results such as patient populations involved, outcome criteria, and dosages of evaluated drugs are discussed.     

High-density lipoproteins： an emerging target in the prevention of cardiovascular disease

High-density lipoproteins （HDLs） have been well established to protect against the development of atherosclerotic cardiovascular disease. It has become apparent that in addition to the promotion of reverse cholesterol transport, HDLs possess a number of additional functional properties that may contribute to their beneficial influence on the arterial wall. A number of exciting therapeutic strategies have been developed that target HDL and its ability to protect against the development of atherosclerotic plaque. This paper will review how the promotion of the functional properties of HDL inhibits the formation of atherosclerotic plaque and stabilises lesions in patients with established disease.     

Beta emitter systems and results from clinical trials. state of the art

Vascular brachytherapy has been established as the standard of care for the treatment of in-stent restenosis (ISR). Both beta and gamma emitters are currently in use for the prevention of ISR recurrence. The use of beta sources for vascular application is attractive from both the radiation exposure and safety points of view, and a wide variety of beta sources are available for this application. This review is intended to summarize the clinical trials utilizing beta emitter systems for the treatment of ISR and de novo lesions and their subsequent results.     

Statin therapy for prevention and treatment of acute and chronic cardiovascular disease: update on recent trials and metaanalyses

PURPOSE OF REVIEW: To summarize the evidence from recent clinical trials and metaanalyses on the efficacy of statin therapy to reduce death, myocardial infarction and stroke, and to review the effects of statins in patients with low LDL cholesterol, diabetes, end-stage renal disease, and acute coronary syndrome. RECENT FINDINGS: In large metaanalyses of randomized controlled trials relative risk reductions from statins compared with placebo for patients with manifest or with risk factors for coronary artery disease were 13% for overall mortality, 26% for fatal and nonfatal myocardial infarction, and 18% for fatal and nonfatal stroke. Evidence from large trials suggests that patients with type II diabetes compared with patients without diabetes have similar risk reductions from statins for cardiovascular events, but this benefit is not seen in patients with diabetes and end-stage renal disease. In patients with acute coronary syndrome, early treatment with high-dose atorvastatin reduces cardiovascular morbidity after the first 4 months following the event, but the impact on mortality endpoints remains less clear. Results from recent trials in patients with stable coronary artery disease or type II diabetes suggest that statins provide benefit at considerable low LDL cholesterol levels. Therefore, target values for LDL cholesterol of less than 1.8 mmol/l (<70 mg/dl) should be considered for all patients with coronary artery disease or equivalent coronary risk. SUMMARY: For patients at high risk of coronary artery disease there is growing evidence for the concept of 'the lower, the better' regarding LDL cholesterol levels. Ongoing trials are further investigating the safety of lower target values in patients at various risk of coronary artery disease.     

Use of biomarkers in clinical trials of Alzheimer disease: from concept to application

Research progress during the last decades has resulted in an unprecedented accumulation of knowledge regarding the molecular pathogenesis of Alzheimer disease (AD). These important achievements toward clarifying the mechanistic processes underlying AD are being translated into ongoing development of biomarkers and their use in clinical trials. AD biomarkers are biochemical and anatomical variables (e.g. cerebrospinal fluid, positron emission tomography, and structural MRI) that measure AD-related pathologic features (i.e. amyloid deposition and neurodegeneration) in vivo. Biomarkers are utilized as 'diagnostic biomarkers' and/or 'endpoint biomarkers' in symptomatic or disease-modifying clinical trials. Diagnostic biomarkers play an important role in population enrichment by refining selection criteria, stratifying populations, and increasing the statistical power of trials. Endpoint biomarkers may be used as outcome measures to monitor the rate of disease progression and detect treatment effects. AD biomarkers do not reach abnormal levels or peak simultaneously, but do so in a time-dependent order. The choice of biomarkers for a clinical trial must take into consideration the type of therapeutic intervention, the clinical stage of AD, and the time dependence of biomarker changes during disease progression. The combination of amyloid and neurodegeneration biomarkers is highly desirable since they capture different aspects of the disease. Clinical trials for every clinical stage of AD would benefit from quantification and standardization of biomarkers. However, this is still a work in progress.     

Impact of postmenopausal hormone therapy on cardiovascular events and cancer: pooled data from clinical trials.

OBJECTIVE: To examine the incidence of cardiovascular diseases and cancer from published clinical trials that studied other outcomes of postmenopausal hormone therapy as some surveys have suggested that it may decrease the incidence of cardiovascular diseases and increase the incidence of hormone dependent cancers. DESIGN: Trials that compared hormone therapy with placebo, no therapy, or vitamins and minerals in comparable groups of postmenopausal women and reported cardiovascular or cancer outcomes were searched from the literature. SUBJECTS: 22 trials with 4124 women were identified. In each group, the numbers of women with cardiovascular and cancer events were summed and divided by the numbers of women originally allocated to the groups. RESULTS: Data on cardiovascular events and cancer were usually given incidentally, either as a reason for dropping out of a study or in a list of adverse effects. The calculated odds ratios for women taking hormones versus those not taking hormones was 1.39 (95% confidence interval 0.48 to 3.95) for cardiovascular events without pulmonary embolus and deep vein thrombosis and 1.64 (0.55 to 4.18) with them. It is unlikely that such results would have occurred if the true odds ratio were 0.7 or less. For cancers, the numbers of reported events were too low for a useful conclusion. CONCLUSIONS: The results of these pooled data do not support the notion that postmenopausal hormone therapy prevents cardiovascular events.