Abstract P168: Clinical Benefit of Reduction in LDL and Triglycerides: Meta-Analyses of Major Coronary Events

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

The aim of this study is to compare the efficacy and safety of combination containing Atorvastatin plus Fenofibrate (ATO+FENO) and to determine whether combination of Fenofibrate had clinically significant benefit over Atorvastatin alone (ATO) in patients with Hyperlipidemia. This is a single centric, open labelled, prospective study, involving 50 Hyperlipidemic patients of 18 years and older. Data of only Hyperlipidemic patients with Low Density Lipoprotein (LDL –C) ≥ 140 - 60 mg/dl, Total Cholesterol (TC): 200-240 mg/dl and Triglyceride (TG): ≥ 165- < 400 mg/dl and who were prescribed either Atorvastatin 10 mg and Atorvastatin plus Fenofibrate 160 mg were included in the study. Efficacy end points included the change in LDL-C, HDL-C, TC and TG at week 12 and the safety of the treatment was also evaluated based on adverse events. Total of 50 patients were enrolled in the study but 1 patient lost follow up in ATO Group and 2 patients in ATO + FENO Group. Therefore 24 patients in ATO and 23 patients in ATO + FENO group completed study. A statistically significant reduction in LDL-C, TG and TC was seen in both the groups (Atorvastatin 10 mg and Atorvastatin plus Fenofibrate 160 mg). Similarly a statistically significant increase in HDL-C levels was observed in both the groups. ATO + FENO treatment showed a statistically significant reduction in TG at week 12 as compared to ATO alone. Decrease in LDL-C, TC, and TG were 24.86%, 24.81%, and 30.13% respectively and increasing HDL-C 42.37% in ATO + FENO group while the reduction was 21.1%, 21.31%, and 22.84% respectively and increasing HDL-C 38.2% in ATO alone group. The most common adverse events were headache, myalgia and nausea. ATO + FENO treatment showed a greater reduction in lipid parameters as compared to ATO alone (percentage change). Both treatments were well tolerated with similar incidence of adverse events. Study demonstrated that combination treatment was more effective than Atorvastatin alone in reducing LDL-C, Total Cholesterol and Triglyceride. It was also better in increasing HDL-C as compared to Atorvastatin. Statin in combination of fenofibrate may have lesser adverse effects. Thus Combination therapy seems to be a better treatment in patients having Hyperlipidemia.

Evolocumab, a monoclonal inhibitor of proprotein convertase subtilisin/kexin 9, has been shown to reduce proatherogenic lipoproteins in patients with or without familial hypercholesterolemia (FH), diabetes mellitus, or atherosclerotic cardiovascular disease (ASCVD). We explored the safety profile and clinical effectiveness of evolocumab in an outpatient population of Emirati individuals with FH diagnosed per Dutch Lipid Clinic Network criteria, previous ASCVD, or statin intolerance. This study was a retrospective review of patients initiating evolocumab treatment for any indication at Imperial College London Diabetes Centre between 2017 and 2020. All individuals followed up for at least 90 days or with at least one lipid panel postinitiation were included. Participants were subclassified into primary prevention (no previous ASCVD event, n=81) and secondary prevention (any prior clinical ASCVD event, n=102) groups. Evolocumab was initiated in 183 individuals (mean [SD] age, 51.5 [12.4] years; 51% male); 108 (59%) had a clinical or genetic FH diagnosis, and 70.5% had diabetes mellitus. Statin intolerance was a treatment indication in 60 (32.8%) individuals. At 90 days, substantial reductions in serum LDL-C, triglycerides (TG), and total cholesterol:HDL-C (TC:HDL-C) were observed in both the primary and secondary prevention groups, and both FH and non-FH individuals. In the primary prevention group, median (interquartile range) reduction in LDL-C was 43.7% (10.8%; 63.0%); TG, 15.0% (7.2%; 35.3%); and TC:HDL-C, 31.5% (11.1%; 46.0%). In the secondary prevention group, median (interquartile range) reduction in LDL-C was 48.3% (22%; 70%); TG, 19.6% (1.2%; 32.5%); and TC:HDL-C, 32.6% (14.6%; 46.3%) (all, P < 0.0001). American College of Cardiology/American Heart Association LDL-C targets were consistently achieved in 114 (62.3%) patients during a follow-up of 359 (79-639) days. Nonattainment of the LDL-C target was attributed to nonadherence in 36 (52.2%) patients and discontinuation of treatment in 14 (20.3%) patients. Evolocumab was discontinued in 4 patients because of adverse events. This study is the first from the Middle East and North Africa region that reports the real-world efficacy of evolocumab in a mixed risk population of individuals with FH and other non-FH indications. Clinically meaningful and sustained reductions in LDL-C, TG, and cholesterol ratios were observed after evolocumab initiation. Few adverse events were reported in this predominantly Arabic population, consistent with previous safety reports for evolocumab. Notable strengths of this study include a relatively large cohort, patient heterogeneity and high retention, and a minimum follow-up of 1 year. Despite these strengths, the study has some limitations, including the selection bias due to the retrospective design and absence of comparative group.

Background/Introduction Dyslipidemia is a significant risk factor for cardiovascular disease (CVD), and a residual risk of CVD remains despite the current standard of care. While combination therapies are often employed, some patients experience safety concerns and adverse side effects. Angiopoietin-like protein 3 (ANGPTL3) has emerged as a promising therapeutic target for the treatment of dyslipidemia. Genome-wide association studies have identified ANGPTL3 as a critical regulator of blood lipid levels in humans. It modulates lipid and lipoprotein metabolism by inhibiting lipoprotein lipase (LPL) and endothelial lipase (EL). BW-00112 is a fully synthetic, chemically optimized, double-stranded ANGPTL3 siRNA conjugated with N-acetylgalactosamine (GalNAc) for targeted delivery. This innovative approach shows great potential in addressing unmet needs in the management of dyslipidemia. Purpose The primary objective of this study was to assess the safety and tolerability of a single dose of BW-00112 in Chinese healthy subjects with 100 mg/dL ≤ LDL-C &amp;lt; 190 mg/dL and 100 mg/dL≤ TG &amp;lt;500 mg/dL up to 12 weeks. The secondary objectives of this study were to characterize pharmacokinetics (PK) profile and evaluate the pharmacodynamics (PD) effect (ANGPTL3, TG, LDL-C, non-HDL-C) of a single dose of BW-00112 up to 12 weeks. Methods This was a phase 1, randomized, double-blind, placebo-controlled, single dose study to evaluate the safety, tolerability, PK, and PD of subcutaneous doses of BW-00112 in Chinese healthy subjects with elevated LDL-C who were not receiving lipid-lowering therapy. Results BW-00112 was well tolerated with subcutaneous administration as a single dose ranging from 150 mg to 600 mg in Chinese healthy subjects. There were no serious adverse events, and no death or study discontinuations due to treatment-emergent adverse events (TEAEs). Most of the TEAEs were mild in severity. Adverse events of special interest, including injection site reactions and abnormalities in liver function, did not raise safety concerns. Exposure (AUC0-last and Cmax) increased in a dose-dependent manner within the linear range of 150 mg to 600 mg. However, the increase was slightly more than dose proportional. BW-00112 at doses of 150 mg to 600 mg resulted in substantial reductions in ANGPTL3 levels (mean -76% to -89%) 12 weeks after dosing. BW-00112 at doses of 150 mg to 600 mg also led to reductions in triglyceride (mean -62% to -76%), LDL-C (mean -31% to -34%), ApoB (mean -26% to -31%), Non-HDL-C (mean -32% to -36%), and remnant-C (mean -38% to -41%). Conclusion BW-00112 was generally well tolerated when administered subcutaneously as a single dose ranging from 150 mg to 600 mg. Substantial PD effects were observed with single subcutaneous doses of BW-00112 ranging from 150 mg to 600 mg, including reductions in ANGPTL3, triglycerides, LDL-C, ApoB, non-HDL-C, and remnant-C. No big difference was observed on safety, PK, and PD in Australian and Chinese healthy subjects.Reductions in serum ANGPTL3 and lipids

Rationale for different formulations of omega-3 fatty acids leading to differences in residual cardiovascular risk reduction

Cardiac rehabilitation programs should be transforming themselves from cardiac exercise facilities to comprehensive risk-reduction centers. Exercise will always have a place in cardiac rehabilitation. Postcoronary event patients who participate in exercise rehabilitation enjoy lower mortality rates and improved physical and psychological function. 1–3 Furthermore, cardiac rehabilitation exercise is a crucial intervention for older CHD patients striving to maintain physical independence. 4 However, the clinical benefits of exercise can be greatly amplified by strict attention to the measurement and treatment of coronary risk factors and by the attainment of well-defined risk factor goals. 5–9 Individual rehabilitation programs will need to carefully and thoughtfully develop risk factor modules and practice ongoing quality improvement with collection of outcomes data. The days of blindly applying a single exercise intervention over a 36-session period to all patients are all but over. Third-party payors, patients, and referring physicians are appropriately expecting improved clinical outcomes over a relatively short-term follow-up period (2–4 years). These goals can only be attained with a comprehensive, active, and participatory approach to cardiac risk reduction. HISTORICAL PERSPECTIVE Cardiac rehabilitation programs were established in the 1960s and 1970s when hospitalizations for acute myocardial infarction and surgical revascularization were prolonged and deconditioning was extreme. 10 As inpatient reambulation extended into the outpatient period, closely supervised, electrocardiographically monitored exercise programs developed, with physicians on-site to respond to potential cardiac emergencies. The focus was almost exclusively on exercise. These programs were shown to improve functional capacity for patients with coronary heart disease (CHD), and combined randomized-controlled trials (analyzed by meta-analysis) demonstrated a mortality benefit. 1,2 It has since been demonstrated that the acute risk of cardiac rehabilitation exercise is exceedingly low. 11–13 Home-exercise programs have been developed and appear to be safe for low-and moderate-risk patients. 14,15 Cardiac rehabilitation participation criteria have expanded to include patients with percutaneous coronary interventions, recent valvular heart surgery, chronic heart failure, heart transplantation, peripheral arterial disease, and the elderly. 16 By the early 1990s, the benefits of risk factor modification on clinical outcomes in patients with CHD were demonstrated. Randomized-controlled clinical trials that included combinations of exercise, low-fat diets 7,17–19 and lipid-lowering therapy 7,20–22 documented a slowing of the atherosclerotic process and a marked decrease in cardiac events and cardiac hospitalizations. The Stanford Coronary Risk Intervention Project (SCRIP) model is particularly relevant to outpatient cardiac rehabilitation as it provides an example of multi-risk intervention that can be emulated in the cardiac rehabilitation setting. 7,23 Physicians in clinical practice have not been particularly effective in assisting CHD patients to attain well-defined risk factor goals. For example, recent studies have documented that only 9% to 25% of CHD patients in practice settings have met the NCEP guidelines for lipid management 24–29 (Table 1). A significant percentage of patients are not taking preventive medications that have been shown to improve long-term outcomes. 8 In many settings it has been demonstrated that a systematic approach to the measurement and treatment of coronary risk factors is required to attain risk factor goals. The "art" of medicine is less effective than systematic screening and well-defined treatment algorithms.Table 1: UNDERTREATMENT OF HYPERLIPIDEMIA IN PATIENTS WITH CORONARY HEART DISEASECardiac rehabilitation programs and preventive cardiology clinics need to embrace the challenge of secondary prevention. It is our only viable future. We, furthermore, believe that exercise-only programs will find themselves excluded from reimbursement plans for the chronic care of CHD. Certainly, there is a role for exercise to improve functional capacity for the prevention and treatment of cardiac disability and for its preventive effects at the level of the coronary vasculature. 1,2,30–32 However, third-party payors eventually will limit on-site, monitored exercise to all but the highest risk and least functional patients. A system of care that systematically reduces risk in CHD patients by defining and treating hyperlipidemia, by offering successful weight-loss programs and nutritional counseling, by optimizing hypertensive and diabetic care, by recognizing and treating depression, and by optimizing preventive pharmacologic therapies, is the most likely system to be accepted as the standard of care. The concept of cardiac rehabilitation as the site for comprehensive risk-reduction has been recognized by the Cardiac Rehabilitation Clinical Practice Guidelines 16 under its byline "Cardiac Rehabilitation as Secondary Prevention." The American Heart Association and the Cardiac Rehabilitation Certification program of the American Association of Cardiovascular and Pulmonary Rehabilitation also promote it. 5 The Core Components for Cardiac Rehabilitation/Secondary Prevention were recently published jointly in Circulation5 and in the Journal of Cardiopulmonary Rehabilitation6 and need to be widely embraced (Figure 1).Figure 1.: Risk factor goals (data from Balady et al 5,6). LDL, low-density lipoprotein; HDL, high-density lipoprotein; BP, blood pressure; BMI, body mass index; HBA 1C , glycosylated hemoglobin.How does an exercise-only cardiac rehabilitation program transform to become a comprehensive risk-reduction center? The key components of making a successful transition from an exercise-only program to a comprehensive secondary prevention program are: the adoption of the case-management system of patient management, and the gradual implementation of "risk factor modules." CASE MANAGEMENT SYSTEM OF CARE Case management is the cornerstone of multiple risk reduction and provides a structural framework for the organization of cardiac rehabilitation programs. It involves the coordination of risk-reduction care for clusters of patients by a single individual, most commonly a nurse or exercise physiologist, with appropriate medical supervision. The inter-relatedness of coronary risk factors demands an integrated approach to management. While lifestyle skills will remain the foundation of risk factor interventions, providing both important metabolic and psychosocial benefits, there also is an important role for concomitant physician-directed pharmacologic therapy. It is in the application of behavioral modification principles and treatment algorithms that case management has been shown to be a safe and effective method of providing multiple risk reduction interventions. Case management for the treatment of CHD is based on: □ Screening to identify persons with disease □ Risk stratification and triage of those identified □ Assignment of individual to a case-manager □ Institution of intensive risk-reduction interventions based on clinical practice guidelines □ Medical surveillance of safety, efficacy, and adherence to risk reduction efforts □ Measurement of medical outcomes and patient satisfaction □ Systematic follow-up and institution of change in therapies as indicated Medical care in the United States in the 21st century is hampered by reimbursement issues, lack of continuity in medical insurance coverage, lack of continuity of healthcare providers, limited time with healthcare providers, and a focus on isolated "chief complaint" physician office visits. On the other hand, disease management is more effective than standard medical care because it is based on integrated approaches and services. Case management provides a model for coronary heart disease management by integrating patient, family, environment, lifestyle, and community. Several recent studies document the relative ineffectiveness of standard physician office visits on the management of CHD risk factors. 24–29 Sueta et al 24 evaluated the degree of treatment of hyperlipidemia in patients with CHD. The authors audited medical charts in 140 predominately cardiovascular practices in the United States. A total of 58,890 outpatient records were reviewed; 83% of patients were diagnosed with CHD. All patients reviewed had at least two office visits recorded in a 12-month period between July 1, 1994 and October 1, 1996. This study revealed a large screening gap with 56% of patients not having a recent LDL-cholesterol (LDL-C) documented, 61% of screened patients not receiving appropriate lipid-lowering therapy, and only 25% of patients at the National Cholesterol Education Program (NCEP II) goal of ≤ 100 mg/dL 30 (Figure 2). Patients with a documented LDL-C in their charts were four times more likely to receive lipid-lowering therapy.Figure 2.: Office-based lipid management in coronary artery disease. Aggregate data n = 48,586. Adapted from Sueta et al. 24The Lipid Treatment Assessment Project (L-TAP) similarly evaluated the percentages of dyslipidemic patients receiving lipid-lowering therapy and achieving LDL-C goals. In this study, Pearson et al 27 targeted the practice patterns of primary care physician where patients with dyslipidemia were regularly seen. Participating physicians completed a survey regarding their own demographic status, professional characteristics, and practice profiles. Awareness and adherence to NCEP II guidelines also were assessed. In L-TAP, the primary outcome measured was the success rate of appropriately screened and stratified patients reaching NCEP II LDL-C levels 9 (Table 1). These results demonstrate that in primary care, as in specialty practice, a large gap exists in the achievement of LDL-C goals as only 18% of CHD patients had reached an LDL-C of < 100 mg/dL. These studies are pivotal in that they demonstrate clearly the need for improved models for healthcare delivery. In contrast, the benefits of case management have been documented in several clinical settings. The Butterworth Health System in Grand Rapids, Michigan reorganized their cardiac rehabilitation program to focus on improvement of long-term patient outcomes using a case-management model. 33 The new model included the use of referral pathways, education sessions, and intervention by social workers as indicated. In addition, they added regular phone call follow-up to assess effectiveness of risk-reduction interventions. At 1 year, 77% of patients were on lipid-lowering medications, 78% reported exercising at least 3 days per week, and 66% of prior smokers reported smoking cessation. Although these results are based on self-report, the model of care deserves close attention. Two key studies, the MULTIFIT Study 34 and the SCRIP study 7 demonstrated the powerful impact of case management. MULTIFIT is a case-management program for men and women hospitalized with acute myocardial infarction in Northern California. This study randomized patients to special risk reduction intervention by nurse case managers versus usual care. The special intervention patients received education and counseling regarding smoking cessation, regular physical activity, and nutrition. Medical management, such as lipid-lowering therapy, was instituted as indicated for risk factors not controlled by lifestyle change. Much of the intervention was mediated via phone and mail contact. The special intervention group showed greater improvement at 6 months and 1 year in functional capacity, rates of smoking cessation and changes in LDL-C compared with the usual care group. This case management system subsequently was adopted by the Kaiser Permanente Health Care System. The SCRIP study was a randomized-controlled clinical trial funded by the National Institutes of Health to evaluate the efficacy of physician-directed, nurse coordinated multi-risk factor intervention, in men and women with CHD. 7 Outcome measures included quantitative coronary arteriography, risk factor measures, rehospitalization rates, and rates of recurrent coronary events. This study used nurse case-managers to supervise and coordinate care. The case managers worked with a team of nutritionists, psychologists, and physicians to provide clinical and lifestyle interventions, striving to attain nationally recognized goals for risk factor reduction. 8 The study was conducted over a 4-year period and demonstrated both clinical and angiographic benefits (Table 2). The intervention group demonstrated a reduction of hospitalizations and clinical coronary events. Angiographic benefits included both less progression and greater stabilization of plaque in the intervention group compared with the usual care group.Table 2: STANFORD CORONARY RISK INTERVENTION PROJECT (SCRIP) RESULTS 7Fonarow et al 35 recently published the results of the Cardiac Hospitalization Atherosclerosis Management Program (CHAMP). In this study, the investigators evaluated the efficacy of a case management approach to discharge planning for persons admitted to the UCLA Medical Center with a diagnosis of CAD or other vascular diseases (Figure 3). The study followed a case management approach emphasizing the appropriate use of aspirin, cholesterol lowering agents, beta-adrenergic blocking agents, and angiotensin-converting enzyme inhibitors (ACE-I). These interventions were applied in conjunction with outpatient exercise, nutrition, and smoking cessation counseling. At completion of the study, utilization of beta blockers, ACE-I, aspirin, and lipid-lowering agents were all significantly increased (Tables 3 and 4). There also was a significant increase in the percentage of patients achieving a LDL-C ≤ 100 mg/dL (58% versus 6%, P < 0.001) and a reduction in recurrent myocardial infarction and 1-year mortality.Table 3: CHAMP MEDICATION UTILIZATION RATES AT DISCHARGETable 4: CHAMP MEDICATION UTILIZATION RATES AND LDL LEVELS AT 1 YEAR POST-HOSPITAL DISCHARGEFigure 3.: Cardiac Hospitalization Atherosclerosis Management Program algorithm for patients with evident atherosclerosis. Reprinted from Fonarow et al. 35 © 2001, with permission from Excerpta Medical Inc.In summary, these data support the efficacy of the case-management model of healthcare regarding long-term adherence to risk-reduction efforts both in the acute and chronic care setting. Case management must be instituted in existing cardiac rehabilitation programs, where, for example, selected qualified staff are each assigned specific patients to serve as their case manager. Assignments can be made to individual case managers on an alternating basis as consecutive patients are admitted to the program, or on the basis of staff specialization, disease severity or patient complexity. Risk Factor Modules From the point of view of implementing multi-risk reduction in the cardiac rehabilitation setting, modules of care need to be organized for each individual risk factor. The case-manager can then refer individual patients to selected modules based upon their baseline screening values. Beyond screening for a risk factor, setting up a module requires an integrated system of care that includes staffing, an education component, counseling of lifestyle interventions including nutrition and exercise, with long-term follow-up of the risk factor measure. For selected risk factors such as hyperlipidemia or hypertension, initiation, modification, and monitoring of pharmacologic therapy by the medical director in concert with the referring physician is also a consideration. Hyperlipidemia Module Exercise alone has relatively modest effects on improving the lipid profile in CHD patients. 36,37 The most prominent effect is an improvement of HDL-cholesterol on the order of 8% to 10%, or roughly an increase of 3 to 4 mg/dL over as short as a 3-month training period. While this seems subtle in absolute terms, an improvement of this magnitude using the pharmacologic agent gemfibrozil in CHD patients with an isolated low HDL-cholesterol was recently associated with a 22% decrease in major coronary events over a 5-year period. 38 Cardiac rehabilitation exercise also is associated with a 20% decrease in fasting triglyceride levels for patients whose baseline values are above 200 mg/dL. 35 On the other hand, in the absence of significant weight loss, LDL-C effects of exercise are minimal. Nutritional counseling and dietary change can result in LDL-C reductions that usually do not exceed 10%. Accordingly, most patients with CHD and LDL-C elevations will need to be treated with pharmacologic lipid-lowering agents to reach lipid goals, while lifestyle measures are implemented. The cardiac rehabilitation baseline screening evaluation should include a full fasting lipid profile taken either before coronary revascularization or at least 1 month after an acute coronary event. The rehabilitation program should then participate actively in attaining lipid goals. This includes both nutritional counseling (by nutritionists or trained nurses) weight loss when indicated, and pharmacologic therapy. If well-recognized lipid-lowering algorithms recommend lipid-lowering therapy, 9 the medical director of the program, in communication with the primary physician, should institute lipid-lowering therapy. Using such a model in a quality improvement project at the University of Vermont, the application of appropriate lipid-lowering therapy was tripled (compared with a control group), with the intervention group attaining significantly lower lipid values. 39 At cardiac rehabilitation completion, a repeat lipid profile should be obtained and re-assessment of therapy and long-term goal attainment can be performed. Obesity Module Obesity is highly prevalent in cardiac rehabilitation populations with rates of overweight (body mass index > 25 kg/m 2 ) ranging from 70% to 88%. 40,41 Obesity (body mass index > 30) is present in 35% to 53% of patients. In CHD patients, obesity is associated with very high prevalences of lipid abnormalities, hypertension, insulin resistance, type II diabetes, and clotting abnormalities. 40 Conversely, weight loss in CHD patients acts as a multi-risk intervention. 42 Lipid abnormalities improve along with improvements in blood pressure and glucose control. 42,43 In the cardiac rehabilitation setting, substantial weight loss does not occur with exercise alone. 37 A targeted weight loss intervention is required. A behaviorally based weight reduction program has been described and incorporated into the cardiac rehabilitation setting. 44–46 It is delivered in 12 to 16 weekly group sessions and incorporates the behavioral concepts of daily caloric goals (500 kcal deficit per day yields a 1 lb weight loss per week), dietary records, stimulus control, problem solving, social support, and relapse prevention training. 44,45 It is coordinated by a nutritionist or a cardiac rehabilitation nurse. At the University of Vermont such a program, coordinated by a nurse clinician, has resulted in an average weight loss of 9 to 10 lbs over an 11-week period with a significant decrease in serum cholesterol levels. 46 Cardiac rehabilitation programs should provide, in one form or another, an effective weight loss program for obese patients as part of the cardiac rehabilitation/preventive cardiology experience. Alternatively, patients may be referred to affiliated weight management programs or dieticians. Simply recommending weight loss does not result in any sustained benefit. While physicians play an important role in motivating patients to lose weight they generally do not possess the skills, nor have the time, to accomplish weight loss on a systematic basis. Hypertension Module Hypertension is highly prevalent among individuals with coronary artery disease, noted in 30% to 38% of patients with myocardial infarction enrolled in large clinical trials. 47 Hypertension has been reported to be present in 47% to 65% of consecutive patients enrolled in cardiac rehabilitation programs. 48 The of in to of is not However, the cardiac rehabilitation staff can with the primary care physician to evaluate and this important risk factor. medical includes a focus on dietary caloric and and of physical and also should be reviewed and A high percentage of CHD patients will be taking beta-adrenergic blocking agents or medications, to their preventive 8 is at least treated in most CHD patients referred to cardiac rehabilitation. The physical for patients with should include the □ Two or more blood pressure by 2 with the patient either or and after for at least 2 □ in the values are the should be Cardiac rehabilitation program staff can greatly the primary care physician in the treatment and surveillance of patients with are the foundation for treatment of and pharmacologic therapy when studies have demonstrated that regular physical the of In hypertensive men short-term physical blood pressure for 8 to 12 after exercise, and average blood pressure is lower on exercise than on In hypertensive physical for 16 to a decrease in blood is sustained after reduction in In addition, there is a significant decrease in as early as 16 after the of exercise. The treatment goals for are by and in adherence to long-term both lifestyle and pharmacologic therapy, has been identified as the major for control of high blood Cardiac rehabilitation provides patient education and support at improving patient of specific therapies and treatment goals, the interventions to lifestyle, and or other social may improve long-term adherence to treatment and blood pressure control. Module has effects on both glucose and insulin These include increased to of glucose by the of use more glucose than and Patients with in cardiac rehabilitation programs special particularly they are taking insulin or The patient should include regarding and of This is important particularly when insulin is part of the treatment The and of of are important to Patients should be regarding the effect of exercise on blood glucose levels and the of may occur up to several after the exercise and treatment of should be reviewed with diabetic patients. diabetic patients are to and that may with or be by exercise, the medical evaluation should include an of the lower Patients should be to and exercise. glucose levels should be before and after exercise to provide an of that to exercise. glucose levels of < and > mg/dL should exercise at that The results of blood glucose monitoring may the need for a modification of the insulin Module smoking cessation is associated with a marked decrease in coronary event rates in coronary patients. The results with smoking cessation after a coronary event have been obtained with a intervention that place in the acute The intervention is at relapse prevention and includes of behavioral These include stimulus control, with of when and long-term contact. At 1 year, in one study, cessation rates were significantly increased from in to 61% with the intervention. In the outpatient cardiac rehabilitation setting, the of smokers and who is the of the treatment generally recommend a care approach to smoking cessation. These □ a regarding the of □ the patient is to and providing making this □ the method such as a group program or individual counseling □ for associated with such as increased or increased by behavioral □ therapies as indicated □ a to the □ support as such as regular exercise, of and providing a to social support □ follow-up to support relapse prevention and to The of cardiac rehabilitation programs to reach and social for a and more effective of achieving successful smoking cessation than in an office setting. Module Assessment of psychosocial is to successful rehabilitation of the cardiac of should the □ there of □ is the of or and their □ the patient the loss of a heart or is the patient to in to 22% of infarction patients. levels of are associated with increased medical and patients after myocardial infarction are more likely to social more and are less likely to to than those who are not The that to medical outcomes are not but may be in part to increased and The have been shown to increase the risk for myocardial and cardiac It should be noted that participation in cardiac rehabilitation with a management of is associated with an decrease in and improved clinical particularly for patients with high baseline the of and treating in cardiac patients is recognized as an part of comprehensive cardiac rehabilitation and secondary prevention. may be in that such as also are of cardiac disease. In addition, many patients may be to and many healthcare may be to such screening should be as part of the evaluation for patients cardiac prevention programs. These should include an patient in and as as a of should be A of and are also to in this screening These include the is a on a of 10 is at least to and the a where a of 5 If significant is then a treatment must be This should be in concert with the primary healthcare with psychologists, or other behavioral should be to with evaluation and management of these patients, particularly do not improve after participation in group exercise and management. and Exercise will always have a place in cardiac but the challenge before is to in place effective programs for risk factor management. Individual programs will need to carefully and thoughtfully develop risk factor modules and practice ongoing quality improvement with collection of outcomes data. referring and third-party payors are expecting improved clinical outcomes over a relatively short-term period of 2 to 4 These goals can only be attained each and program on attaining risk factor goals with a comprehensive and participatory approach to CHD management. The authors for

Background The role of microRNA as biomarkers able to predict major coronary events (MACE) has not been fully elucidated, reproducibility being a critical issue. Aim To identify circulating microRNA signatures able to predict MACE. Methods We employed a PCR-based method to screen 754 microRNAs in a cohort of 60-year-olds (60YOs) from Stockholm, using a nested case-control design (100 cases vs 100 matched controls). The association of microRNAs and their interaction with the risk of MACE (myocardial infarction (MI), angina and sudden cardiac death) was estimated with random-effect logistic regression and expressed as OR with 95% CI. A bioinformatics approach identified microRNA clusters based on predicted targets. Main findings were tested in 58 MI and 60 age and sex matched referents from the the Nord-Trøndelag Health (HUNT) Study, a longitudinal population health study conducted in Norway. Results Fifty-five microRNAs were found to be associated with risk of MACE in the 60YO. MicroRNA-145-3p was associated with the largest estimated risk increase of MACE after adjustment for the common CV risk factors (OR: 2.18; 95% CI: 1.27–3.75). Interaction analysis revealed that increasing plasma levels of microRNA-320b modulated the association of 16 microRNAs with risk of MACE. As an example the estimated MACE risk associated with microRNA-145-3p was 1.47 (0.87–2.47) in the presence of low (&lt;25th percentile) and 4.00 (1.79- 8.93) in the presence of high (&gt;75th percentile) miRNA 320b expression levels. Sixteen microRNA pairs could be classified in 4 functional clusters with 492 predicted gene targets, mainly involved in the regulation of inflammation, thrombosis and lipid metabolism. Eight miRNAs interacting pairs belonging to cluster 2 and 4 showed a similar association trend with MI risk in the HUNT study. Conclusions We report the identification of microRNA signatures predicting risk of MACE in middle-aged Scandinavian men and women. These signatures could be a valuable tool to improve CV disease prediction in the aged.

Lowering low-density lipoprotein cholesterol (LDL-C) is known to reduce risk of recurrent coronary heart disease in middle-aged men. However, this effect has been uncertain in elderly people and women. To estimate the risk reduction of coronary heart disease and total mortality associated with statin drug treatment, particularly in elderly individuals and women. Trials published in English-language journals were retrieved by searching MEDLINE (1966-December 1998), bibliographies, and authors' reference files. Studies in which participants were randomized to statin or control treatment for at least 4 years and clinical disease or death was the primary outcome were included in the meta-analysis (5 of 182 initially identified). Information on sample size, study drug duration, type and dosage of statin drug, participant characteristics at baseline, reduction in lipids during intervention, and outcomes was abstracted independently by 2 authors (J.H. and S.V.) using a standardized protocol. Disagreements were resolved by consensus. Data from the 5 trials, with 30 817 participants, were included in this meta-analysis. The mean duration of treatment was 5.4 years. Stati n drug treatment was associated with a20% reduction in total cholesterol, 28% reduction in LDL-C, 13% reduction in triglycerides, and 5% increase in high-density lipoprotein cholesterol. Overall, statin drug treatment reduced risk 31 % in major coronary events (95% confidence interval [CI], 26%-36%) and 21 % in all-cause mortality (95% CI, 14%-28%). The risk reduction in major coronary events was similar between women (29%; 95% Cl, 13 %-42 %) and men (31 %; 95% CI, 26%-35%), and between persons aged at least 65 years (32%; 95% CI, 23%-39%) and persons younger than 65 years (31 %; 95% CI, 24%-36%). Our meta-analysis indicates that reduction in LDL-C associated with statin drug treatment decreases the risk of coronary heart disease and all-cause mortality. The risk reduction was similar for men and women and for elderly and middle-aged persons.

Adipose differentiation-related protein (ADFP; also known as ADRP or adipophilin), is a lipid droplet (LD) protein found in most cells and tissues. ADFP expression is strongly induced in cells with increased lipid load. We have inactivated the Adfp gene in mice to better understand its role in lipid accumulation. The Adfp-deficient mice have unaltered adipose differentiation or lipolysis in vitro or in vivo. Importantly, they display a 60% reduction in hepatic triglyceride (TG) and are resistant to diet-induced fatty liver. To determine the mechanism for the reduced hepatic TG content, we measured hepatic lipogenesis, very-low-density lipoprotein (VLDL) secretion, and lipid uptake and utilization, all of which parameters were shown to be similar between mutant and wild-type mice. The finding of similar VLDL output in the presence of a reduction in total TG in the Adfp-deficient liver is explained by the retention of TG in the microsomes where VLDL is assembled. Given that lipid droplets are thought to form from the outer leaflet of the microsomal membrane, the reduction of TG in the cytosol with concomitant accumulation of TG in the microsome of Adfp-/- cells suggests that ADFP may facilitate the formation of new LDs. In the absence of ADFP, impairment of LD formation is associated with the accumulation of microsomal TG but a reduction in TG in other subcellular compartments.

Aims/hypothesisLipoprotein-associated phospholipase A2 (Lp-PLA2) activity has an independent prognostic association with major coronary events (MCE). However, no study has investigated whether type 2 diabetes status modifies the effect of Lp-PLA2 activity or inhibition on the risk of MCE. We investigate the interaction between diabetes status and Lp-PLA2 activity with risk of MCE. Subsequently, we test the resulting hypothesis that diabetes status will play a role in modifying the efficacy of an Lp-PLA2 inhibitor.MethodsA retrospective cohort study design was utilised in two study populations. Discovery analyses were performed in the Genetics of Diabetes Audit and Research in Tayside Scotland (GoDARTS) cohort based in Scotland, UK. Participants were categorised by type 2 diabetes control status: poorly controlled (HbA1c ≥ 48 mmol/mol or ≥6.5%) and well-controlled (HbA1c < 48 mmol/mol or <6.5%) diabetes (n = 7420). In a secondary analysis of the Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy (STABILITY) trial of Lp-PLA2 inhibitor (darapladib) efficacy, 15,828 participants were stratified post hoc by type 2 diabetes diagnosis status (diabetes or no diabetes) at time of recruitment. Lp-PLA2 activity was then divided into population-specific quartiles. MCE were determined from linked medical records in GoDARTS and trial records in STABILITY. First, the interaction between diabetes control status and Lp-PLA2 activity on the outcome of MCE was explored in GoDARTS. The effect was replicated in the placebo arm of STABILITY. The effect of Lp-PLA2 on MCE was then examined in models stratified by diabetes status. This helped determine participants at higher risk. Finally, the effect of Lp-PLA2 inhibition was assessed in STABILITY in the higher risk group. Cox proportional hazards models adjusted for confounders were used to assess associations.ResultsIn GoDARTS, a significant interaction between increased Lp-PLA2 activity (continuous and quartile divided) and diabetes control status was observed in the prediction of MCE (p < 0.0001). These effects were replicated in the placebo arm of STABILITY (p < 0.0001). In GoDARTS, stratified analyses showed that, among individuals with poorly controlled diabetes, the hazards of MCE for those with high (Q4) Lp-PLA2 activity was 1.19 compared with individuals with lower (Q1–3) Lp-PLA2 activity (95% CI 1.11, 1.38; p < 0.0001) and 1.35 (95% CI 1.16, 1.57; p < 0.0001) when compared with those with the lowest activity (Q1). Those in the higher risk group were identified as individuals with the highest Lp-PLA2 activity (Q4) and poorly controlled diabetes or diabetes. Based on these observations in untreated populations, we hypothesised that the Lp-PLA2 inhibitor would have more benefit in this higher risk group. In this risk group, Lp-PLA2 inhibitor use was associated with a 33% reduction in MCE compared with placebo (HR 0.67 [95% CI 0.50, 0.90]; p = 0.008). In contrast, Lp-PLA2 inhibitor showed no efficacy in individuals with low activity, regardless of diabetes status, or among those with no baseline diabetes and high Lp-PLA2 activity.Conclusions/interpretationThese results support the hypothesis that diabetes status modifies the association between Lp-PLA2 activity and MCE. These results suggest that cardiovascular morbidity and mortality associated with Lp-PLA2 activity is especially important in patients with type 2 diabetes, particularly those with worse glycaemic control. Further investigation of the effects of Lp-PLA2 inhibition in diabetes appears warranted.Data availabilitySTABILITY trial data are available from clinicaltrials.gov repository through the GlaxoSmithKline clinical study register https://clinicaltrials.gov/ct2/show/NCT00799903. GoDARTS datasets generated during and/or analysed during the current study are available following request to the GoDARTS Access Managements Group https://godarts.org/scientific-community/.Graphical abstract

The lowering of blood pressure after stroke

Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis

Although numerous studies have established the efficacy of micronized fenofibrate (MF) and gemfibrozil in improving lipid profiles, there are limited comparative data on the lipid-lowering effects of these two agents. The objective of this study was to evaluate the mean changes in lipid values of hypertriglyceridemic patients crossed over from gemfibrozil to MF. The Medical charts of 21 patients were analyzed retrospectively. Patients were maintained on gemfibrozil 600 mg twice daily for a minimum of 3 months. The patient's last fasting lipid profile on gemfibrozil was compared to the first lipid profile after crossover to MF 200 to 201 mg/day. Patients were excluded if there were alterations in other lipid-lowering therapy during the cross-over or documented non-adherence. The lipid profiles after the crossover showed a significant reduction in triglycerides (56%; P &lt; 0.05) and TC/HDL ratio (38%; P &lt; 0.05) and a significant increase in HDL (22%; P &lt; 0.05). There were nonsignificant changes in other lipid values: TC (-22%; P = 0.058), LDL (+5%; P = 0.866) and LDL/HDL ratio (+6; P = 1.0). The results show that MF had additional favorable effects on triglycerides, HDL, and TC/HDL ratio compared with gemfibrozil. A larger, randomized trial to confirm these effects is warranted.

VI. Drug Therapy

The Scandinavian Simvastatin Survival Study (4S) demonstrated pronounced reductions in mortality and major coronary events in a cohort of patients with established coronary heart disease (CHD). The present study provides a detailed, post hoc assessment of the efficacy and safety of simvastatin therapy in the following subgroups of 4S patients: those > or = 65 years of age, those < 65 years of age, women, and men. The 4S cohort of 4444 CHD patients included 827 women and 1021 patients > or = 65 years of age. Total cholesterol at baseline was 5.5 to 8.0 mmol/L with triglycerides < or = 2.5 mmol/L. Patients were randomized to therapy with simvastatin 20 to 40 mg daily or placebo for a median follow-up period of 5.4 years. End points consisted of all-cause and CHD mortality, major coronary events (primarily CHD death and nonfatal myocardial infarction), other acute CHD and atherosclerotic events, hospitalizations for CHD and cardiovascular events, and coronary revascularization procedures. Mean changes in serum lipids were similar in the different subgroups. In patients > or = 65 years of age in the simvastatin group, relative risks (95% confidence intervals) for clinical events were as follows: all-cause mortality, 0.66 (0.48 to 0.90); CHD mortality, 0.57 (0.39 to 0.83); major coronary events, 0.66 (0.52 to 0.84); any atherosclerosis-related event, 0.67 (0.56 to 0.81); and revascularization procedures, 0.59 (0.41 to 0.84). In women, the corresponding figures were 1.16 (0.68 to 1.99); 0.86 (0.42 to 1.74), 0.66 (0.48 to 0.91), 0.71 (0.56 to 0.91), and 0.51 (0.30 to 0.86), respectively. Cholesterol lowering with simvastatin produced similar reductions in relative risk for major coronary events in women compared with men and in elderly (> or = 65 years of age) compared with younger patients. There were too few female deaths to assess the effects on mortality in women. Because mortality rates increased substantially with age, the absolute risk reduction for both all-cause and CHD mortality in simvastatin-treated subjects was approximately twice as great in the older patients.