Scandinavian Simvastatin Survival Study Research Articles

The Differential Impact of Medical Therapy and Lifestyle Modification on Cardiovascular Health and Risk of Adverse Cardiovascular Events: A Narrative Review.

Cardiovascular diseases (CVDs) continueto be a worldwide health concern, requiring effective strategies for risk reduction. This article explores the extensive collaboration between medical therapy and lifestyle modifications in the management of CVDs, aiming to interpret whether a single approach holds the key to reducing major cardiovascular events. In the realm of pharmaceutical therapy, statins, beta-blockers, angiotensin-converting-enzyme (ACE) inhibitors, and antiplatelet agents have shown significant effectiveness, as evidenced by landmark trials such as Scandinavian Simvastatin Survival Study (4S) and Heart Outcomes Prevention Evaluation (HOPE). Concurrently, lifestyle adjustments, encompassing physical activity, dietary changes,and management of stress, emerge as indispensable elements in cardiovascular care. The article discusses the pivotal role of patient adherence, tailored approaches, and the synergistic impact of combining medical therapy and lifestyle modifications. Challenges, such as socioeconomic disparities and uncertainties in lipid management, underscore the need for ongoing research and precision medicine. Digital health interventions offer novel avenues for personalized care. Despite advancements, uncertainties persist regarding the optimal balance between medical and lifestyle interventions in lowering major cardiovascular event risks. This article emphasizes the ongoing evolution of cardiovascular care, highlighting the imperative need for evidence-based guidelines tailored to individual patient needs.

5 Conservative treatment for PAD - Risk factor management.

5 Conservative treatment for PAD - Risk factor management.

Are gliflozins the new statins for diabetes?

Since the first demonstration by the 4S (Scandinavian Simvastatin Survival Study) trial that treatment of dyslipidemia significantly decreased by 55% the risk of major cardiovascular events (MACE) in patients with type 2 diabetes (T2D) [1], statins have been consecrated as vital drugs for cardiovascular (CV) prevention. Twenty-five year later the original publication of the 4S trial, the American Diabetes Association (ADA) claims that for patients of all ages with diabetes and atherosclerotic cardiovascular disease (ASCVD) or 10-year ASCVD risk >20%, high-intensity statin therapy should be added to lifestyle therapy [2].

PCSK9 Inhibitors: Clinical Relevance, Molecular Mechanisms, and Safety in Clinical Practice.

Coronary artery disease (CAD) is one of the leading causes of mortality. High circulating levels of low-density lipoprotein (LDL) in the blood are associated with cardiovascular mortality, whether through an etiological role or through its association with the progression of CAD per se. Randomized clinical trials have shown that, when LDL levels are reduced, cardiovascular risk is also reduced, which reinforces this association. The first major trial involving a hypolipidemic agent of the statin family, the Scandinavian Simvastatin Survival Study (4S), was published in 1994 and found a significant reduction in mortality in patients at high cardiovascular risk. However, even in subsequent studies with different statins, a residual risk persisted, and this seems not to have changed over time; it is speculated that this risk may be due to statin intolerance. In this scenario, the potential exists for novel hypolipidemic agents to drive a true revolution in the therapy of dyslipidemia. The recent discovery of PCSK9 inhibitors (PCSK9i), a class of hypolipidemic monoclonal antibodies, is extremely promising. PCSK9 inhibition is capable of promoting a mean LDL reduction of up to 60%, with potential for very significant clinical repercussions, as every 38 mg/dL reduction in LDL appears to be associated with a 22% reduction in cardiovascular risk. This review addresses a brief history of PCSK9i, major trials of these drugs, cardiovascular outcomes, and aspects related to their efficacy and safety. Finally, the molecular mechanisms and possible pleiotropic effects of PCSK9i are also discussed.

PRM114 - SYNTHETIC SAMPLE GENERATION OF THE 4S STUDY PLACEBO POPULATION USING A STOCHASTIC RESAMPLING TECHNIQUE

To generate a synthetic sample of individuals with mean characteristics that reflect those of a population in clinical research. In R we developed a stochastic resampling technique to generate a semi-random sample of people with characteristics that match those of the control group in the Scandinavian Simvastatin Survival Study (4S). The sample was matched on binary variables (gender ratio, age, smoking status, diabetes) and on continuous factors (BMI, systolic blood pressure, total cholesterol: HDL cholesterol ratio, number of cigarettes smoked per day and units of alcohol consumed per week). The descriptive statistics generated for the synthetic sample matched the target sample to an accuracy of 2 decimal points. The algorithm successfully generated a sample of 2,222 individuals with characteristics closely matching those of the 4S study control group. The only notable difference in the data summary was that the range of TC in the 4S study control group was 5.01 to 25 whereas in the synthetic sample the generated range was 5.01 to 12. The samples were well matched for all continuous variables. The average values reported in the 4S study for BMI, systolic BP, TC, and HDL were 26.0 (SD = 3.3), 139.1 (SD = 19.6), 6.7 (SD = 0.7), and 1.4 (SD = 0.3), respectively. From the synthetic sample the average values were 26.0 (SD = 4.2, 95% CI [17.84, 34.18]), 139.1 (SD = 20.1, 95% CI [99.62, 178.52]), 6.7 (SD = 1.1, 95% CI [4.54, 8.94]), and 1.4 (SD = 0.3, 95% CI [0.75, 2.06]), respectively. This new method was successful in generating synthetic samples that are comparable to the originals in aggregate. These synthetic samples can be used to model the likely impact of new therapies or predict mortality for various sub-groups and will be a useful tool in the planning and preparation of clinical trials.

Solving the clinical inertia conundrum

Solving the clinical inertia conundrum

Dyslipidemia.

Dyslipidemia.

Reduction of Vascular Inflammation, LDL-C, or Both for the Protection from Cardiovascular Events?

Background:Low density lipoprotein cholesterol (LDL-C) and low grade arterial inflammation are key pathogenic factors for atherosclerosis and its manifestation, cardiovascular disease (CVD).Objective:In this narrative review we assessed if decreasing LDL-C levels or inflammation or both is more effective in reducing CVD events.Results:In the Scandinavian Simvastatin Survival Study (4S), all statin trials of the 90s’ and the Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) the benefit came from the LDL-C reduction. In the GREak and Atorvastatin Coronary heart disease Evaluation (GREACE), the Treating to New Targets (TNT), and the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) trials both mechanisms in combination produced significant benefits. In the Atorvastatin for Reduction of MYocardial Damage during Angioplasty (ARMYDA) trials and the Canakinumab Antiinflammatory Thrombosis Outcome Study (CANTOS) with a human antibody targeting IL-1β with no lipid lowering effect, the reduction in arterial inflammation played the only beneficial role because there was no change in lipids levels.Conclusion:Both LDL-C and inflammation reduction are beneficial to the reduction of CVD risk. However, canakinumab is a very expensive drug that only induced a 15% reduction in CVD events, thus drastically reducing the possibility for it to be used in clinical practice. Besides, canakinumab is associated with increased infections, some fatal. A potent statin with anti-inflammatory effects is probably the best choice for the majority of those needing hypolipidaemic drug therapy.

No evidence to support high-intensity statin in Chinese patients with coronary heart disease

No evidence to support high-intensity statin in Chinese patients with coronary heart disease

Formulation of Treatment Recommendations for Statins

To the Editor Drs Ridker and Wilson 1 proposed that statin guidelines formulate treatment recommendations through consideration of “… patient populations for whom clinical trials have demonstrated benefit.” They failed to provide a clear definition of benefit. The authors cited approximately 20 randomized clinical trials; however, the measures of benefit varied widely between some of these trials. In addition, the vascular events terminology is insufficiently specific. Efficacy measures in randomized clinical trials of statins often include outcomes that differ in their clinical importance, ranging from death to clinician-driven end points such as revascularization procedures and hospitalizations. For example, in the Scandinavian Simvastatin Survival Study (4S), 2 in which participants with a history of coronary heart disease were enrolled, the primary efficacy measure was total mortality. In the Subcutaneous Heparin and Angioplasty Restenosis Prevention (SHARP) trial, 3 in which participants with chronic kidney disease were enrolled, the modified efficacy outcome was a broad composite of events (ie, nonfatal myocardial infarction, coronary death, nonhemorrhagic stroke, or any arterial revascularization procedure). In fact, a reduction in revascularization procedures contributed most to the statistically significant result in SHARP. 4 Even though total mortality was reduced in the 4S trial (relative risk, 0.70 [95% CI, 0.58-0.85]; P < .001), this was not the case in SHARP (rate ratio, 1.02 [95% CI, 0.941.11]; P =. 63). Despite the qualitative differences in the benefit demonstrated in these 2 clinical settings, Ridker and Wilson 1 endorsed statin therapy equally for patients with chronic kidney disease as for patients with a history of coronary heart disease. The authors suggested incorporation of the number needed to treat metric into clinical decision making, but the number needed to treat for which outcome? Guidelines that use oversimplified and ambiguous references to benefit or lack of benefit (without specification of the efficacy measures tested in the relevant trials) are unlikely to be usable by clinicians and patients. In our view, before guideline panels engage in interpretation and application of evidence, they should first specify for guideline users a hierar

Formulation of Treatment Recommendations for Statins

To the Editor Drs Ridker and Wilson 1 proposed that statin guidelines formulate treatment recommendations through consideration of “… patient populations for whom clinical trials have demonstrated benefit.” They failed to provide a clear definition of benefit. The authors cited approximately 20 randomized clinical trials; however, the measures of benefit varied widely between some of these trials. In addition, the vascular events terminology is insufficiently specific. Efficacy measures in randomized clinical trials of statins often include outcomes that differ in their clinical importance, ranging from death to clinician-driven end points such as revascularization procedures and hospitalizations. For example, in the Scandinavian Simvastatin Survival Study (4S), 2 in which participants with a history of coronary heart disease were enrolled, the primary efficacy measure was total mortality. In the Subcutaneous Heparin and Angioplasty Restenosis Prevention (SHARP) trial, 3 in which participants with chronic kidney disease were enrolled, the modified efficacy outcome was a broad composite of events (ie, nonfatal myocardial infarction, coronary death, nonhemorrhagic stroke, or any arterial revascularization procedure). In fact, a reduction in revascularization procedures contributed most to the statistically significant result in SHARP. 4 Even though total mortality was reduced in the 4S trial (relative risk, 0.70 [95% CI, 0.58-0.85]; P < .001), this was not the case in SHARP (rate ratio, 1.02 [95% CI, 0.941.11]; P =. 63). Despite the qualitative differences in the benefit demonstrated in these 2 clinical settings, Ridker and Wilson 1 endorsed statin therapy equally for patients with chronic kidney disease as for patients with a history of coronary heart disease. The authors suggested incorporation of the number needed to treat metric into clinical decision making, but the number needed to treat for which outcome? Guidelines that use oversimplified and ambiguous references to benefit or lack of benefit (without specification of the efficacy measures tested in the relevant trials) are unlikely to be usable by clinicians and patients. In our view, before guideline panels engage in interpretation and application of evidence, they should first specify for guideline users a hierar

Statins: Can we advocate them for primary prevention of heart disease?

The discovery of cholesterol-lowering agents, namely HMG-CoA reductase inhibitors or statins, ushered in a series of large cholesterol reduction trials. The first of these studies was the Scandinavian Simvastatin Survival Study (4S) in which hypercholesterolemic men with CHD who were treated with simvastatin had a reduction in major coronary events of 44% and a reduction in total mortality of 30%. Many more secondary prevention trials followed to establish unequivocally the benefit of cholesterol reduction. Strategies that aim to improve primary prevention are important for managing the overall burden of disease. Recently therefore, the role of statin in primary prevention is being debated. The JUPITER trial and more recently the Cholesterol Treatment Trialists collaborators, proved that incidences of first major cardiovascular events in apparently healthy individuals were reduced by statins. Statins have also been discussed to be having certain pleiotropic effects on other diseases like diabetes, cancer and osteoporosis. However, issues of cost effectiveness and adverse effects like myositis, and transaminitis still loom large. The medical community needs to debate and evolve a possible consensus on the path breaking subject.

Dyslipidemia

Dyslipidemia

High-capacity selective uptake of cholesteryl ester from native LDL during macrophage foam cell formation

Macrophage foam cells are a defining pathologic feature of atherosclerotic lesions. Recent studies have demonstrated that at high concentrations associated with hypercholesterolemia, native LDL induces macrophage lipid accumulation. LDL particles are taken up by macrophages as part of bulk fluid pinocytosis. However, the uptake and metabolism of cholesterol from native LDL during foam cell formation has not been clearly defined. Previous reports have suggested that selective cholesteryl ester (CE) uptake might contribute to cholesterol uptake from LDL independently of particle endocytosis. In this study we demonstrate that the majority of macrophage LDL-derived cholesterol is acquired by selective CE uptake in excess of LDL pinocytosis and degradation. Macrophage selective CE uptake does not saturate at high LDL concentrations and is not down-regulated during cholesterol accumulation. In contrast to CE uptake, macrophages exhibit little selective uptake of free cholesterol (FC) from LDL. Following selective uptake from LDL, CE is rapidly hydrolyzed by a novel chloroquine-sensitive pathway. FC released from LDL-derived CE hydrolysis is largely effluxed from cells but also is subject to ACAT-mediated reesterification. These results indicate that selective CE uptake plays a major role in macrophage metabolism of LDL.

Comprehensive diabetes cardiovascular treatment = sugar + blood pressure + lipids

Comprehensive diabetes cardiovascular treatment = sugar + blood pressure + lipids

HMG CoA Reduction in Patients with Average Cholesterol Concentrations

Featured Article: Sacks FM, Pfeffer MA, Moye LA, Rouleau JL, Rutherford JD, Cole TG, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med 1996;335:1001–9.4 In 1984, a National Heart, Lung and Blood Institute trial demonstrated that reducing LDL cholesterol (LDL-C)5 with a combination of diet and large doses of the cholesterol-binding resin cholestyramine reduced coronary events (1) and slowed the progression of coronary artery obstruction (2) in men with increased cholesterol concentrations. Resins were not well tolerated, however, and patient compliance was poor. Subsequently, the availability of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HmG CoA) reductase inhibitors changed the approach to cholesterol management, because these drugs were well tolerated and caused marked reductions in total cholesterol (TC) and LDL-C in the majority of individuals. Two important clinical-outcome trials were launched promptly for patients with hypercholesterolemia. The Scandinavian Simvastatin Survival Study (3) enrolled patients with coronary artery disease and hypercholesterolemia [average TC, 261 mg/dL (6.6 mmol/L); average LDL-C, 188 mg/dL (4.87 mmol/L)], and the West of Scotland Coronary Prevention Study (4) used pravastatin in men without clinical coronary disease [average TC, 272 mg/dL (7.0 mmol/L); average LDL-C, 192 mg/dL (5.0 mmol/L)]. On the basis of the earlier findings (1, 2), we assumed that these trials would show clinical benefit; however, patients with the …

Sudden Acceleration of Diabetes Quality Measures

THE MODERN ERA IN DIABETES PERFORMANCE MEAsurement began in 1997, when the Diabetes Quality Improvement Project (DQIP), the first national disease-specific measure, set recommended thresholds for intermediate outcomes (glycated hemoglobin [HbA1c] levels, blood pressure, and low-density lipoprotein cholesterol [LDL-C] levels). These thresholds, if not achieved, would clearly result in greater population morbidity and mortality. The DQIP explicitly stated that such threshold measures were neither guidelines nor standards and that lower intermediate outcome values should not be used for public reporting owing to lack of evidence for efficacy and the absence of validated risk-adjustment models that would allow for fair comparisons. Also in the 1990s, major randomized trials such as the Diabetes Control and Complications Trial, Scandinavian Simvastatin Survival Study, United Kingdom Prospective Diabetes Study, West of Scotland Coronary Prevention Study, and Hypertension Optimal Treatment Study established stronger evidence for treatment of intermediate-outcome risk factors. These pivotal studies provided the impetus for studies conducted from 2000 onward to determine optimal values for these risk factors to reduce cardiovascular risk in patients with longer duration of disease. The successor to the DQIP, the National Quality Improvement Alliance (Alliance), made few major changes to the measure set from 2001 through 2005 other than to decrease threshold levels for HbA1c from 9.5% to 9.0% and for blood pressure from 140/90 mm Hg to 140/80 mm Hg and to add a threshold level for LDL-C of less than 100 mg/dL. The Alliance members, including liaisons from federal agencies and major professional societies, were aware that planned major trials would inform the choice of threshold values for optimal measures by the end of the decade. However, beginning in 2004, the National Committee for Quality Assurance (NCQA) added optimal measures for HbA1c, blood pressure, and cholesterol to the Diabetes Physician Recognition Program—HbA1c values less than 7%, blood pressure less than 130/80 mm Hg, and LDL-C values less than 100 mg/dL—which were adopted by the Bridges to Excellence pay-for-performance program. In 2005 the Minnesota Community Measurement Program developed a composite measure, termed the Diabetes 5 (D5), that was based on these optimal measures for HbA1c, blood pressure, and LDL-C; administration of aspirin; and nonsmoking status. Despite unanimous opposition from the Technical Advisory Panel of the Alliance, the NCQA approved the optimal measure set in May 2006. Even though inconsistent with guidelines from nonspecialty societies, these measures were widely viewed as evidence-based standards of care because they were based on the guidelines of specialty societies that lent their leadership to the industry-sponsored public service campaign. Coincidentally, 1 week after approval of the optimal measure set, scientific concerns were again raised at an Agency for Healthcare Research and Quality–sponsored conference on diabetes performance measures attended by representatives from key federal agencies, professional societies, the NCQA, and members of academic medicine. In addition to methodological concerns related to selection bias, lack of case-mix adjustment, patient preferences, and measurement variability, the possibility was raised of unintended—and unmeasured—consequences such as harms, costs, and polypharmacy. Indeed, only 2 months later the National Quality Forum did not endorse the “optimal measures.” Much has since changed. The glycemic treatment group in the ACCORD (Action to Control Cardiovascular Risk in Diabetes) study was prematurely terminated because of increased deaths in the intensive treatment group, and the NCQA measure was then modified. Then, the hypertension treatment approach in ACCORD failed to demonstrate benefit of tighter blood pressure control, resulting in modification of NCQA’s optimal measure of 130/80 mm Hg. Although the lipid treatment intervention was designed to evaluate the efficacy of fibrates, the subanalysis did not demonstrate benefit of lower lipid levels; however, this finding needs further evaluation. In the absence of new evidence from 1998 to 2008 and despite ongoing major trials

Baseline cholesterol absorption and the response to ezetimibe/simvastatin therapy: a post-hoc analysis of the ENHANCE trial

Subjects with increased cholesterol absorption might benefit more from statin therapy combined with a cholesterol absorption inhibitor. We assessed whether baseline cholesterol absorption markers were associated with response to ezetimibe/simvastatin therapy, in terms of LDL-cholesterol (LDL-C) lowering and cholesterol absorption inhibition, in patients with familial hypercholesterolemia (FH). In a posthoc analysis of the two-year ENHANCE trial, we assessed baseline cholesterol-adjusted campesterol (campesterol/TC) and sitosterol/TC ratios in 591 FH patients. Associations with LDL-C changes and changes in cholesterol absorption markers were evaluated by multiple regression analysis. No association was observed between baseline markers of cholesterol absorption and the extent of LDL-C response to ezetimibe/simvastatin therapy (beta = 0.020, P = 0.587 for campesterol/TC and beta<0.001, P = 0.992 for sitosterol/TC). Ezetimibe/simvastatin treatment reduced campesterol levels by 68% and sitosterol levels by 62%; reductions were most pronounced in subjects with the highest cholesterol absorption markers at baseline, the so-called high absorbers (P < 0.001). Baseline cholesterol absorption status does not determine LDL-C lowering response to ezetimibe/simvastatin therapy in FH, despite more pronounced cholesterol absorption inhibition in high absorbers. Hence, these data do not support the use of baseline absorption markers as a tool to determine optimal cholesterol lowering strategy in FH patients. However, due to the exploratory nature of any posthoc analysis, these results warrant further prospective evaluation in different populations.

Statins

Coronary heart disease (CHD) is the leading cause of death in India resulting in loss of young Indians. Statins have proved to reduce the CHD mortality in various clinical trials. The aim of the study is to find the cost-effectiveness ratio (CER) for each major coronary event averted and a coronary death avoided by use of statins in different clinical settings based on the data from the major clinical trials on statins. Using electronic database and as per our inclusion and exclusion criteria we selected the West of Scotland Coronary Prevention Study (WOSCOPS), the Air Force Coronary Atherosclerosis Prevention Study (AFCAPS) and the Anglo-Scandinavian Cardiac Outcomes Trial--Lipid Lowering Arm (ASCOT-LLA) study for primary prevention; the Cholesterol and Recurrent Events Trial (CARE), the Long-term Intervention with Pravastatin in Ischemic Disease (LIPID) Study and the Scandinavian Simvastatin Survival Study (4S) for secondary prevention and two studies, the Heart Protection Study (HPS) and the Pravastatin in elderly individuals at risk of vascular disease (PROSPER) study for high-risk patients. The results of these studies were used for cost-effectiveness analysis of statins in different patient groups. Absolute risk reduction, Number Needed to Benefit (NNTB), NNTB/year for total sample and in subgroups of males, females and age >65 was derived. CER for branded and generic versions was calculated by using the prices of statins listed in Indian Drug Review Triple i. Cost-effectiveness ratio (CER) in primary prevention studies i.e., the WOSCOPS, the AFCAPS and the ASCOT-LLA was Rs. 25.8 lacs, Rs. 23.8 lacs and Rs. 7.9 lacs per major coronary event averted respectively. CER in secondary prevention studies i.e., the CARE and the LIPID was approximately Rs. 20 lacs per major coronary event averted while it was Rs. 52.4 lacs and Rs. 37 lacs per coronary heart disease (CHD) death avoided. CER from the 4S was Rs. 6.9 lacs per major coronary event and Rs. 16.9 lacs per CHD death averted. CER in the HPS and the PROSPER study was Rs. 17.9 lacs and Rs. 27.1 lacs per major coronary event avoided in high-risk patients. Cost associated with the use of statins is higher in primary prevention as compared to secondary prevention. More studies are needed to confirm the cost-effectiveness of statins to make any decision for health policy.

Triglycerides and HDL Cholesterol

Diabetes carries a high risk of atherosclerosis, and cardiovascular disease, especially coronary heart disease (CHD) and stroke, is by far the leading cause of death among patients with type 2 diabetes. Although statins reduce the risk of major vascular events by about one-fifth per millimole per liter reduction in LDL cholesterol, with similar proportional reductions in major coronary events, stroke, and the need for coronary revascularization, the residual risk remains high. In the Scandinavian Simvastatin Survival Study (4S) (1), although the relative risk reduction in diabetic patients was larger than in nondiabetic patients, simvastatin-treated diabetic patients were still at higher risk of death than the placebo-treated nondiabetic patients. Multifactorial intervention reduces the risk even further, but significant danger remains. Current guidelines call for an aggressive treatment strategy to reduce LDL cholesterol, blood pressure, and glucose levels in diabetic patients, but data concerning the management of high triglyceride (TG) levels and low HDL cholesterol levels remains inconclusive. This article reviews the data concerning diabetic dyslipidemia and its management. The cluster of lipid abnormalities associated with type 2 diabetes is defined by a high concentration of TG and small dense LDL and a low concentration of HDL cholesterol. Plasma LDL cholesterol levels are generally normal. Insulin resistance is believed to contribute to this atherogenic dyslipidemia by increasing the hepatic secretion of VLDL and other apolipoprotein (apo)B-containing lipoprotein particles, as a result of increased free fatty acid flux to the liver (2,3). This may also be the result of a diminished suppressive effect of insulin on apoB secretion, either at the level of the regulation of apoB degradation, or inhibition of microsomal TG transfer protein activity (4). Through the action of cholesterol ester transfer protein, TGs are transferred from VLDL to HDL, creating TG-rich HDL particles, which are hydrolyzed by hepatic …