EULAR recommendations for cardiovascular disease risk management in patients with rheumatoid arthritis and other forms of inflammatory joint disorders: 2015/2016 update.

Patients with rheumatoid arthritis (RA) and other inflammatory joint disorders (IJD) have increased cardiovascular disease (CVD) risk compared with the general population. In 2009, the European League Against Rheumatism (EULAR) taskforce recommended screening, identification of CVD risk factors and CVD risk management largely based on expert opinion. In view of substantial new evidence, an update was conducted with the aim of producing CVD risk management recommendations for patients with IJD that now incorporates an increasing evidence base. A multidisciplinary steering committee (representing 13 European countries) comprised 26 members including patient representatives, rheumatologists, cardiologists, internists, epidemiologists, a health professional and fellows. Systematic literature searches were performed and evidence was categorised according to standard guidelines. The evidence was discussed and summarised by the experts in the course of a consensus finding and voting process. Three overarching principles were defined. First, there is a higher risk for CVD in patients with RA, and this may also apply to ankylosing spondylitis and psoriatic arthritis. Second, the rheumatologist is responsible for CVD risk management in patients with IJD. Third, the use of non-steroidal anti-inflammatory drugs and corticosteroids should be in accordance with treatment-specific recommendations from EULAR and Assessment of Spondyloarthritis International Society. Ten recommendations were defined, of which one is new and six were changed compared with the 2009 recommendations. Each designated an appropriate evidence support level. The present update extends on the evidence that CVD risk in the whole spectrum of IJD is increased. This underscores the need for CVD risk management in these patients. These recommendations are defined to provide assistance in CVD risk management in IJD, based on expert opinion and scientific evidence.

Efficacy and safety of LDL-lowering therapy among men and women: meta-analysis of individual data from 174,000 participants in 27 randomised trials.

BACKGROUND: Whether statin therapy is as effective in women as in men is debated, especially for primary prevention. We undertook a meta-analysis of statin trials in the Cholesterol Treatment Trialists' (CTT) Collaboration database to compare the effects of statin therapy between women and men. METHODS: We performed meta-analyses on data from 22 trials of statin therapy versus control (n=134,537) and five trials of more-intensive versus less-intensive statin therapy (n=39,612). Effects on major vascular events, major coronary events, stroke, coronary revascularisation and mortality were weighted per 1.0 mmol/L reduction in LDL cholesterol and effects in men and women compared with a Cox model that adjusted for non-sex differences. For subgroup analyses, we used 99% CIs to make allowance for the multiplicity of comparisons. FINDINGS: 46,675 (27%) of 174,149 randomly assigned participants were women. Allocation to a statin had similar absolute effects on 1 year lipid concentrations in both men and women (LDL cholesterol reduced by about 1.1 mmol/L in statin vs control trials and roughly 0.5 mmol/L for more-intensive vs less-intensive therapy). Women were generally at lower cardiovascular risk than were men in these trials. The proportional reductions per 1.0 mmol/L reduction in LDL cholesterol in major vascular events were similar overall for women (rate ratio [RR] 0.84, 99% CI 0.78-0.91) and men (RR 0.78, 99% CI 0.75-0.81, adjusted p value for heterogeneity by sex=0.33) and also for those women and men at less than 10% predicted 5 year absolute cardiovascular risk (adjusted heterogeneity p=0.11). Likewise, the proportional reductions in major coronary events, coronary revascularisation, and stroke did not differ significantly by sex. No adverse effect on rates of cancer incidence or non-cardiovascular mortality was noted for either sex. These net benefits translated into all-cause mortality reductions with statin therapy for both women (RR 0.91, 99% CI 0.84-0.99) and men (RR 0.90, 99% CI 0.86-0.95; adjusted heterogeneity p=0.43). INTERPRETATION: In men and women at an equivalent risk of cardiovascular disease, statin therapy is of similar effectiveness for the prevention of major vascular events. FUNDING: UK Medical Research Council, British Heart Foundation, Australian National Health and Medical Research Council, European Community Biomed Program.

Systemic inflammation in patients with inflammatory joint diseases does not influence statin dose needed to obtain LDL cholesterol goal in cardiovascular prevention.

OBJECTIVES: There is a lipid paradox in rheumatoid arthritis describing that despite low lipids related to systemic inflammation, there is an increased cardiovascular (CV) risk. Our aim was to evaluate if baseline lipid levels or baseline systemic inflammation were associated with the statin dose sufficient to achieve lipid targets in patients with inflammatory joint diseases. METHODS: In this longitudinal, short-term follow-up observational report, we evaluated 197 patients who did and 36 patients who did not reach the recommended low density lipoprotein cholesterol (LDL-c) target. The patients were, after CV risk evaluation, classified to either primary or secondary CV prevention with lipid lowering treatment (LLT). LLT was initiated with statins and adjusted until at least two lipid targets were achieved. Intensive LLT was defined as rosuvastatin ≥20 mg, atorvastatin and simvastatin at the highest dose (80 mg), and conventional LLT were defined as all lower doses. RESULTS: In an independent sample t test, systemic inflammation or lipid levels at baseline were not associated with the statin dose (intensive or conventional) needed to achieve recommended LDL-c target (C reactive protein/erythrocyte sedimentation rate: p=0.10 and p=0.11, and LDL-c/total cholesterol: p=0.17 and p=0.34, respectively). The baseline inflammatory status and lipid levels in patients who did and did not obtain LDL-c goal were comparable (C reactive protein/erythrocyte sedimentation rate: p=0.32 and p=0.64, and LDL-c/total cholesterol: p=0.20 and p=0.83, respectively). CONCLUSIONS: Systemic inflammation or lipid levels did not influence the intensity of statin treatment needed to obtain guideline recommended lipid targets in CV prevention. Whether the background inflammation in patients with inflammatory joint diseases over time influences the CV risk reduction related to statins is yet unknown.

Cardiovascular outcomes and their relationships to lipoprotein components in patients with and without chronic kidney disease: results from the IDEAL trial.

OBJECTIVES: In Incremental Decrease in Endpoints through Aggressive Lipid-lowering (IDEAL), we compared cardiovascular outcomes in patients with and without chronic kidney disease (CKD) (estimated glomerular filtration rate <60 mL min(-1) 1.73 m(-2)) and analysed relationships between lipoprotein components (LC) and major coronary events (MCE) and other cardiovascular (CV) events. DESIGN: Exploratory analysis of CV endpoints in a randomized trial comparing high dose of atorvastatin to usual dose of simvastatin on MCE. SETTINGS: Patients with CKD were compared with the non-CKD patients. Cox regression models were used to study the relationships between on-treatment levels of LC and incident MCE. FINDINGS: Chronic kidney disease was strongly associated with cardiovascular end-points including total mortality. In patients with CKD, a significant benefit of high dose atorvastatin treatment was found for any CV events, stroke and peripheral artery disease, but not for MCE. However, all cardiovascular end-points except stroke and CV mortality were reduced in the non-CKD group. Differential changes in LC or relationships to LC could not explain the different treatment outcomes in MCE in the two groups. INTERPRETATION: Chronic kidney disease was a powerful risk factor for all cardiovascular end-points. The reason why the significant reductions achieved by high-dose statin treatment in most CV end-points in the non-CKD group were only in part matched by similar reductions in the CKD patients is not apparent. This difference did not result from differential changes in or relations to LC, but limited power may have increased the possibility of chance findings.

Lipids, myocardial infarction and ischaemic stroke in patients with rheumatoid arthritis in the Apolipoprotein-related Mortality RISk (AMORIS) Study.

OBJECTIVES: To examine the rates of acute myocardial infarction (AMI) and ischaemic stroke (IS) and to examine the predictive value of total cholesterol (TC) and triglycerides (TG) for AMI and IS in patients with rheumatoid arthritis (RA) and people without RA. METHODS: In the Apolipoprotein MOrtality RISk (AMORIS) Study 480 406 people (including 1779 with RA, of whom 214 had an AMI and 165 an IS) were followed for 11.8 (range 7-17) years. Cox regression analysis was used to calculate HR per SD increase in TC or TG with 95% CI. All values were adjusted for age, diabetes and hypertension. RESULTS: The levels of TC and TG were significantly lower in patients with RA than in people without RA. Despite this, the rate of AMI and IS per 1000 years was at least 1.6 times higher in RA than non-RA. TC was nearly significantly predictive for AMI (HR/SD 1.13 (95% CI 0.99 to 1.29), p=0.07) and significantly predictive for future IS in RA (HR/SD 1.20 (95% CI 1.03 to 1.40), p=0.02). TG had no relationship to development of AMI (1.07, 0.94 to 1.21, p=0.29), but was weakly related to IS (1.13, 0.99 to 1.27, p=0.06). In contrast, both TC and TG were significant predictors of AMI and IS in people without RA. CONCLUSIONS: Patients with RA had 1.6 times higher rate of AMI and IS than people without RA. TC and TG were significant predictors of AMI and IS in people without RA, whereas the predictive value in RA was not consistent.

Effects of a low glycemic load diet versus a low-fat diet in subjects with and without the metabolic syndrome.

BACKGROUND AND AIM: Although many studies report benefits of low glycemic diets, the clinical effects as a whole are mixed. The study aim was to compare a low glycemic load (LGL) diet versus a low-fat diet in a trial with a moderately intense dietary intervention in subjects with varying degrees of metabolic syndrome. METHODS AND RESULTS: Men and women aged 30-65 years, with a BMI of 28-40 kg/m(2) (28-35 for women) and at least one criterion of metabolic syndrome were randomized to the two diets. A total of 202 subjects were included, of which 126 (62%) had metabolic syndrome (>or=3 criteria). The completion rate was 81%. At 3 months, weight loss was greater in the LGL group (-4.8+/-3.9 kg versus -3.8+/-3.5 kg; P=0.06) compared to the low-fat group. At 1 year, however, weight loss was similar in both groups (-4.0+/-5.5 kg versus -4.3+/-6.2 kg; n.s.), but waist circumference reduction was less in the LGL group (-3.9+/-5.3 cm versus -5.8+/-6.8 cm; P=0.03). In contrast, diastolic blood pressure decreased significantly more in the LGL group (-4.0+/-8.7 mmHg versus -1.1+/-8.5 mmHg; P=0.02). We also observed a significant interaction between the presence of the metabolic syndrome and the effect of the two diets on waist circumference, with a less favorable effect of the LGL diet in subjects without the syndrome (P=0.039). CONCLUSION: After 12 months, both diets reduced body weight and the metabolic disturbances similarly, but the LGL diet appeared more suitable for subjects with metabolic syndrome, and was less effective in those without it.

Influence of low high-density lipoprotein cholesterol and elevated triglyceride on coronary heart disease events and response to simvastatin therapy in 4S.

BACKGROUND: Patients with low HDL cholesterol (HDL-C) and elevated triglyceride had an increased risk for coronary heart disease (CHD) events and received the greatest benefit with fibrate therapy in substudy analyses of the Helsinki Heart Study and the Bezafibrate Infarction Prevention Study. METHODS AND RESULTS: In this post hoc analysis of the Scandinavian Simvastatin Survival Study, which enrolled patients with elevated LDL cholesterol (LDL-C) and CHD, subgroups defined by HDL-C and triglyceride quartiles were compared to examine the influence of HDL-C and triglyceride on CHD events and response to therapy. Patients in the lowest HDL-C (<1.00 mmol/L [39 mg/dL]) and highest triglyceride (>1.80 mmol/L [159 mg/dL]) quartiles (lipid triad; n=458) had increased proportions of other features of the metabolic syndrome (increased body mass index, hypertension, diabetes), men, prior myocardial infarction, prior revascularization, and beta-blocker use than patients in the highest HDL-C (>1.34 mmol/L [52 mg/dL]) and lowest triglyceride (<1.11 mmol/L [98 mg/dL]) quartiles (isolated LDL-C elevation; n=545). The major coronary event rate was highest in lipid triad patients on placebo (35.9%), and this subgroup had the greatest event reduction (relative risk 0.48, 95% CI 0.33 to 0.69); a significant treatment-by-subgroup interaction (P=0.03) indicated a greater treatment effect in the lipid triad subgroup than the isolated LDL-C elevation subgroup. CONCLUSIONS: Patients with elevated LDL-C, low HDL-C, and elevated triglycerides were more likely than patients with isolated LDL-C elevation to have other characteristics of the metabolic syndrome, had increased risk for CHD events on placebo, and received greater benefit with simvastatin therapy.

Noninvasive evaluation of the effect of timolol on left ventricular performance after myocardial infarction and the consequence for prognosis.

Left ventricular performance was evaluated noninvasively in 111 patients participating at one study center in the Norwegian Multicenter Study on Timolol After Myocardial Infarction. Systolic time intervals were measured in 55 patients treated with timolol and in 56 patients receiving placebo. Measurements were made before randomization, and after 1, 3 and 12 months of treatment. During the treatment period, the pre-ejection period/left ventricular ejection time ratio was significantly lower in the timolol-treated group, indicating better left ventricular function than in the placebo-treated patients. In the 27 patients who died during the follow-up period of 50 to 72 months, there was a significant increase in the pre-ejection period/left ventricular ejection time ratio from baseline to the last performed recording, indicating a deterioration in left ventricular performance in these patients. No such change occurred in the group that survived the entire follow-up period. Deterioration of left ventricular function is related to a high long-term mortality rate after myocardial infarction, and left ventricular function is better preserved in patients treated with timolol than in patients receiving placebo.

Randomized trial of low molecular weight heparin (dalteparin) in prevention of left ventricular thrombus formation and arterial embolism after acute anterior myocardial infarction: the Fragmin in Acute Myocardial Infarction (FRAMI) Study.

OBJECTIVES: The present trial investigated the efficacy and safety of dalteparin in the prevention of arterial thromboembolism after an acute anterior myocardial infarction (MI). BACKGROUND: Left ventricular (LV) thrombus formation is associated with increased risk of arterial embolism in patients with an acute MI. Thrombolytic and antiplatelet therapy do not prevent thrombus formation. METHODS: A total of 776 patients were enrolled in a multicenter, randomized, double-blind, placebo-controlled trial of subcutaneous dalteparin (150 IU/kg body weight every 12 h during the hospital period). Thrombolytic therapy and aspirin were administered in 91.5% and 97.6% of patients, respectively. The primary study end point was the composite of thrombus formation diagnosed by echocardiography and arterial embolism on day 9 +/- 2. RESULTS: Of 517 patients with echocardiographic recordings available for end point analysis, thrombus formation or embolism, or both, was found in 59 (21.9%) of 270 patients (59 with thrombus, none with embolism) in the placebo group and 35 (14.2%) of 247 patients (34 with thrombus, 1 with embolism) in the dalteparin group (p = 0.03). The risk reduction of thrombus formation associated with dalteparin treatment was 0.63 (95% confidence interval 0.43 to 0.92, p = 0.02). Analyses of all randomized patients (388 in each group) revealed no significant difference between the placebo and dalteparin groups with respect to arterial embolism (6 vs. 5 patients), reinfarction (8 vs. 6 patients) and mortality rates (23 vs. 23 patients, p = NS for all). Dalteparin was associated with an increased risk of hemorrhage: major in 11 dalteparin group patients (2.9%) verus 1 placebo group patient (0.3%, p = 0.006); minor in 52 dalteparin group patients (14.8%) versus 8 placebo group patients (1.8%, p < 0.001). CONCLUSIONS: Dalteparin treatment significantly reduces LV thrombus formation in acute anterior MI but is associated with increased hemorrhagic risk.

Reduced coronary events in simvastatin-treated patients with coronary heart disease and diabetes or impaired fasting glucose levels: subgroup analyses in the Scandinavian Simvastatin Survival Study.

BACKGROUND: Patients with diabetes mellitus (DM) have a marked increase in coronary heart disease (CHD) events relative to those without DM. In a previous report from the Scandinavian Simvastatin Survival Study using a clinical case definition of DM (n = 202), simvastatin-treated patients had significantly fewer CHD events compared with placebo-treated control subjects. OBJECTIVE: To examine the effect of simvastatin therapy on CHD in patients with DM and impaired fasting glucose levels. METHODS: Using the 1997 American Diabetes Association diagnostic criteria, we assessed the effect of simvastatin therapy post hoc for an average of 5.4 years in Scandinavian Simvastatin Survival Study patients with normal fasting glucose (n = 3237), impaired fasting glucose (n = 678), and DM (n = 483). RESULTS: Simvastatin-treated patients with DM had significantly reduced numbers of major coronary events (relative risk [RR] = 0.58; P = .001) and revascularizations (RR = 0.52; P = .005). Total (RR = 0.79; P = .34) and coronary (RR = 0.72; P = .26) mortality were also reduced in DM, but not significantly, due to small sample size. In impaired fasting glucose (IFG) subjects, simvastatin use significantly reduced the number of major coronary events (RR = 0.62; P = .003), revascularizations (RR = 0.57; P = .009), and total (RR = 0.57; P = .02) and coronary (RR = 0.45; P = .007) mortality. CONCLUSION: Our results extend previous findings in patients with DM to a larger cohort, confirming the benefit of cholesterol lowering with simvastatin treatment on CHD events. In addition, significant decreases in total mortality, major coronary events, and revascularizations were observed in simvastatin-treated patients with impaired fasting glucose levels. These results strongly support the concept that cholesterol lowering with simvastatin therapy improves the prognosis of patients with elevated fasting glucose levels (> or =6.0 mmol/L [> or =110 mg/ dL]) or DM and known CHD.

Safety and tolerability of cholesterol lowering with simvastatin during 5 years in the Scandinavian Simvastatin Survival Study.

BACKGROUND: Long-term safety is an important consideration in the selection and use of drugs, such as lipid-lowering agents, that are prescribed to reduce the risk of clinical events during long periods. METHODS: The Scandinavian Simvastatin Survival Study was designed to evaluate the effects of cholesterol lowering with simvastatin on mortality and morbidity in patients with coronary heart disease. The 4444 patients aged 35 to 70 years (mean, 58.9 years) with angina pectoris or previous myocardial infarction and serum cholesterol levels of 5.5 to 8.0 mmol/L (213-310 mg/dL) receiving a lipid-lowering diet were randomly assigned to take double-blind treatment with simvastatin, 20 to 40 mg once daily, or placebo. In addition to previously reported end-point events, detailed clinical and laboratory safety data were collected during a median follow-up period of 5.4 years (range in survivors, 4.9-6.2 years). RESULTS: The only clearly drug-related serious adverse event during the 5.4-year median follow-up period was a single reversible case of myopathy. The frequencies of persistent elevations of hepatic aminotransferase levels above 3 times the upper limit of normal and of nonviral hepatitis in the simvastatin and placebo treatment groups were not significantly different. Examination of the lens showed no between-group differences, and no previously unrecognized adverse effects of the drug were observed. There were no significant between-group differences in adverse events in any body system. In particular, the frequency of adverse events related to the central nervous system was similar in both groups. CONCLUSION: The safety profile of simvastatin, 20 to 40 mg daily, over 5 years was excellent.

Cholesterol lowering with simvastatin improves prognosis of diabetic patients with coronary heart disease. A subgroup analysis of the Scandinavian Simvastatin Survival Study (4S)

OBJECTIVE: To assess in diabetic patients with coronary heart disease (CHD) the effect of cholesterol lowering with simvastatin on mortality and the risk of CHD and other atherosclerotic events. RESEARCH DESIGN AND METHODS: A post hoc subgroup analysis was carried out on data from 202 diabetic patients and 4,242 nondiabetic patients with previous myocardial infarction or angina pectoris, serum total cholesterol 5.5-8.0 mmol/l, and serum triglycerides < or = 2.5 mmol/l who were participating in the Scandinavian Simvastatin Survival Study (4S). Participants in the 4S were randomly assigned to double-blind treatment with simvastatin, 20 mg daily, with blinded dosage titration up to 40 mg daily, according to cholesterol response during the first 6-18 weeks, or placebo. Endpoints were 1) total mortality, 2) major CHD events (CHD death or nonfatal myocardial infarction), 3) other acute atherosclerotic events, 4) myocardial revascularization procedures. RESULTS: Over the 5.4-year median follow-up period, simvastatin treatment produced mean changes in serum lipids in diabetic patients similar to those observed in nondiabetic patients. The relative risks (RRs) of main endpoints in simvastatin-treated diabetic patients were as follows: total mortality 0.57 (95% CI, 0.30-1.08; P = 0.087), major CHD events 0.45 (95% CI, 0.27-0.74; P = 0.002), and any atherosclerotic event 0.63 (95% CI, 0.43-0.92; P = 0.018). The corresponding RRs in nondiabetic patients were the following: 0.71 (95% CI, 0.58-0.87; P = 0.001), 0.68 (95% CI, 0.60-0.77; P < 0.0001), and 0.74 (95% CI, 0.68-0.82; P < 0.0001). CONCLUSIONS: The results strongly suggest that cholesterol lowering with simvastatin improves the prognosis of diabetic patients with CHD. The absolute clinical benefit achieved by cholesterol lowering may be greater in diabetic than in nondiabetic patients with CHD because diabetic patients have a higher absolute risk of recurrent CHD events and other atherosclerotic events.

Effect of simvastatin treatment on cardiovascular resource utilization in impaired fasting glucose and diabetes. Findings from the Scandinavian Simvastatin Survival Study.

OBJECTIVE: The Scandinavian Simvastatin Survival Study showed that simvastatin treatment reduced cardiovascular events in hypercholesterolemic subjects with coronary heart disease. The clinical benefits of therapy were similar in all three subgroups: normal fasting glucose (NFG, n = 3,237), impaired fasting glucose (IFG, n = 678), and diabetes (n = 483). This analysis compared the costs of simvastatin treatment with the costs of cardiovascular disease-related hospitalizations in the three subgroups. RESEARCH DESIGN AND METHODS: The cost of simvastatin treatment was defined as the average retail price and the cost of drug safety monitoring and adverse experiences. The costs of cardiovascular disease-related hospitalizations were determined by actual rates of hospitalization and 1995 MEDSTAT diagnosis-related group costs. RESULTS: Within trial, simvastatin treatment cost approximately $6,000 per patient. Simvastatin treatment reduced cardiovascular disease-related hospitalizations by 23% in NFG (P = 0.001), 30% in IFG (P = 0.015), and 40% in diabetic subjects (P = 0.007) within trial (median follow-up of 5.4 years). Average length of stay was reduced by 2.4 days in diabetic subjects (P = 0.021). Total cardiovascular disease-related hospital days were reduced by 28% (P < 0.001) in NFG, 38% (P = 0.005) in IFG, and 55% (P < 0.001) in diabetic subjects. For NFG subjects, simvastatin reduced the average cost of cardiovascular disease-related hospitalizations by $3,585, which offset 60% of the cost of simvastatin therapy. For IFG subjects, average cardiovascular disease-related hospitalization costs were reduced by $4,478, which offset 74% of the drug cost. For diabetic subjects, there was a net cost savings of $1,801 per subject within trial. CONCLUSIONS: Simvastatin significantly reduced cardiovascular disease-related hospitalizations and total hospital days for all three groups and significantly reduced length of stay for the diabetic group in addition to providing significant clinical benefits. The benefits were greatest in the diabetic group, with estimated cost savings within trial from simvastatin treatment.

Rosuvastatin-Induced Carotid Plaque Regression in Patients With Inflammatory Joint Diseases: The Rosuvastatin in Rheumatoid Arthritis, Ankylosing Spondylitis and Other Inflammatory Joint Diseases Study.

OBJECTIVE: Patients with rheumatoid arthritis (RA) and carotid artery plaques have an increased risk of acute coronary syndromes. Statin treatment with the goal of achieving a low-density lipoprotein (LDL) cholesterol level of ≤1.8 mmoles/liter (≤70 mg/dl) is recommended for individuals in the general population who have carotid plaques. The aim of the ROsuvastatin in Rheumatoid Arthritis, Ankylosing Spondylitis and other inflammatory joint diseases (RORA-AS) study was to evaluate the effect of 18 months of intensive lipid-lowering treatment with rosuvastatin with regard to change in carotid plaque height. METHODS: Eighty-six patients (60.5% of whom were female) with carotid plaques and inflammatory joint disease (55 with RA, 21 with AS, and 10 with psoriatic arthritis) were treated with rosuvastatin to obtain the LDL cholesterol goal. Carotid plaque height was evaluated by B-mode ultrasonography. RESULTS: The mean ± SD age of the patients was 60.8 ± 8.5 years, and the median compliance with rosuvastatin treatment was 97.9% (interquartile range [IQR] 96.0-99.4). At baseline, the median number and height of the carotid plaques were 1.0 (range 1-8) and 1.80 mm (IQR 1.60-2.10), respectively. The mean ± SD change in carotid plaque height after 18 months of treatment with rosuvastatin was -0.19 ± 0.35 mm (P < 0.0001). The mean ± SD baseline LDL cholesterol level was 4.0 ± 0.9 mmoles/liter (154.7 ± 34.8 mg/dl), and the mean reduction in the LDL cholesterol level was -2.3 mmoles/liter (95% confidence interval [95% CI] -2.48, -2.15) (-88.9 mg/dl [95% CI -95.9, -83.1]). The mean ± SD LDL cholesterol level during the 18 months of rosuvastatin treatment was 1.7 ± 0.4 mmoles/liter (area under the curve). After adjustment for age/sex/blood pressure, no linear relationship between a reduction in carotid plaque height and the level of LDL cholesterol exposure during the study period was observed. Attainment of the LDL cholesterol goal of ≤1.8 mmoles/liter (≤70 mg/dl) or the amount of change in the LDL cholesterol level during the study period did not influence the degree of carotid plaque height reduction. CONCLUSION: Intensive lipid-lowering treatment with rosuvastatin induced atherosclerotic regression and reduced the LDL cholesterol level significantly in patients with inflammatory joint disease.

Review of cholesterol-lowering therapy: coronary angiographic and events trials.

Coronary angiographic trials have demonstrated that the lowering of cholesterol slows the progression of atherosclerosis, enhances atherosclerotic regression, limits the formation of new lesions, and reduces the incidence of coronary events. Atherosclerotic progression has been shown to be associated with an increased risk of cardiac death, cardiac death plus nonfatal myocardial infarction (MI), and all coronary events. Most of the atherosclerotic regression trials were too small and of too short duration to demonstrate a significant difference in hard coronary events between patients receiving cholesterol-lowering intervention and controls. However, when data from these studies were pooled, total mortality was found to be reduced by 26% and the rate of nonfatal MI by 39% in actively treated patients. The first events trial to demonstrate clearly a reduction in overall mortality was the Scandinavian Simvastatin Survival Study (4S), in which lowering of serum cholesterol in patients with coronary artery disease (CAD) and hypercholesterolemia also reduced coronary mortality, fatal and nonfatal MI, sudden cardiac death, and the need for revascularization. Reductions in major coronary events were seen consistently in all subgroups of patients studied and regardless of concomitant therapy with aspirin, beta blockers, or calcium antagonists. Further evidence of the benefit of cholesterol-lowering therapy was provided by the West of Scotland Coronary Prevention Study (WOSCOPS), which evaluated men with hypercholesterolemia but no history of CAD. Those receiving active treatment had less overall mortality, lower risk of definite nonfatal MI or death from definite or suspected CAD, and less need for revascularization. The Cholesterol and Recurrent Events (CARE) Study recently showed that lipid-lowering therapy is also beneficial in CAD patients with less severe dyslipidemia.

Pro and con: low-density lipoprotein cholesterol lowering is and will be the key to the future of lipid management.

A wealth of data demonstrate that reduction of cholesterol levels is associated with benefit in reducing coronary artery disease risk. The magnitude of benefit observed with statin treatment, which acts primarily to reduce low-density lipoprotein cholesterol (LDL-C), is greater than that observed with any other lipid-modifying intervention, and data from large statin trials indicate that this benefit is caused by LDL-C reduction. Statin treatment is highly cost-effective compared with other accepted therapies, at least in the secondary prevention setting, and has a superior safety and tolerability profile. For the foreseeable future, LDL-C reduction will remain the goal of lipid-modifying therapy, and statins will remain the primary therapeutic modality for achieving that goal.

Coronary artery disease: the Scandinavian Simvastatin Survival Study experience.

Although hyperlipidemia is a known risk factor for coronary artery disease, lipid-lowering agents were not used widely until recently because evidence was lacking that they could prolong life. In 1987, a large clinical trial, the Scandinavian Simvastatin Survival Study (4S), was designed to test whether such therapy could decrease all-cause mortality in patients with documented coronary artery disease. The prospective, randomized, multicenter trial included 4,444 patients who had had angina pectoris or myocardial infarction (MI), serum total cholesterol of 213-310 mg/dL, and serum triglycerides < or =221 mg/dL. Patients received either simvastatin 20-40 mg/day or placebo and were followed for a median of 5.4 years. Therapy decreased total cholesterol an average of 25%; low-density lipoprotein (LDL) cholesterol, 35%; and triglyceride levels, 10%. Therapy increased high-density lipoprotein (HDL) cholesterol levels 8%. Although noncardiac death rates were similar among the groups, the relative risk of mortality (from any cause) was decreased 30%, and the relative risk of coronary mortality was decreased 42% in the simvastatin arm. The mortality risk reductions were profound in patients > or =60 years of age. Treatment also significantly decreased the relative risk of coronary events and the need for bypass surgery or coronary angioplasty. Patients with diabetes also benefited significantly from simvastatin therapy. The reductions in relative risk of major coronary events were achieved irrespective of such baseline risk factors as hypertension and smoking and such medication factors as aspirin, beta-blocker, and calcium-antagonist use. Simvastatin therapy has been shown to be cost-effective, decreasing per-patient hospitalization costs by 31% or $3,872 in 1995 dollars.

Reducing the risk of coronary events: evidence from the Scandinavian Simvastatin Survival Study (4S).

The Scandinavian Simvastatin Survival Study (4S) was designed to evaluate the effects of cholesterol reduction with simvastatin on mortality and morbidity in patients with coronary artery disease (CAD). A total of 4,444 patients with angina pectoris or previous myocardial infarction and serum cholesterol levels of 213-310 mg/dl (5.5-8.0 mmol/liter) while treated with a lipid-lowering diet were randomly assigned to double-blind treatment with simvastatin or placebo. Over the 5.4 years of median follow-up, simvastatin produced changes in total cholesterol, low density lipoprotein (LDL) cholesterol, and high density lipoprotein (HDL) cholesterol of -25%, -35%, and +8%, respectively, with minimal adverse effects. A total of 256 patients (12%) in the placebo group died compared with 182 (8%) in the simvastatin group, a risk reduction of 30% (p = 0.0003) attributable to a 42% reduction in the risk of coronary death. Noncardiovascular causes accounted for 49 and 46 deaths in the placebo and simvastatin groups, respectively. Major coronary events were experienced by 622 patients (28%) in the placebo group and 431 patients (19%) in the simvastatin group, corresponding to a risk reduction of 34% (p < 0.00001). This risk was also significantly reduced in subgroups consisting of women and patients of both sexes aged > or = 60 years. Other benefits of treatment included a 37% reduction (p < 0.00001) in the risk of undergoing myocardial revascularization procedures. Simvastatin was beneficial regardless of whether patients had a history of myocardial infarction or whether they were smokers or had hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of simvastatin on ischemic signs and symptoms in the Scandinavian simvastatin survival study (4S).

In patients participating in the Scandinavian Simvastatin Survival Study, cholesterol lowering with simvastatin reduced the incidence of carotid bruits and cerebrovascular events as well as new-onset or worsening of angina pectoris and intermittent claudication. These effects suggest that simvastatin may have a general antiatherosclerotic effect not limited to the coronary bed.

Follow-up study of patients randomized in the Scandinavian simvastatin survival study (4S) of cholesterol lowering.

The Scandinavian Simvastatin Survival Study (4S) and other randomized clinical trials have demonstrated that cholesterol-lowering treatment with statins improves prognosis in patients with coronary atherosclerosis compared with placebo. The effect of therapy with statins beyond the typical 5 to 6 years' duration of the trials, in particular regarding the risk of cancer, has not been investigated. This study examines the long-term effects of simvastatin for up to 8 years on cause-specific mortality in patients with coronary heart disease (CHD). We performed an observational, government registry-based study of mortality in the groups originally randomized to simvastatin or placebo in the 4S over an additional 2-year follow-up period, so that the median total follow-up period was 7.4 years (range 6.9 to 8.3 in surviving patients). Randomization took place at outpatient clinics at 94 clinical centers in Denmark, Finland, Iceland, Norway, and Sweden from 1988 to 1989. Of 4,444 patients with CHD, 2,223 and 2,221 were randomized to treatment with placebo or simvastatin therapy, respectively. Patients received treatment with simvastatin, starting at 20 mg/day, with titration to 40 mg/day at 12 or 24 weeks if total cholesterol was >5.2 mmol/L (200 mg/dl), or placebo. After the double-blind period, most patients in both treatment groups received simvastatin as open-label prescription. Of the 1,967 patients originally treated with placebo and surviving the double-blind period, 97 (4.9%) died during the following 2 years. In the group randomized to simvastatin the corresponding number was 74 of the 2, 039 survivors (3.6%). Adding these deaths to those occurring during the original trial, the total was 353 (15.9%) and 256 (11.5%) deaths in the groups originally randomized to placebo and simvastatin, respectively. The relative risk was 0.70 (95% confidence interval 0. 60 to 0.82, p = 0.00002). The total number of cancer deaths was 68 (3.1%) in the placebo group and 52 (2.3%) in the simvastatin group (relative risk 0.73, 95% confidence interval 0.51 to 0.05, p = 0. 087), and the numbers of noncardiovascular and other deaths were similar in both groups. We therefore conclude that treatment with simvastatin for up to 8 years in patients with CHD is safe and yields continued survival benefit.