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.

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.

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.

Triglycerides-diabetes association in healthy middle-aged men: modified by physical fitness? A long term follow-up of 1962 Norwegian men in the Oslo Ischemia Study.

AIMS: To examine the impact of physical fitness (PF) on the association between fasting serum triglycerides (FTG) and diabetes risk and whether temporal changes in FTG predict diabetes risk in healthy middle-aged men. METHODS: FTG and PF (bicycle exercise test) were measured in 1962 men aged 40-59 years in 1972-1975 (Survey 1) and repeated in 1387 still healthy men on average 7.3 years later (Survey 2). Diabetes was diagnosed according to WHO 1985-criteria. RESULTS: During 35 years follow-up 202/1962 (10.3%) men developed diabetes. Compared with the lowest, the upper FTG tertile had a 2.58-fold (95% CI: 1.81-3.74) diabetes risk adjusted for age, fasting blood glucose and maternal diabetes, and a 2.29-fold (95%CI: 1.60-3.33) when also adjusting for PF. Compared with unchanged (±25%) FTG levels (n=664), FTG reduction of more than 25% (n=261) was associated with 56% lower (0.44; 95% CI: 0.24-0.75) diabetes risk, while FTG increase of more than 25% (n=462) was associated with similar risk. These associations were unchanged when adjusted for PF and PF change. CONCLUSIONS: High FTG-levels predicted long-term diabetes risk in healthy middle-aged men, and the association was only modestly weakened when adjusted for PF. A reduction in FTG was associated with decreased diabetes risk.

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.

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.

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.

Radio pumping of ionospheric plasma with orbital angular momentum.

Experimental results are presented of pumping ionospheric plasma with a radio wave carrying orbital angular momentum (OAM), using the High Frequency Active Auroral Research Program (HAARP) facility in Alaska. Optical emissions from the pumped plasma turbulence exhibit the characteristic ring-shaped morphology when the pump beam carries OAM. Features of stimulated electromagnetic emissions (SEE) that are attributed to cascading Langmuir turbulence are well developed for a regular beam but are significantly weaker for a ring-shaped OAM beam in which case upper hybrid turbulence dominates the SEE.

Long-term cardiac outcomes in renal transplant recipients receiving fluvastatin: the ALERT extension study.

Renal transplant recipients (RTR) have an increased risk of premature cardiovascular disease. The ALERT study is the first trial to evaluate the effect of statin therapy on cardiac outcomes following renal transplantation. Patients initially randomized to fluvastatin or placebo in the 5-6 year ALERT study were offered open-label fluvastatin XL 80 mg/day in a 2-year extension to the original study. The primary endpoint was time to first major adverse cardiac event (MACE). Of 1787 patients who completed ALERT, 1652 (92%) were followed in the extension. Mean total follow-up was 6.7 years. Mean LDL-cholesterol was 98 mg/dL (2.5 mmol/L) at last follow-up compared to a pre-study level of 159 mg/dL (4.1 mmol/L). Patients randomized to fluvastatin had a reduced risk of MACE (hazards ratio [HR] 0.79, 95% CI 0.63-0.99, p = 0.036), and a 29% reduction in cardiac death or definite non-fatal MI (HR 0.71, 95% CI 0.55-0.93, p = 0.014). Total mortality and graft loss did not differ significantly between groups. Fluvastatin produces a safe and effective reduction in LDL-cholesterol associated with reduced risk of MACE in RTR. The lipid-lowering and cardiovascular benefits of fluvastatin are comparable to those of statins in other patient groups, and support use of fluvastatin in RTR.

Ionospheric modification at twice the electron cyclotron frequency.

In 2004, a new transmission band was added to the HAARP high-frequency ionospheric modification facility that encompasses the second electron cyclotron harmonic at altitudes between approximately 220 and 330 km. Initial observations indicate that greatly enhanced airglow occurs whenever the transmission frequency approximately matches the second electron cyclotron harmonic at the height of the upper hybrid resonance. This is the reverse of what happens at higher electron cyclotron harmonics. The measured optical emissions confirm the presence of accelerated electrons in the plasma.

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.

Effects of fluvastatin on cardiac events in renal transplant patients: ALERT (Assessment of Lescol in Renal Transplantation) study design and baseline data.

BACKGROUND: Recent clinical trials of primary and secondary prevention of cardiovascular disease have demonstrated that lowering plasma cholesterol with 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors ('statins') reduces morbidity and mortality from coronary heart disease in diverse patient populations. STUDY AIMS: The aim of the present ALERT (Assessment of Lescol in Renal Transplantation) study is to determine whether renal transplant recipients would also benefit from statin therapy. ALERT is a multicentre, randomized, double-blind, placebo-controlled trial to assess the effect of fluvastatin in renal transplant recipients with mild-to-moderate hypercholesterolaemia. The primary objective is to investigate the effects of fluvastatin on major adverse cardiac events (MACE). In addition, the effects on cardiovascular and all-cause mortality, as well as renal function, will be addressed. STUDY POPULATION: The study population contains patients with functioning renal allografts of more than 6 months' duration, recruited from 75 centres in Northern Europe and Canada. Patients of both sexes, aged 30-75 years, with a total cholesterol level of 4.0-9.0 mmol/l (155-348 mg/dl) were included, except for those with a history of myocardial infarction, where the upper limit for inclusion was 7.0 mmol/l (270 mg/dl). STUDY DESIGN: A total of 2100 patients were recruited by the end of October 1997 and will be followed for up to 6 years. This report presents the design features of the study (recruitment, follow-up, sample size, data analysis and study organization), along with baseline results. ALERT is the first large-scale prospective, randomized, double-blind study to address the prevention of cardiovascular mortality in renal transplant patients receiving an HMGCoA reductase inhibitor.

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.

Benefits of early lipid-lowering intervention in high-risk patients: the lipid intervention strategies for coronary patients study.

BACKGROUND: There is controversy about whether lipid-lowering pharmacotherapy should be initiated immediately after an acute coronary event or only after diet and lifestyle changes have proved inadequate. OBJECTIVE: This study, known as the Lipid Intervention Strategies for Coronary Patients Study, compared the efficacy of immediate versus deferred simvastatin treatment in conjunction with dietary advice about reducing lipid levels in hypercholesterolemic patients with acute coronary syndromes. METHODS: This randomized, open-label, parallel-group study included 151 hypercholesterolemic (low-density lipoprotein cholesterol [LDL-C] >3.0 mmol/L) men and women aged 35 to 75 years. Within 4 days of diagnosis of acute myocardial infarction (MI) or unstable angina pectoris, all patients received dietary advice from a specially trained nurse. Subsequently, patients were randomized to 2 treatment groups: 1 group received immediate treatment with simvastatin 40 mg/d; patients in the other group received simvastatin 40 mg/d after 3 months only if their LDL-C remained >3.0 mmol/L. RESULTS: The immediate-simvastatin group (n = 73) and the deferred-simvastatin group (n = 78) were balanced with respect to baseline characteristics. Of the 151 patients, 25% were women, 25% had concomitant hypertension, and 75% had a diagnosis of MI on enrollment. At 3 months, 90% of the patients receiving dietary advice plus immediate simvastatin treatment had achieved the recommended European target LDL-C level of <3.0 mmol/L, compared with 7% of those treated with diet alone. By 6 months, when 92% of the study participants were receiving simvastatin 40 mg/d, the proportion of patients achieving target LDL-C levels was 92% in the group that received immediate simvastatin therapy and 81% in the group that received deferred simvastatin therapy. The reductions in LDL-C (42%-48%) were considered to be clinically comparable between the 2 groups at 12 months. CONCLUSIONS: On the basis of these results, we concluded that few patients with hypercholesterolemia and acute coronary syndromes reach the recommended European target LDL-C level of <3.0 mmol/L with dietary advice alone. However, early treatment with simvastatin 40 mg/d combined with dietary advice and follow-up at a dedicated outpatient clinic specializing in coronary heart disease resulted in 9 out of 10 patients reaching a recommended target LDL-C level of <3.0 mmol/L. Initiation of simvastatin therapy while a patient is hospitalized may increase the likelihood of the patient's lipid levels being managed according to current recommendations after he or she is discharged.

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.

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.

The cost-effectiveness of lipid lowering in patients with diabetes: results from the 4S trial.

AIMS/HYPOTHESIS: The purpose of this study is to investigate the cost-effectiveness of simvastatin in diabetic patients, using prospectively collected outcomes data from the Scandinavian Simvastatin Survival Study. METHODS: Diabetic patients were identified using two different classifications schemes: Clinical history (diabetic, non-diabetic) and the new American Diabetes Association definition (diabetic, impaired fasting glucose, normal fasting glucose). The analysis is based on prospectively collected data from the trial on hospitalization for cardiovascular problems, study drug utilization and mortality. The incremental cost per life year saved with simvastatin is estimated using costs from Sweden (primary) and other European countries. RESULTS: Hospitalizations for cardiovascular problems were considerably reduced with simvastatin therapy, with the greatest differences in the diabetic subgroups. Reductions in hospitalizations in the diabetic group resulted in substantial hospital cost savings that offset 67 to 76 % of the drug cost (depending on the classification used). For the diabetic patients, the estimates of the cost per life-year gained ranged from 1600 Euros (based on clinical history) to 3200 Euros (based on American Diabetes Association) using Swedish costs. In the other evaluated European countries treatment with simvastatin showed a favourable cost-effectiveness ratio independent of differences in local health care unit costs. CONCLUSION/INTERPRETATION: For all subgroups in the diabetic classification schemes, treatment with simvastatin resulted in estimates of cost per life-year gained that were well within the range generally considered to be cost effective. Based on the Scandinavian Simvastatin Survival Study, simvastatin therapy provides good value for money in both diabetic and non-diabetic patients with cardiovascular disease. [Diabetologia (1999) 42: 1293-1301]