West Of Scotland Coronary Prevention Study Research Articles

Statin Use is Not Associated with Future Long-Term Care Admission: Extended Follow-Up of Two Randomised Controlled Trials.

Statins have been associated with later life, long-term care admission in observational studies. However, by preventing vascular events, statins may also prevent or delay admission. We wished to determine statin and long-term care admission associations in a randomised controlled trial context, and describe associations between long-term care admission and other clinical and demographic factors. We used extended follow-up of two randomised trial populations, using national data to assign the long-term care admission outcome, and included individuals screened or recruited to two large randomised trials of pravastatin 40mg daily-the West of Scotland Coronary Prevention Study (WOSCOPS) and the pravastatin in elderly individuals at risk of vascular disease (PROSPER) study. We described univariable and multivariable analyses of potential predictors of long-term care admission with corresponding survival curves of incident long-term care admission and analyses adjusted for competing risk. In total 11,015 (10%) of the trial participants were admitted to long-term care. There was no difference between participants in the statin or placebo arms of either trial in regard to admissions to long-term care. On multivariable analyses, independent associations with incident long-term care admission in the PROSPER trial were age (hazard ratio [HR] 1.06 per year, 95% confidence interval [CI] 1.03-1.09) and male sex (HR 0.72, 95% CI 0.53-0.99). In the WOSCOPS, age (HR 1.12 per year, 95% CI 1.10-1.13) and increasing social deprivation (HR 1.05, 95% CI 1.03-1.08) were associated with incident long-term care admission. We did not demonstrate an association between historical statin use and future long-term care admission. The strongest associations with incident long-term care admission were non-modifiable factors of age, sex and socioeconomic deprivation.

Low-Density Lipoprotein Cholesterol Lowering for the Primary Prevention of Cardiovascular Disease Among Men With Primary Elevations of Low-Density Lipoprotein Cholesterol Levels of 190 mg/dL or Above: Analyses From the WOSCOPS (West of Scotland Coronary Prevention Study) 5-Year Randomized Trial and 20-Year Observational Follow-Up.

Patients with primary elevations of low-density lipoprotein cholesterol (LDL-C) ≥190 mg/dL are at a higher risk of atherosclerotic cardiovascular disease as a result of long-term exposure to markedly elevated LDL-C levels. Therefore, initiation of statin therapy is recommended for these individuals. However, there is a lack of randomized trial evidence supporting these recommendations in primary prevention. In the present analysis, we provide hitherto unpublished data on the cardiovascular effects of LDL-C lowering among a primary prevention population with LDL-C ≥190 mg/dL. We aimed to assess the benefits of LDL-C lowering on cardiovascular outcomes among individuals with primary elevations of LDL-C ≥190 mg/dL without preexisting vascular disease at baseline. We performed post hoc analyses from the WOSCOPS (West of Scotland Coronary Prevention Study) randomized, placebo-controlled trial, and observational posttrial long-term follow-up, after excluding individuals with evidence of vascular disease at baseline. WOSCOPS enrolled 6595 men aged 45 to 64 years, who were randomly assigned to pravastatin 40 mg/d or placebo. In the present analyses, 5529 participants without evidence of vascular disease were included, stratified by LDL-C levels into those with LDL-C <190 mg/dL (n=2969; mean LDL-C 178±6 mg/dL) and those with LDL-C ≥190 mg/dL (n=2560; mean LDL-C 206±12 mg/dL). The effect of pravastatin versus placebo on coronary heart disease and major adverse cardiovascular events were assessed over the 4.9-year randomized controlled trial phase and on mortality outcomes over a total of 20 years of follow-up. Among 5529 individuals without vascular disease, pravastatin reduced the risk of coronary heart disease by 27% (P=0.002) and major adverse cardiovascular events by 25% (P=0.004) consistently among those with and without LDL-C ≥190 mg/dL (P-interaction >0.9). Among individuals with LDL-C ≥190 mg/dL, pravastatin reduced the risk of coronary heart disease by 27% (P=0.033) and major adverse cardiovascular events by 25% (P=0.037) during the initial trial phase and the risk of coronary heart disease death, cardiovascular death, and all-cause mortality by 28% (P=0.020), 25% (P=0.009), and 18% (P=0.004), respectively, over a total of 20 years of follow-up. The present analyses provide robust novel evidence for the short- and long-term benefits of lowering LDL-C for the primary prevention of cardiovascular disease among individuals with primary elevations of LDL-C ≥190 mg/dL.

Legacy effect of statins: 20-year follow up of the West of Scotland Coronary Prevention Study (WOSCOPS).

The West of Scotland Coronary Prevention Study (WOSCOPS) was a randomized, placebo- controlled, primary prevention trial of pravastatin in men aged 45 to 64 (mean age of 55 years) with no history of myocardial infarction at randomization. A total of 6,595 men, with a mean (SD) plasma cholesterol level of 272 (23) mg/dL and mean (SD) low density lipoprotein cholesterol (LDL-C) of 192 (17) mg/dL were randomly assigned to receive pravastatin 40 mg daily or placebo for five years. The primary outcome was a composite of death from coronary heart disease (CHD) and nonfatal myocardial infarction. There was a 31% relative reduction in the primary outcome with pravastatin. There was similar reduction in risk of nonfatal myocardial infarction, death from CHD and death from all cardiovascular causes with no increased risk of death from non-cardiovascular causes nor an increase in incident cancers.

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

Are Routinely Collected NHS Administrative Records Suitable for Endpoint Identification in Clinical Trials? Evidence from the West of Scotland Coronary Prevention Study

BackgroundRoutinely collected electronic patient records are already widely used in epidemiological research. In this work we investigated the potential for using them to identify endpoints in clinical trials.MethodsThe events recorded in the West of Scotland Coronary Prevention Study (WOSCOPS), a large clinical trial of pravastatin in middle-aged hypercholesterolaemic men in the 1990s, were compared with those in the record-linked deaths and hospitalisations records routinely collected in Scotland.ResultsWe matched 99% of fatal study events by date. We showed excellent matching (97%) of the causes of fatal endpoint events and good matching (>80% for first events) of the causes of nonfatal endpoint events with a slightly lower rate of mismatching of record linkage than study events (19% of first study myocardial infarctions (MI) and 4% of first record linkage MIs not matched as MI). We also investigated the matching of non-endpoint events and showed a good level of matching, with >78% of first stroke/TIA events being matched as stroke/TIA. The primary reasons for mismatches were record linkage data recording readmissions for procedures or previous events, differences between the diagnoses in the routinely collected data and the conclusions of the clinical trial expert adjudication committee, events occurring outside Scotland and therefore being missed by record linkage data, miscoding of cardiac events in hospitalisations data as ‘unspecified chest pain’, some general miscoding in the record linkage data and some record linkage errors.ConclusionsWe conclude that routinely collected data could be used for recording cardiovascular endpoints in clinical trials and would give very similar results to rigorously collected clinical trial data, in countries with unified health systems such as Scotland. The endpoint types would need to be carefully thought through and an expert endpoint adjudication committee should be involved.

Long-term impact on healthcare resource utilization of statin treatment, and its cost effectiveness in the primary prevention of cardiovascular disease: a record linkage study

AimsTo assess the impact on healthcare resource utilization, costs, and quality of life over 15 years from 5 years of statin use in men without a history of myocardial infarction in the West of Scotland Coronary Prevention Study (WOSCOPS).MethodsSix thousand five hundred and ninety-five participants aged 45–54 years were randomized to 5 years treatment with pravastatin (40 mg) or placebo. Linkage to routinely collected health records extended follow-up for secondary healthcare resource utilization to 15 years. The following new results are reported: cause-specific first and recurrent cardiovascular hospital admissions including myocardial infarction, heart failure, stroke, coronary revascularization and angiography; non-cardiovascular hospitalization; days in hospital; quality-adjusted life years (QALYs); costs of pravastatin treatment, treatment safety monitoring, and hospital admissions.ResultsFive years treatment of 1000 patients with pravastatin (40 mg/day) saved the NHS £710 000 (P < 0.001), including the cost of pravastatin and lipid and safety monitoring, and gained 136 QALYs (P = 0.017) over the 15-year period. Benefits per 1000 subjects, attributable to prevention of cardiovascular events, included 163 fewer admissions and a saving of 1836 days in hospital, with fewer admissions for myocardial infarction, stroke, heart failure and coronary revascularization. There was no excess in non-cardiovascular admissions or costs (or in admissions associated with diabetes or its complications) and no evidence of heterogeneity of effect over sub-groups defined by baseline cardiovascular risk.ConclusionFive years' primary prevention treatment of middle-aged men with a statin significantly reduces healthcare resource utilization, is cost saving, and increases QALYs. Treatment of even younger, lower risk individuals is likely to be cost-effective.

N-terminal pro-B-type natriuretic peptide and the prediction of primary cardiovascular events: results from 15-year follow-up of WOSCOPS

AimsTo test whether N-terminal pro-B-type natriuretic peptide (NT-proBNP) was independently associated with, and improved the prediction of, cardiovascular disease (CVD) in a primary prevention cohort.Methods and resultsIn the West of Scotland Coronary Prevention Study (WOSCOPS), a cohort of middle-aged men with hypercholesterolaemia at a moderate risk of CVD, we related the baseline NT-proBNP (geometric mean 28 pg/mL) in 4801 men to the risk of CVD over 15 years during which 1690 experienced CVD events. Taking into account the competing risk of non-CVD death, NT-proBNP was associated with an increased risk of all CVD [HR: 1.17 (95% CI: 1.11–1.23) per standard deviation increase in log NT-proBNP] after adjustment for classical and clinical cardiovascular risk factors plus C-reactive protein. N-terminal pro-B-type natriuretic peptide was more strongly related to the risk of fatal [HR: 1.34 (95% CI: 1.19–1.52)] than non-fatal CVD [HR: 1.17 (95% CI: 1.10–1.24)] (P= 0.022). The addition of NT-proBNP to traditional risk factors improved the C-index (+0.013; P < 0.001). The continuous net reclassification index improved with the addition of NT-proBNP by 19.8% (95% CI: 13.6–25.9%) compared with 9.8% (95% CI: 4.2–15.6%) with the addition of C-reactive protein. N-terminal pro-B-type natriuretic peptide correctly reclassified 14.7% of events, whereas C-reactive protein correctly reclassified 3.4% of events. Results were similar in the 4128 men without evidence of angina, nitrate prescription, minor ECG abnormalities, or prior cerebrovascular disease.ConclusionN-terminal pro-B-type natriuretic peptide predicts CVD events in men without clinical evidence of CHD, angina, or history of stroke, and appears related more strongly to the risk for fatal events. N-terminal pro-B-type natriuretic peptide also provides moderate risk discrimination, in excess of that provided by the measurement of C-reactive protein.Clinical trial registrationWOSCOPS was carried out and completed prior to the requirement for clinical trial registration.

Fatty liver: cause or consequence

Diabet. Med. 29, 1097 (2012) This year’s Dorothy Hodgkin Lecture (2012) at Diabetes UK was awarded to Christopher Byrne. In this months issue of Diabetic Medicine, he summarizes that lecture and proposes ‘that fatty acid fluxes through the liver are crucial for the pathogenesis of non-alcoholic fatty liver disease (NAFLD) and for increasing insulin resistance’ [1]. Non-alcoholic fatty liver disease is an established component of the metabolic syndrome and represents a spectrum of liver disease from uncomplicated fatty liver to end-stage liver disease. Non-alcoholic fatty liver disease has a prevalence of 17–33% in the general population and is as high as 70% in Type 2 diabetes. Increasing evidence implicates non-alcoholic fatty liver disease as an independent risk factor for Type 2 diabetes and cardiovascular disease. However, simply proving an association does not imply reverse causality. Last year, the recipient of the Dorothy Hodgkin Lecture was Naveed Sattar and his lecture was published earlier this year [2]. Indeed, Naveed contributed to the early evidence that that surrogates of liver fat (alanine aminotransferase; ALT) may predict new-onset diabetes based on data from the West of Scotland Coronary Prevention Study (WOSCOPS). He discussed the use of biomarkers for diabetes, including non-alcoholic fatty liver disease, in his lecture. He crystallizes the problem in the following sentences. ‘There remains debate in some quarters over whether excess liver fat is simply a consequence of peripheral insulin resistance driving hyperinsulinaemia, in turn driving de novo lipogenesis in the face of continued caloric excess, or whether excess calories, perhaps particularly excess carbohydrate, directly drive de novo hepatic lipogenesis, with subsequent deterioration in hepatic insulin resistance.’ In addition to the arguments presented by both Naveed Sattar and Chris Byrne, readers may be interested in an excellent recent review of mechanisms of insulin resistance and the role of ectopic lipid accumulation published in Cell this year by Samuel and Shulman [3]. If non-alcoholic fatty liver disease is an aetiological driver of insulin resistance and subsequent Type 2 diabetes and cardiovascular disease, then reversal of non-alcoholic fatty liver disease should lead to a decrease in risk of diabetes and cardiovascular disease. In table 2 of Christopher Byrne’s review, he lists potential treatments [1]. We eagerly await the results of randomized clinical trials that address this issue, including the WELCOME study (Wessex Evaluation of fatty Liver and Cardiovascular markers in NAFLD with OMacor therapy) that is testing the effects of high-dose purified n-3 long-chain fatty acids and is due for completion in 2012.

Genome-Wide Study of Gene Variants Associated with Differential Cardiovascular Event Reduction by Pravastatin Therapy

Statin therapy reduces the risk of coronary heart disease (CHD), however, the person-to-person variability in response to statin therapy is not well understood. We have investigated the effect of genetic variation on the reduction of CHD events by pravastatin. First, we conducted a genome-wide association study of 682 CHD cases from the Cholesterol and Recurrent Events (CARE) trial and 383 CHD cases from the West of Scotland Coronary Prevention Study (WOSCOPS), two randomized, placebo-controlled studies of pravastatin. In a combined case-only analysis, 79 single nucleotide polymorphisms (SNPs) were associated with differential CHD event reduction by pravastatin according to genotype (P<0.0001), and these SNPs were analyzed in a second stage that included cases as well as non-cases from CARE and WOSCOPS and patients from the PROspective Study of Pravastatin in the Elderly at Risk/PHArmacogenomic study of Statins in the Elderly at risk for cardiovascular disease (PROSPER/PHASE), a randomized placebo controlled study of pravastatin in the elderly. We found that one of these SNPs (rs13279522) was associated with differential CHD event reduction by pravastatin therapy in all 3 studies: P = 0.002 in CARE, P = 0.01 in WOSCOPS, P = 0.002 in PROSPER/PHASE. In a combined analysis of CARE, WOSCOPS, and PROSPER/PHASE, the hazard ratio for CHD when comparing pravastatin with placebo decreased by a factor of 0.63 (95% CI: 0.52 to 0.75) for each extra copy of the minor allele (P = 4.8×10−7). This SNP is located in DnaJ homolog subfamily C member 5B (DNAJC5B) and merits investigation in additional randomized studies of pravastatin and other statins.

Cardiovascular Pharmacogenomics: Current Status and Future Directions—Report of a National Heart, Lung, and Blood Institute Working Group

The National Heart, Lung, and Blood Institute (NHLBI) convened a Working Group on January 7, 2011, at George Washington University in Washington, DC, to provide recommendations to the NHLBI that would guide informed decisions on research directions and priorities in the field of cardiovascular

Inheritance of coronary artery disease in men: an analysis of the role of the Y chromosome

SummaryBackgroundA sexual dimorphism exists in the incidence and prevalence of coronary artery disease—men are more commonly affected than are age-matched women. We explored the role of the Y chromosome in coronary artery disease in the context of this sexual inequity.MethodsWe genotyped 11 markers of the male-specific region of the Y chromosome in 3233 biologically unrelated British men from three cohorts: the British Heart Foundation Family Heart Study (BHF-FHS), West of Scotland Coronary Prevention Study (WOSCOPS), and Cardiogenics Study. On the basis of this information, each Y chromosome was tracked back into one of 13 ancient lineages defined as haplogroups. We then examined associations between common Y chromosome haplogroups and the risk of coronary artery disease in cross-sectional BHF-FHS and prospective WOSCOPS. Finally, we undertook functional analysis of Y chromosome effects on monocyte and macrophage transcriptome in British men from the Cardiogenics Study.FindingsOf nine haplogroups identified, two (R1b1b2 and I) accounted for roughly 90% of the Y chromosome variants among British men. Carriers of haplogroup I had about a 50% higher age-adjusted risk of coronary artery disease than did men with other Y chromosome lineages in BHF-FHS (odds ratio 1·75, 95% CI 1·20–2·54, p=0·004), WOSCOPS (1·45, 1·08–1·95, p=0·012), and joint analysis of both populations (1·56, 1·24–1·97, p=0·0002). The association between haplogroup I and increased risk of coronary artery disease was independent of traditional cardiovascular and socioeconomic risk factors. Analysis of macrophage transcriptome in the Cardiogenics Study revealed that 19 molecular pathways showing strong differential expression between men with haplogroup I and other lineages of the Y chromosome were interconnected by common genes related to inflammation and immunity, and that some of them have a strong relevance to atherosclerosis.InterpretationThe human Y chromosome is associated with risk of coronary artery disease in men of European ancestry, possibly through interactions of immunity and inflammation.FundingBritish Heart Foundation; UK National Institute for Health Research; LEW Carty Charitable Fund; National Health and Medical Research Council of Australia; European Union 6th Framework Programme; Wellcome Trust.

The inverse relationship between alanine aminotransferase in the normal range and adverse cardiovascular and non-cardiovascular outcomes

High serum alanine aminotransferase (ALT) levels have been associated with increased risk of diabetes and with increased mortality, but associations of variations of ALT in the normal range with outcomes have been less well studied. We studied the relationship between ALT, mortality and cardiovascular events in the West of Scotland Coronary Prevention Study (WOSCOPS) and the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) trials that explicitly excluded subjects with clinically significant liver damage, plus the Leiden 85-plus, a study of survivors to age 85 years. The associations between ALT and morbidity and mortality outcomes were investigated using Cox proportional hazard models adjusting for a comprehensive panel of cardiovascular risk factors. In all three study cohorts, ALT displayed an independent inverse relationship with all-cause mortality so that hazard ratios for fourth versus first quarter of ALT were all below 1.0; HRs 0.64 [95% confidence interval (CI) 0.50-0.81], 0.86 (0.73-1.01), 0.66 (0.50-0.87); WOSCOPS, PROSPER, Leiden 85-plus, respectively. In WOSCOPS and PROSPER, ALT was also inversely associated with risk of fatal plus non-fatal cardiovascular events, including coronary heart disease (CHD) events and stroke. In three independent populations, ALT in the normal range displayed an inverse relationship with total mortality, cardiovascular events and non-cardiovascular events in middle-to-older aged subjects without evidence of clinically significant liver damage, independent of traditional cardiovascular and other risk factors. These findings indicate that the relationship between ALT and clinical outcomes is more complex than generally appreciated.

High-Sensitivity C-Reactive Protein, Vascular Imaging, and Vulnerable Plaque

As demonstrated in a meta-analysis of 54 prospective cohort studies, increasing levels of high-sensitivity C-reactive protein (hsCRP) associate with increased risk of myocardial infarction, stroke, and cardiovascular death, and the magnitude of hazard associated with hsCRP is at least as large as that of cholesterol and blood pressure.1 After publication of randomized trial data demonstrating that patients with low levels of low-lipoprotein (LDL) cholesterol but with elevated levels of hsCRP benefit greatly from statin therapy,2 screening guidelines in the United States and Canada have endorsed the use of hsCRP among intermediate-risk patients as a proven method to target lipid-lowering therapy.3,4 Based on this accumulating evidence-base, global risk algorithms, such as the Reynolds Risk Score, that include inflammatory biomarker data and family history are in common use in many preventive cardiology practices.5,6 Thus, hsCRP has fulfilled the following 3 main criteria for effectiveness as a novel clinical biomarker: (1) Its measurement independently predicts cardiovascular risk in diverse populations, (2) its measurement identifies a patient population that clearly benefits from a therapy it otherwise would not have received, and (3) its measurement leads to cost-effective (and in many circumstances, cost-saving) improvements in patient outcome.7 Article see p 201 Despite the consistency of these clinical data, the relationship between hsCRP and underlying atherosclerosis is complex. On the one hand, cross-sectional studies have reported no or minimal association between hsCRP levels and carotid intima-medial thickness measured by ultrasound8,9 or between hsCRP and total plaque burden as assessed by coronary artery calcification.10,11 However, hsCRP levels do associate with an increasing prevalence of thin-cap atheromas prone to plaque rupture and sudden death12; correlate with more advanced luminal lesions in …

Systemic Inflammation and the Dynamics of HDL Cholesterol–Associated Residual Cardiovascular Risk

Introduction: Randomized clinical trials of statin therapy demonstrate reduction in cardiovascular events when used for both primary and secondary prevention. However, residual vascular risk persists in many participants assigned to active statin treatment [1]. The lipid residual vascular risk in statintreated participants has been most consistently attributed to the association between low on-trial levels of high-density lipoprotein (HDL) cholesterol and increased cardiovascular events [2]. In the West of Scotland Coronary Prevention Study (WOSCOPS), low HDL cholesterol levels were associated with increased cardiovascular event rates when the HDL concentration was 100 mg/dL) [4]. Consistent with WOSCOPS, there was a threshold level of HDL cholesterol where cardiovascular risk was increased in TNT. Aims: This analysis of the Justification for the Use of statins in Primary prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) trial examined the relationships between baseline and on-trial levels of HDL cholesterol and apolipoprotein A1 and the composite primary endpoint of first non-fatal myocardial infarction or stroke, hospitalization for unstable angina, arterial revascularization, or cardiovascular death in both in placebo-treated and rosuvastatin-treated groups [5].

Genetic variants in the KIF6 region and coronary event reduction from statin therapy

A single nucleotide polymorphism (SNP) in KIF6, a member of the KIF9 family of kinesins, is associated with differential coronary event reduction from statin therapy in four randomized controlled trials; this SNP (rs20455) is also associated with the risk for coronary heart disease (CHD) in multiple prospective studies. We investigated whether other common SNPs in the KIF6 region were associated with event reduction from statin therapy. Of the 170 SNPs in the KIF6 region investigated in the Cholesterol and Recurrent Events trial (CARE), 28 were associated with differential event reduction from statin therapy (P interaction < 0.1 in Caucasians, adjusted for age and sex) and were further investigated in the Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis In Myocardial Infarction 22 (PROVE IT-TIMI22) and West of Scotland Coronary Prevention Study (WOSCOPS). These analyses revealed that two SNPs (rs9462535 and rs9471077), in addition to rs20455, were associated with event reduction from statin therapy (P interaction < 0.1 in each of the three studies). The relative risk reduction ranged from 37 to 50% (P < 0.01) in carriers of the minor alleles of these SNPs and from −4 to 13% (P > 0.4) in non-carriers. These three SNPs are in high linkage disequilibrium with one another (r 2 > 0.84). Functional studies of these variants may help to understand the role of KIF6 in the pathogenesis of CHD and differential response to statin therapy.Electronic supplementary materialThe online version of this article (doi:10.1007/s00439-010-0892-6) contains supplementary material, which is available to authorized users.

Fasting plasma glucose in non-diabetic participants and the risk for incident cardiovascular events, diabetes, and mortality: results from WOSCOPS 15-year follow-up†

The evidence base for fasting plasma glucose (FPG) in the non-diabetic range as a risk factor for cardiovascular disease (CVD) is inconclusive. We investigated this question in the West of Scotland Coronary Prevention Study (WOSCOPS). In WOSCOPS, we related FPG in 6447 men (mean age 55 years) with hypercholesterolaemia, but no history of CVD or diabetes, to the risk of cardiovascular events and mortality over 14.7 years of follow-up; 2381 non-fatal/fatal cardiovascular events and 1244 deaths occurred. Participants were divided into fifths of baseline FPG, Q1 (< or =4.3 mmol/L) to Q5 (>5.1-6.9 mmol/L). Q2 was designated the referent based on previous studies which have suggested a J-shaped relationship between FPG and CVD. Compared with Q2 (>4.3-4.6 mmol/L), men in Q5 had no elevated risk for cardiovascular events [hazard ratio (HR) 0.95 (0.83-1.08)], or all-cause mortality [HR 0.96 (0.80-1.15)] in fully adjusted analyses despite a significant risk for incident diabetes [HR 22.05 (10.75-45.22)]. After further dividing Q5 into fifths, Q5a-e, individuals in Q5e (FPG 5.8-6.9 mmol/L) were also not at increased risk of cardiovascular events [HR 1.05 (0.82-1.35)] or other endpoints compared with Q2. All results were similar using Q1 as the referent. Elevations in FPG in the non-diabetic range were not associated with long-term risk of cardiovascular events in middle-aged men in WOSCOPS. These data suggest that the current FPG cutoff for diagnosing diabetes also appropriately identifies western men at risk of CVD.

CCR2 and coronary artery disease: a woscops substudy

BackgroundSeveral lines of evidence support a role for CCL2 (monocyte chemotactic protein-1) and its receptor CCR2 in the development of atherosclerosis. The aim of the present study was to determine the association of the CCR2 Val64Ile polymorphism with the development of coronary artery disease in the WOSCOPS study sample set.FindingsA total of 443 cases and 1003 controls from the West of Scotland Coronary Prevention Study (WOSCOPS) were genotyped for the Val64Ile polymorphism in the CCR2 gene. Genotype frequencies were compared between cases and controls. The CCR2 Val64Ile polymorphism was found not to be associated with coronary events in this study population (odds ratio 1.15, 95% CI 0.82-1.61, p = 0.41).ConclusionsThis case-control study does not support an association of the CCR2 Val64Ile polymorphism with coronary artery disease in the WOSCOPS sample set and does not confirm a possible protective role for CCR2 Val64Ile in the development of coronary artery disease.

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.

Statin use in patients with chronic kidney disease stages 2–4: targeting beyond improved mortality rates

The well-designed study by Neves et al. [1] showed that statin and/or vitamin D non-use were independent risk factors of mortality (p = 0.005) in their cohort of patients (n = 95) with chronic kidney disease (CKD) stages 4 and 5 (mean estimated glomerular filtration rate [eGFR] = 16.1 ml/min/1.73 m). After a mean follow-up of 24.1 ± 9.8 months, all patients receiving both statins and vitamin D were alive (18 of 18 patients; 100%). In contrast, only 24 of the 43 patients (56.4%) receiving neither a statin nor vitamin D were alive at the end of the study [1]. Statin use in patients with CKD offers several advantages besides improving mortality rates. Cardiovascular disease (CVD) is the leading cause of death in patients with stages 4 and 5 CKD [2, 3]. Mortality from CVD in this population is approximately 10 to 20 times higher than in the general population [4]. In an analysis of the Pravastatin Pooling Project [5], a subject-level database combining the results from 3 randomized trials of the effects of pravastatin 40 mg/day vs. placebo, the benefit induced by statin use on CVD risk in 19,700 participants with mild/moderate CKD was determined. The 3 randomized studies included in this analysis were the following: the Cholesterol and Recurrent Events (CARE) trial [6], the Long-term Intervention with Pravastatin in Ischemic Disease (LIPID) study [7] and the West of Scotland Coronary Prevention Study (WOSCOPS) [8]. Of the 19,700 total participants in these studies, 12,333 (62.6%) had mild CKD, as defined by an estimated glomerular filtration rate (eGFR) of 60 to 89.9 ml/min/1.73 m and 4,491 (22.8%) had moderate CKD as defined by an eGFR of 30 to 59.9 ml/min/1.73 m. Pravastatin significantly reduced the adjusted incidence of the primary outcome of coronary mortality, non-fatal myocardial infarction and coronary revascularization (hazard ratio [HR], 0.77; 95% confidence interval [CI] 0.68–0.86) and the expanded outcome (cardiovascular mortality, non-fatal myocardial infarction, coronary revascularization or stroke; HR, 0.79; 95% CI 0.71–0.88) in people with moderate CKD [5]. Thus, the effects of statin use in patients with CKD not only include reduction of mortality rates, but also a decrease in CVD events (non-fatal myocardial infarction, stroke and revascularization episodes). K. I. Paraskevas (&) Department of Vascular Surgery, Red Cross Hospital, Athens, Greece e-mail: paraskevask@hotmail.com

Does intensive cholesterol lowering increase the risk of diabetes?

To the Editor: Dr Kostapanos and colleagues reported that in hyperlipidaemic patients with impaired fasting glucose, rosuvastatin treatment was associated with a dose-dependent increase in insulin resistance (1). In the accompanying editorial, Dr Wierzbicki highlighted the puzzling effects of cholesterol-lowering drugs on diabetes risk (2). We suggest that the effect of statin therapy on the subsequent risk of diabetes might be influenced by the amount of drug-induced cholesterol reduction. Increasing evidence indicates that statins, beyond their cholesterol-lowering action, may exert a variety of inhibitory effects on inflammatory processes; this anti-inflammatory potential seems to be mediated to a considerable part independent of cholesterol lowering (3). On the other hand, it is well known that the development of type 2 diabetes may be preceded by subclinical systemic inflammation, which is believed to be pathogenic in diabetogenesis by way of an increase in insulin resistance or even a decrease in insulin secretion (4). However, mounting evidence suggests also a critical role for endogenous cholesterol in the normal function of pancreatic beta-cells. It has recently been demonstrated that the inhibition of cholesterol biosynthesis impairs insulin secretion (5). Moreover, an observational study performed in a very large number of Veteran patients found that statin therapy was associated with a rise of fasting plasma glucose levels over a mean duration of 2 years in patients with and without diabetes (6). Retrospective analysis of the West of Scotland Coronary Prevention Study (WOSCOPS) revealed that 5 years of treatment with pravastatin reduced diabetes incidence by 30% (7). It was suggested that although lowering of triglyceride levels could have influenced diabetes incidence, other mechanisms such as anti-inflammatory action might have been involved. In the multivariate Cox model, baseline total cholesterol did not predict the development of diabetes (7). Of note, the median low density lipoprotein (LDL) cholesterol level in individuals assigned to pravastatin at the end of follow-up was roughly 140 mg/dl (8). Furthermore, pravastatin did not decrease diabetes incidence in the Long-Term Intervention with Pravastatin in Ischemic Disease (LIPID) trial, which included glucose-intolerant patients (median LDL cholesterol level in the pravastatin group at the end of the trial was roughly 110 mg/dl) (9). On the other hand, in the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) trial, which studied apparently healthy persons without hyperlipidaemia but with elevated high-sensitivity C-reactive protein levels (10), the risk of diabetes was significantly increased by a factor of 1.25 among individuals receiving rosuvastatin 20 mg daily compared with placebo. Strikingly, among persons assigned to rosuvastatin, the median LDL cholesterol level at 12 months was 55 mg/dl. Estimates of global diabetes prevalence (11) indicate that the number of people with diabetes, a pathology closely related to unhealthy lifestyles, is projected to increase from 246 million to up to 380 million by 2025. On the basis of these projections, it is therefore imperative that a serious battle against this pandaemia should mainly rely on lifestyle modifications. In this setting, it should be noted that salutary lifestyle measures, which might exert their beneficial actions through an anti-inflammatory mechanism without a strong cholesterol-lowering effect, beyond reducing cardiovascular events and total mortality, might also reduce the risk of diabetes and other chronic degenerative diseases. Therefore, it is plausible that, at high statin doses, the drug-induced cholesterol depletion is limiting, overwhelming any anti-inflammatory beneficial effect on diabetogenesis. Lowering cholesterol at the expense of increasing diabetes might be counterproductive over the long-term. Most importantly, this needs our attention, given the widespread use of statins at high doses even in the primary prevention of cardiovascular disease. None.