Hyperlipidemias: Durrington P

Soran H, Durrington P. · Central Manchester and Manchester Children University Hospital, Department of Endocrinology, Oxford Road, Manchester M13 9WL, UK. · Expert Opin Pharmacother. · Pubmed #18671469 No free full text.

Abstract: BACKGROUND: Rosuvastatin is a fully synthetic statin developed by AstraZeneca. It is a competitive inhibitor of 3-hydroxy-3-methyl-glutaryl-CoA reductase. OBJECTIVE: We reviewed the efficacy, characteristics, safety and clinical effectiveness of rosuvastatin. METHODS: We conducted a Pubmed and Medline literature search (January 2000 to March 2008) to identify all papers on rosuvastatin published in English. Other relevant papers and textbooks from the author's personal collection were also used as references. CONCLUSION: Rosuvastatin has a potent low-density lipoprotein cholesterol (LDL-C) lowering action. In addition it has potentially favourable effects on high-density lipoprotein (HDL), non-HDL-C, triglycerides and the apolipoprotein B : A1 ratio. Theoretically, if assumptions about these lipoprotein effects hold true and translate to better cardiovascular outcomes, rosuvastatin could prove to be the most clinically effective statin. However, while results from vascular imaging studies are encouraging overall, it is not clear whether these will translate into favourable cardiovascular outcomes because of lack of trial results. There are, as yet, no published mortality and cardiovascular outcome data from randomised, controlled trials to support LDL-C lowering with rosuvastatin rather than other statins. However, the early termination of one outcome trial has recently been announced because of clear benefits announced from rosuvastatin therapy compared with placebo.

Greene O, Durrington P. · University Department of Medicine, Manchester Royal Infirmary, Oxford Road, Manchester M13 9WL, UK. · J R Soc Med. · Pubmed #15121812 links to  free full text

Abstract: Life expectancy in familial hypercholesterolaemia (FH) has been greatly improved by the advent of statin therapy. In the UK, however, these agents are not licensed for use in children. We approached 169 physicians responsible for lipid clinics for information on their practice in young patients, and valid responses were received from 54%. A typical lipid clinic has only 3.5 patients aged under 16 with FH. In boys aged 10-15 years 65% of physicians were prepared to treat with bile acid sequestrants but only 23% with statins. There was greater reluctance to treat in girls of the same age, corresponding figures being 52% and 12%. Despite the efficacy of statins in reducing low-density-lipoprotein cholesterol, these agents are little used in children with FH. Their safety and clinical efficacy should be assessed by a randomized double-blind trial.

Durrington P. · University Department of Medicine, Manchester Royal Infirmary, Oxford Road, M13 9WL, Manchester, UK. > · Lancet. · Pubmed #12957096 No free full text.

Abstract: The lowering of serum cholesterol is increasingly recognised as essential in the prevention of coronary heart disease and other atherosclerotic disease. The success of statin trials and the need to deploy these drugs effectively in the population has led increasingly to the identification of many people whose serum cholesterol, triglycerides, and HDL-cholesterol require clinical assessment, and frequently treatment. Lipid disorders are mainly straightforward, but some are complex or resistant to simple treatment strategies. I have reviewed the clinical manifestations of disordered lipid metabolism (dyslipidaemia) and its management.

Durrington P. · Department of Medicine, Manchester Royal Infirmary, University of Manchester, UK. · Int J Clin Pract. · Pubmed #12137445 No free full text.

Abstract: Several guidelines for the prevention and management of coronary heart disease (CHD) have been published. These generally recommend lipid-lowering therapy in patients with and without established CHD on the basis of their low-density lipoprotein cholesterol (LDL-C) levels and, for cases without established CHD, their risk-factor profile. Statins are the preferred lipid-lowering agent for the prevention of CHD because of overwhelming clinical trial evidence that they can significantly reduce the occurrence of CHD mortality and morbidity. Despite the guidelines, only approximately one-third of eligible patients receive lipid-lowering therapy in clinical practice--even for secondary prevention of CHD--and many treated patients fail to achieve their target LDL-C levels. This underuse must affect patients' clinical outcome and quality of life and has economic consequences for society. Reasons for the underuse may include physicians' and patients' attitudes and knowledge, and the perceptions of physicians and healthcare purchasers about economic factors. Health economic evaluations have confirmed that secondary prevention with statins is cost-effective, and that primary prevention is also reasonably cost-effective, depending on the absolute CHD risks in targeted individuals. Newer statins with greater efficacy in reducing LDL-C levels may allow patients to reach target levels more quickly and without the need for dose titration, thus improving clinical outcomes and being more cost-effective in the long term. This proposition should be testedin future clinical trials.

Caslake MJ, Stewart G, Day SP, Daly E, McTaggart F, Chapman MJ, Durrington P, Laggner P, Mackness M, Pears J, Packard CJ. · Department of Pathological Biochemistry, Glasgow Royal Infirmary University NHS Trust, 4th Floor Queen Elizabeth Building, 10 Alexandra Parade, Glasgow G31 2ER, UK. · Atherosclerosis. · Pubmed #14644393 No free full text.

Abstract: This randomised, double-blind, placebo-controlled crossover study evaluated the effects of rosuvastatin (40 mg/day for 8 weeks) on atherogenic apolipoprotein B-containing lipoprotein subfractions. Subjects, recruited based on raised plasma triglyceride (TG) or low-density lipoprotein cholesterol (LDL-C), were divided into normotriglyceridaemic (NTG, n = 13; TG < 2.0 mmol/l) and hypertriglyceridaemic (HTG, n = 16; TG > or = 2.0 mmol/l) groups. Similar reductions on rosuvastatin were observed for both groups in LDL-C (NTG -60%; HTG -56%), apoB (both -49%), intermediate-density lipoprotein (NTG -57%; HTG -54%) and LDL circulating mass (NTG -52%, HTG -58%) (all P < 0.001 versus placebo), i.e., these changes were phenotype independent. Phenotype dependency in response was observed in HTG relative to NTG in concentration of small dense LDL (LDL-III) (NTG -44%, P = NS; HTG -69%, P < 0.001), very-low-density lipoprotein1 (NTG -18%, P = NS; HTG 46%, P < 0.01), and remnant-like particle cholesterol (NTG -31%, P = NS; HTG -48%, P < 0.05). Rosuvastatin reduced cholesteryl ester transfer protein (CETP) by 33% in NTG and 37% in HTG (both P < 0.001); a reduction in cholesteryl ester transfer activity (-59%, P < 0.001) was observed in HTG only. Rosuvastatin therefore, in addition to lowering LDL and apoB-concentrations, largely corrected the TG and LDL abnormalities in subjects who had the propensity to develop the atherogenic lipoprotein phenotype.

Ara R, Pandor A, Tumur I, Paisley S, Duenas A, Williams R, Rees A, Wilkinson A, Durrington P, Chilcott J. · Health Economics and Decision Science, ScHARR, University of Sheffield, Regent Court, 30 Regent Street, Sheffield S1 4DA, UK. · Am J Cardiovasc Drugs. · Pubmed #19159125 No free full text.

Abstract: OBJECTIVE: To evaluate the cost effectiveness of long-term ezetimibe monotherapy in patients with established cardiovascular disease (CVD) who do not tolerate statins or in whom they are contraindicated. METHODS: A Markov model was used to estimate the potential costs and benefits associated with ezetimibe monotherapy compared with no treatment. The benefits associated with ezetimibe treatment were informed by a systematic review of clinical evidence and a published relationship linking changes in low-density lipoprotein cholesterol (LDL-C) levels to cardiovascular events. RESULTS: In the absence of data from clinical outcome trials, surrogate endpoints such as changes in lipid levels were used as indicators of clinical outcomes. A meta-analysis of seven placebo-controlled trials included in the review showed that ezetimibe was associated with a statistically significant mean reduction (from baseline to endpoint) in LDL-C of 18.56% (95% CI -19.68, -17.44; p < 0.00001) compared with placebo. Using 10,000 Monte Carlo simulations, it is estimated that ezetimibe monotherapy would prevent an average of 49 nonfatal myocardial infarctions, 11 nonfatal strokes, and 37 cardiovascular deaths in a cohort of 1,000 patients aged 55 years with a baseline LDL-C concentration of 4.0 mmol/L. Events avoided provide an additional 211 quality-adjusted life-years (QALYs) over the 45 years modeled. With a mean incremental cost of pound 4,861,000 (year 2006 value), the discounted cost per QALY is pound 23,026 (Jackknife CI 22 979, 23 074). The model is reasonably robust to variations in key parameters. Incremental cost-effectiveness ratios fall below pound 20,000 per QALY for cohorts with baseline LDL-C values >4.5 mmol/L. CONCLUSION: Ezetimibe monotherapy compared with no treatment is a cost-effective alternative for individuals with a history of CVD and high LDL-C levels, who do not tolerate statins or in whom they are contraindicated.

Neil A, Cooper J, Betteridge J, Capps N, McDowell I, Durrington P, Seed M, Humphries SE. · NIHR School of Primary Care Research, Division Public Health and Primary Health Care, University of Oxford, Old Road Headington, Oxford, UK. · Eur Heart J. · Pubmed #18840879 links to  free full text

Abstract: AIMS: To examine the changes in coronary, all-cause, and cancer mortality in patients with heterozygous familial hypercholesterolaemia (FH) before and after lipid-lowering therapy with statins. METHODS AND RESULTS: A total of 3382 patients (1650 men) aged <80 years were recruited from 21 lipid clinics in the United Kingdom and followed prospectively between 1980 and 2006 for 46 580 person-years. There were 370 deaths, including 190 from coronary heart disease (CHD) and 90 from cancer. The standardized mortality ratio (compared with the population in England and Wales) was calculated before and from 1 January 1992. In patients aged 20-79 years, CHD mortality fell significantly by 37% (95% CI = 7-56) from 3.4- to 2.1-fold excess. Primary prevention resulted in a 48% reduction in CHD mortality from 2.0-fold excess to none, with a smaller reduction of nearly 25% in patients with established disease. Coronary mortality was reduced more in women than in men. In patients without known CHD at registration, all-cause mortality from 1992 was 33% (21-43), lower than in the general population, mainly due to a 37% (21-50) lower risk of fatal cancer. CONCLUSION: The results emphasize the importance of early identification of FH and treatment with statins.

Ara R, Pandor A, Tumur I, Paisley S, Duenas A, Williams R, Wilkinson A, Durrington P, Chilcott J. · Health Economics and Decision Science, School of Health and Related Research, University of Sheffield, Sheffield, United Kingdom. · Clin Ther. · Pubmed #18803993 No free full text.

Abstract: BACKGROUND: Ezetimibe has been reported to improve lipid control in patients with established cardiovascular disease (CVD). OBJECTIVE: The aim of this study was to estimate the potential long-term impact on health status of prescribing ezetimibe in combination with statin therapy in patients with established CVD and evaluate its cost-effectiveness in a health economic model. METHODS: A Markov model was used to compare ezetimibe and statin combination therapy with statin monotherapy. A published relationship linking changes in low-density lipoprotein cholesterol and cardiovascular events was used to estimate the cardiovascular events avoided through lipid-lowering therapies. The model was populated using results of extensive literature searches and a meta-analysis of clinical evidence. An adjustment was applied to model second-line lipid-lowering benefits. Conservative assumptions were used to extend the patient pathway beyond the clinical evidence. The analysis took the perspective of the UK Department of Health; therefore, only direct costs were included. Costs were calculated as year-2006 British pounds. RESULTS: For a cohort of 1,000 hypothetical male patients aged 55 years, ezetimibe coadministered with current statin therapy was estimated to prevent a mean of 43 nonfatal myocardial infarctions, 7 nonfatal strokes, and 26 cardiovascular deaths over a lifetime, compared with doubling the current statin dose. The events avoided would provide a mean of 134 additional quality-adjusted life-years (QALYs). With a mean incremental cost of pound 3,693,000, the lifetime discounted cost per QALY gained would be pound 27,475 (95% CI, pound 27,331- pound 27,620) and would rise to pound 32,000 for men aged 75 years. CONCLUSIONS: The results suggest that, in some instances, ezetimibe coadministration may be cost-effective compared with statin monotherapy, but there are several limitations with this model. The economic effects of ezetimibe must be revisited when long-term effectiveness and safety data become available.

Gemmell I, Heller RF, Payne K, Edwards R, Roland M, Durrington P. · Evidence for Population Health Unit, School of Epidemiology and Health Sciences, University of Manchester, Manchester M13 9PT, UK. · Qual Saf Health Care. · Pubmed #17074870 No free full text.

Abstract: OBJECTIVE: To use population impact measures to help prioritise the National Service Framework (NSF) strategies recommended by the UK government for reducing the population burden of coronary heart disease (CHD). DESIGN: Modelling study. SETTING: Primary care. DATA SOURCES: Published data on incidence, baseline risk and prevalence of risk factors for CHD and the proportion treated, eligible for treatment, and adhering to the different interventions. Data from meta-analyses and systematic reviews for relative risk and relative risk reduction associated with different risk factors and interventions. MAIN OUTCOME MEASURES: Population impact measures for the decline in the prevalence of a risk factor and the increased uptake of interventions expressed as number of CHD events prevented in the population. RESULTS: If lifestyle targets for primary prevention are met, 73 522 (95% CI 54,117 to 95,826) CHD events would be prevented per year, with the greatest gain coming from reduced cholesterol and blood pressure levels. In those at high risk of developing CHD, achieving target levels for lifestyle interventions would prevent 4410 (95% CI 1993 to 8014) CHD events and for pharmacological treatments 2008 (95% CI 790 to 3627) CHD events. For patients with established CHD, achieving NSF targets will result in the prevention of 3067 (95% CI 1572 to 5878) CHD events through improved drug treatment and 1103 (95% CI 179 to 2097) events through lifestyle interventions. CONCLUSION: Current strategies focus largely on secondary prevention, but many more cardiovascular events would be prevented by meeting the government's public health and primary prevention targets than targeting people at high risk or those with established heart disease.

Durrington P. · University of Manchester, Department of Medicine, Manchester Royal Infirmary, UK. · Diabet Med. · Pubmed #11048824 No free full text.

This publication has no abstract.