2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular riskThe Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS)

Associations between modifiable exposures and disease seen in observational epidemiology are sometimes confounded and thus misleading, despite our best efforts to improve the design and analysis of studies. Mendelian randomization-the random assortment of genes from parents to offspring that occurs during gamete formation and conception-provides one method for assessing the causal nature of some environmental exposures. The association between a disease and a polymorphism that mimics the biological link between a proposed exposure and disease is not generally susceptible to the reverse causation or confounding that may distort interpretations of conventional observational studies. Several examples where the phenotypic effects of polymorphisms are well documented provide encouraging evidence of the explanatory power of Mendelian randomization and are described. The limitations of the approach include confounding by polymorphisms in linkage disequilibrium with the polymorphism under study, that polymorphisms may have several phenotypic effects associated with disease, the lack of suitable polymorphisms for studying modifiable exposures of interest, and canalization-the buffering of the effects of genetic variation during development. Nevertheless, Mendelian randomization provides new opportunities to test causality and demonstrates how investment in the human genome project may contribute to understanding and preventing the adverse effects on human health of modifiable exposures.

/pdf/mendelian-randomization-can-genetic-epidemiology-contribute-vb0zjyrtxf.pdf

‘Mendelian randomization’: can genetic epidemiology contribute to understanding environmental determinants of disease?

https://air.unimi.it/bitstream/2434/689390/2/main.pdf

2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk

The Task Force for the Management of Dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS) 

Developed with the special contribution of the European Assocciation for Cardiovascular Prevention & Rehabilitation (EACPR) 

ABI
: ankle-brachial index

/pdf/2016-esc-eas-guidelines-for-the-management-of-dyslipidaemias-3oe2qnm09b.pdf

2016 ESC/EAS Guidelines for the Management of Dyslipidaemias

Overexpression of human epidermal growth factor receptor type 2 (HER2) in breast cancer is associated with decreased overall survival. Trastuzumab, a humanized monoclonal antibody that targets HER2, is approved by the Food and Drug Administration for patients with invasive breast cancers that overexpress HER2. This review considers the mechanism of action and the use of this agent.

/pdf/trastuzumab-mechanism-of-action-and-use-in-clinical-practice-51yqp7njy8.pdf

Trastuzumab — Mechanism of Action and Use in Clinical Practice

Objectives To evaluate the clinical effectiveness and cost-effectiveness of statins for the primary and secondary prevention of cardiovascular events in adults with, or at risk of, coronary heart disease (CHD). Data sources Electronic databases were searched between November 2003 and April 2004. Review methods A review was undertaken to identify and evaluate all literature relating to the clinical and cost effectiveness of statins in the primary and secondary prevention of CHD and cardiovascular disease (CVD) in the UK. A Markov model was developed to explore the costs and health outcomes associated with a lifetime of statin treatment using a UK NHS perspective. Results Thirty-one randomised studies were identified that compared a statin with placebo or with another statin, and reported clinical outcomes. Meta-analysis of the available data from the placebo-controlled studies indicates that, in patients with, or at risk of, CVD, statin therapy is associated with a reduced relative risk of all cause mortality, cardiovascular mortality, CHD mortality and fatal myocardial infarction (MI), but not of fatal stroke. It is also associated with a reduced relative risk of morbidity [non-fatal stroke, non-fatal MI, transient ischaemic attack (TIA), unstable angina] and of coronary revascularisation. It is hardly possible, on the evidence available from the placebo-controlled trials, to differentiate between the clinical efficacy of atorvastatin, fluvastatin, pravastatin and simvastatin. However, there is some evidence from direct comparisons between statins to suggest that atorvastatin may be more effective than pravastatin in patients with symptomatic CHD. There is limited evidence for the effectiveness of statins in different subgroups. Statins are generally considered to be well tolerated and to have a good safety profile. This view is generally supported both by the evidence of the trials included in this review and by postmarketing surveillance data. Increases in creatine kinase and myopathy have been reported, but rhabdomyolysis and hepatotoxicity are rare. However, some patients may receive lipid-lowering therapy for as long as 50 years, and long-term safety over such a timespan remains unknown. In secondary prevention of CHD, the incremental cost-effectiveness ratios (ICERs) increase with age varying between pound 10,000 and pound 17,000 per quality adjusted life year (QALY) for ages 45 and 85 respectively. Sensitivity analyses show these results are robust. In primary prevention of CHD there is substantial variation in ICERs by age and risk. The average ICERs weighted by risk range from pound 20,000 to pound 27,500 for men and from pound 21,000 to pound 57,000 for women. The results are sensitive to the cost of statins, discount rates and the modelling time frame. In the CVD analyses, which take into account the benefits of statins on reductions in stroke and TIA events, the average ICER weighted by risk level remains below pound 20,000 at CHD risk levels down to 0.5%. Limitations of the analyses include the requirement to extrapolate well beyond the timeframe of the trial period, and to extrapolate effectiveness results from higher risk primary prevention populations to the treatment of populations at much lower risk. Consequently, the results for the lower age bands and lower risks are subject to greater uncertainty and need to be treated with caution. Conclusions There is evidence to suggest that statin therapy is associated with a statistically significant reduction in the risk of primary and secondary cardiovascular events. As the confidence intervals for each outcome in each prevention category overlap, it is not possible to differentiate, in terms of relative risk, between the effectiveness of statins in primary and secondary prevention. However, the absolute risk of CHD death/non-fatal MI is higher, and the number needed to treat to avoid such an event is consequently lower, in secondary than in primary prevention. The generalisability of these results is limited by the exclusion, in some studies, of patients who were hypersensitive to, intolerant of, or known to be unresponsive to, statins, or who were not adequately compliant with study medication during a placebo run-in phase. Consequently, the treatment effect may be reduced when statins are used in an unselected population. The results of the economic modelling show that statin therapy in secondary prevention is likely to be considered cost-effective. In primary prevention, the cost-effectiveness ratios are dependent on the level of CHD risk and age, but the results for the CVD analyses offer support for the more aggressive treatment recommendation issued by recent guidelines in UK. Evidence on clinical endpoints for rosuvastatin is awaited from on-going trials. The potential targeting of statins at low-risk populations is however associated with major uncertainties, particularly the likely uptake and long-term compliance to lifelong medication by asymptomatic younger patients. The targeting, assessment and monitoring of low-risk patients in primary care would be a major resource implication for the NHS. These areas require further research.

https://www.crd.york.ac.uk/CRDWeb/PrintPDF.php?AccessionNumber=32007000514&Copyright=Health+Technology+Assessment+%28HTA%29+database%3Cbr+%2F%3ECopyright+%26copy%3B+2009+Queen%27s+Printer+and+Controller+of+HMSO%3Cbr+%2F%3E

A systematic review and economic evaluation of statins for the prevention of coronary events

Objectives To estimate the clinical effectiveness and cost-effectiveness of docetaxel and paclitaxel compared with non-taxane, anthracycline-containing chemotherapy regimens, for the adjuvant treatment of women with early-stage breast cancer. Data sources Major electronic databases were searched between October 2005 and February 2006. Review methods A systematic review of the literature on adjuvant taxane versus anthracycline non-taxane chemotherapy for women with early breast cancer was undertaken. A mathematical model was developed to synthesise the available data on costs, disease-free survival and health-related quality of life (HRQoL) of patients receiving taxane-containing chemotherapy versus non-taxane-containing chemotherapy. Results Eight of the 11 selected trials (six docetaxel and five paclitaxel) reported a significant improvement in disease-free survival (DFS) or time to recurrence (TTR) for taxanes over comparator regimens. Docetaxel was associated with more adverse events than paclitaxel, most notably febrile neutropenia. Taxanes produced cardiotoxicity, although this was not reported to be greater than for anthracycline comparator arms in all trials. Treatment-related deaths were uncommon. Where reported, all chemotherapy regimens caused HRQoL to deteriorate during treatment. Following treatment, there were no clinically significant differences between taxane and comparator treatment groups. There were few data available comparing licensed regimens of taxanes with chemotherapy regimens commonly used in the UK. The three trials selected as the basis for the economic analysis were those that used the taxanes in accordance with current UK marketing authorisation and had also reported in full. The estimated incremental cost-effectiveness ratio for docetaxel compared to FAC6, based on the BCIRG 001 study, is 12,000 pounds (7000-39,000 pounds) and for paclitaxel compared with Adriamycin/cyclophosphamide, based on the NSABP B28 and CALGB 9344 studies, is 43,000 pounds (16,000 pounds-dominated) and 39,000 pounds (12,000 pounds-dominated), respectively. However, the comparators used in these trials restrict the generalisability of the results, as they do not conform to current standard care in the UK, typically FEC6 and E4-CMF4. An exploratory indirect comparison shows that the benefits of taxane containing regimens compared to regimens in current use in the UK is subject to large uncertainty due to the lack of direct trial comparisons between these interventions. Assumptions regarding the benefits in the taxane arm after the trial follow-up period and the annual rate of recurrence in this period have the most significant influence on the ICER. Conclusions There is a large degree of heterogeneity in the evidence base for the effectiveness of taxane- compared with non-taxane-containing regimens in terms of the interventions, comparators and populations. Eight of the 11 trials providing effectiveness data reported a significant improvement in DFS or TTR for taxanes over comparator regimens. The remaining three trials found no significant differences between the groups in DFS/TTR. The cost-effectiveness results suggest that the cost per quality-adjusted life-year for taxane- compared with non-taxane-containing chemotherapy varies between 12,000 pounds and 43,000 pounds, depending on the taxane under consideration and the specific trial used as the basis of the analysis. However, the comparators used in these trials do not conform to current standard care in the UK. More research is needed, comparing taxanes used in line with their current UK marketing authorisation and with anthracycline-containing regimens commonly used in the UK. The on-going TACT trial is expected to provide useful data. There are currently few data on the effectiveness of taxanes for the over-70s. Further research is required into the long-term outcomes of taxane therapy, such as whether there are any long-term adverse events that significantly impact on overall survival or quality of life and whether the increases in DFS will translate into increases in overall survival.

Taxanes for the adjuvant treatment of early breast cancer: systematic review and economic evaluation.

Objectives: 

To evaluate the clinical and costeffectiveness
of capecitabine and tegafur with uracil
(UFT/LV) as first-line treatments for patients with
metastatic colorectal cancer, as compared with 5-
fluorouracil/folinic acid (5-FU/FA) regimens.
Data sources: Electronic databases, reference lists of
relevant articles and sponsor submissions were also
consulted.


Review methods: 

Systematic searches, selection
against criteria and quality assessment were performed
to obtain data from relevant studies. Costs were
estimated through resource-use data taken from the
published trials and the unpublished sponsor
submissions. Unit costs were taken from published
sources, where available. An economic evaluation was
undertaken to compare the cost-effectiveness of
capecitabine and UFT/LV with three intravenous 5-
FU/LV regimens widely used in the UK: the Mayo, the
modified de Gramont regimen and the inpatient de
Gramont regimens.


Results: 

The evidence suggests that treatment with
capecitabine improves overall response rates and has
an improved adverse effect profile in comparison with
5-FU/LV treatment with the Mayo regimen, with the
exception of hand–foot syndrome. Time to disease
progression or death after treatment with UFT/LV in
one study appears to be shorter than after treatment
with 5-FU/LV with the Mayo regimen, although it also
had an improved adverse effect profile. Neither
capecitabine nor UFT/LV appeared to improve healthrelated
quality of life. Little information on patient
preference was available for UFT/LV, but there was
indicated a strong preference for this over 5-FU/LV.
The total cost of capecitabine and UFT/LV treatments
were estimated at £2111 and £3375, respectively,
compared with the total treatment cost for the Mayo
regimen of £3579. Cost estimates were also presented
for the modified de Gramont and inpatient de Gramont
regimens. These were £3684 and £6155, respectively.
No survival advantage was shown in the RCTs of the
oral drugs against the Mayo regimen. Cost savings of
capecitabine and UFT/LV over the Mayo regimen were
estimated to be £1461 and £209, respectively. Drug
acquisition costs were higher for the oral therapies
than for the Mayo regimen, but were offset by lower
administration costs. Adverse event treatment costs
were similar across the three regimens. It was inferred
that there was no survival difference between the oral
drugs and the de Gramont regimens. Cost savings of
capecitabine and UFT/LV over the modified de
Gramont regimen were estimated to be £1353 and
£101, respectively, and over the inpatient de Gramont
regimen were estimated to be £4123 and £2870,
respectively.

Conclusions:

 The results show that there are cost
savings associated with the use of oral therapies. No
survival difference has been proven between the oral
drugs and the Mayo regimen. In addition, no evidence
of a survival difference between the Mayo regimen and
the de Gramont regimens has been identified.
However, improved progression-free survival and an
improved adverse event profile have been shown for
the de Gramont regimen over the Mayo regimen.
Further research is recommended into the following
areas: quality of life data should be included in trials of
colorectal cancer treatments; the place of effective oral
treatments in the treatment of colorectal cancer, the
safety mechanisms needed to ensure compliance and
the monitoring of adverse effects; the optimum
duration of treatment; the measurement of patient
preference; and a phase III comparative trial of
capecitabine and UFT/LV versus modified de Gramont
treatment to determine whether there was any survival
advantage and to collate the necessary economic data.

/pdf/clinical-and-cost-effectiveness-of-capecitabine-and-tegafur-30aov47f1h.pdf

Clinical and cost-effectiveness of capecitabine and tegafur with uracil for the treatment of metastatic colorectal cancer: systematic review and economic evaluation.

Background: Coronary heart disease (CHD) is a major cause of morbidity and mortality in the UK. The social and health service costs are large, and CHD prevention remains a government high priority. The major preventative approach is the modification of common risk factors (tobacco smoking, high blood pressure, physical inactivity, unhealthy diet and high blood cholesterol). The statins are a new class of drugs that lower blood cholesterol. This review systematically examines the evidence for statins in the light of existing treatments and provides cost-effectiveness estimates for statins and other treatments. Objectives: This review aimed to answer the following questions. By how much do low fat and other diets reduce blood cholesterol, and how effective are they in reducing CHD risk? Does treatment with statins reduce CHD events and are relative reductions in these events independent of the level of CHD risk? How effective are non-cholesterol lowering drug treatments for reducing CHD risk relative to dietary and cholesterol lowering drug treatments? What is the relative cost-effectiveness of different approaches to reducing cholesterol and/or CHD? Methods: Data sources. A search of MEDLINE citations from 1993 to November 1997 was made using the standard randomised controlled trial (RCT) and meta-analysis filters. The references obtained, together with information supplied by investigators working in the field of cholesterol lowering, were used to compile a list of statin trials. Study selection. The review included RCTs with ≥6 months follow-up in which clinical event outcomes were measured. Data extraction and synthesis. A data abstraction form was developed. Effect sizes were estimated using the statistical computer package META97 and further analysis was conducted with the EGRET package using logistic regression models. Heterogeneity in fixed effects models was investigated by sensitivity analyses. Estimates of statin effectiveness were made from pooled data. Effects of other CHD prevention treatments were taken from published meta-analyses and individual RCTs. Cost-effectiveness analyses were performed using a life-table approach which calculated the years of survival expected with and without treatment. Costs were direct costs of drugs and health service costs and were considered as gross and net (i.e. not taking account and taking account of potential NHS savings, respectively) and were presented as discounted and undiscounted. Costs per life-year gained were used as the cost-effectiveness index. Results: Five major trials of statins were identified. Data from these and from another 18 RCTs demonstrated significant reductions in CHD events. In secondary prevention (i.e. prevention among people with evidence of cardiovascular diseases) the relative reductions in total and CHD mortality were 21% (95% CI, 14-27%) and 26% (95% CI, 17-34%), respectively. There were similar reductions for non-fatal myocardial infarctions and greater reductions for combined end-points (including revascularisation end-points). In primary prevention (i.e. among people without evidence of cardiovascular disease) there were significant reductions for combined end-points and non-fatal myocardial infarction, but not for total and CHD mortality. The primary prevention trials were too small to have adequate power to detect effects on mortality outcomes alone. Statins are effective across a wide range of levels of blood cholesterol, including levels considered normal in the UK. Other treatments that reduce CHD risk were considered in this review. For primary prevention these were advice on smoking cessation, nicotine replacement and antihypertensive drugs; other treatments considered for secondary prevention were advice on smoking cessation, aspirin, beta-blockers, oily fish diet and Mediterranean diet. Except for smoking interventions, these treatments have numbers needed to treat that are broadly similar to those for statins. The cost-effectiveness of statins depends on the cost of the statin used and the CHD risk in the population treated. Gross, discounted estimates based on CHD risk in the trials considered ranged from £5400 to £13,300 per life-year gained at levels of risk expected in primary prevention, and from £3800 to £9300 at levels of risk consistent with secondary prevention. Use of low cost statins had the potential to reduce gross costs by 60%. The cost-effectiveness of other treatments was much better than for statins. Gross discounted cost per life-year saved of aspirin (£53), bendrofluazide treatment for elderly people with hypertension (£45), low cost mixed drug antihypertensive regimens for middle-aged people (£1509), beta-blockers following myocardial infarction (£227) and Mediterranean diet following myocardial infarction (£293) were all lower than for statins. Conclusions: Implications for health care. The evidence on efficacy supports the use of statins over a wide range of CHD risks covering both primary and secondary prevention. Although statins are less cost-effective than other treatments, there is consensus that their use in secondary prevention is acceptable because they achieve effects additional to those of other treatments. However, there is evidence that these other treatments are insufficiently used in the UK and that greater efforts are required to ensure that highly cost-effective treatments are used optimally. The limited cost-effectiveness of statins in primary prevention indicates that their indiscriminate use might be a poor use of resources. Cost-effectiveness clearly improves with increasing baseline CHD risk. Scoring systems and guidelines have been developed to measure individual risk: most of these assume that 3% annual CHD risk marks the threshold between cost-effective and cost-ineffective use of statins. However, these scoring systems and guidelines have major weaknesses because they are derived from American data that are now out of date, and they do not consider variations between regional, ethnic or socio-economic groups. The price of statins is a major determinant of their relative cost-effectiveness: lower cost statins are available and their use would improve cost-effectiveness to the levels of low cost anti-hypertensive regimens. As the price of drugs is agreed by the Department of Health, there may be a case for further examining the prices of statins, given the very large potential market for these drugs in primary prevention. Targeting statin treatment at people aged 55 years and older would further improve cost-effectiveness. In public health terms, the major approaches to the primary prevention of CHD remain the fiscal and legislative control of tobacco, the reduction of hidden saturated fats and calories in the diet, encouraging and extending facilities available for physical activity throughout life, and the reduction of levels of poverty. Recommendations for research: Areas of further research, which would help inform policy and practice in CHD prevention, include the following. Trials to examine the long-term effects of dietary modification with the oily fish or Mediterranean diet, both of which show promise but require stronger evidence of effect. Studies of the effects of different types of statin, and of the effects of statins in people aged 75 years and older. Continued surveillance of statin-treated patients for long-term adverse effects. Investigation of the translation of the effects of treatments found in trials to routine clinical practice. Evaluation of CHD risk prediction scoring systems in clinical practice (which will require longitudinal follow-up of patients to compare predicted and observed event rates) and the effects of risk scoring systems on professional and patient behaviour, risk levels and outcomes. Investigation of patient preferences (and their determinants) for specific types of treatment (e.g. drugs versus lifestyle modification) in primary and secondary prevention.

/pdf/what-role-for-statins-a-review-and-economic-model-3cpw2so3nj.pdf

What role for statins? A review and economic model.

Health-related quality of life is an important issue in the treatment of breast cancer and health-state utility values are essential for cost-utility analysis. A literature review was conducted to identify published values for common health states for breast cancer. In total, 13 databases were searched and 49 articles were identified providing 476 unique utility values. Where possible mean utility estimates were pooled using ordinary least squares with utilities clustered within study group and weighted by both number of respondents and inverse of the variance of each utility. Regressions included controls for disease state, utility assessment method and other features of study design. Utility values found in the review were summarized for six categories: screening-related states; preventative states; adverse events in breast cancer and its treatment; nonspecific breast cancer; metastatic breast cancer states; and early breast cancer states. The large number of values identified for metastatic breast cancer and early breast cancer states enabled data to be synthesized by meta-regression. Utilities were found to vary significantly between valuation methods and depending on who conducted the valuation. For metastatic breast cancer, values significantly varied by severity of condition, treatment and side-effects. Despite the numerous studies it is not feasible to generate a definitive list of health-state utility values that can be used in future economic evaluations owing to the complexity of the health states involved and the variety of methods used to obtain values. Future research into quality of life in breast cancer should make greater use of validated generic preference-based measures for which public preferences exist.

Sue Ward

Papers

A systematic review and economic evaluation of statins for the prevention of coronary events

Taxanes for the adjuvant treatment of early breast cancer: systematic review and economic evaluation.

Clinical and cost-effectiveness of capecitabine and tegafur with uracil for the treatment of metastatic colorectal cancer: systematic review and economic evaluation.

What role for statins? A review and economic model.

Health-state utility values in breast cancer.