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The effectiveness of dental implants is widely studied, especially in terms of their clinical outcomes. However, from the policymaker's point of view, variables other than safety and efficacy, such as the costs and effectiveness of dental implants as compared to other treatment alternatives, are vital in decision making. This paper compares the costs of different treatment strategies in a randomized clinical trial in patients with resorbed mandibles and persistent problems with their conventional dentures: treatment with a mandibular overdenture on permucosal dental implants, an overdenture on a transmandibular implant, new dentures after preprosthetic surgery, and new dentures only. Data were gathered on an individual patient level to gain insight into specific cost episodes. Direct costs were subdivided into labor, material, technique, and overhead. Data concerning these components were gathered during the consecutive treatment phases in the first year. Results show that the resources used to treat a patient with an overdenture supported by a transmandibular implant are seven times those of a complete new set of dentures. Comparison of the cost ratio of an implant-retained overdenture supported by permucosal implants and conventional new prostheses proves less unfavorable: 1:3. New dentures after preprosthetic surgery are almost as expensive as treatment with permucosal implants. [ABSTRACT FROM AUTHOR]

This paper reports the most cost-effective policy options to support and improve breast cancer control in Costa Rica and Mexico. Total costs and effects of breast cancer interventions were estimated using the health care perspective and WHO-CHOICE methodology. Effects were measured in disability-adjusted life years (DALYs) averted. Costs were assessed in 2009 United States Dollars (US$). To the extent available, analyses were based on locally obtained data. In Costa Rica, the current strategy of treating breast cancer in stages I to IV at a 80% coverage level seems to be the most cost-effective with an incremental cost-effectiveness ratio (ICER) of US$4,739 per DALY averted. At a coverage level of 95%, biennial clinical breast examination (CBE) screening could improve Costa Rica's population health twofold, and can still be considered very cost-effective (ICER US$5,964/DALY). For Mexico, our results indicate that at 95% coverage a mass-media awareness raising program (MAR) could be the most cost-effective (ICER US$5,021/DALY). If more resources are available in Mexico, biennial mammography screening for women 50–70 yrs (ICER US$12,718/DALY), adding trastuzumab (ICER US$13,994/DALY) or screening women 40–70 yrs biennially plus trastuzumab (ICER US$17,115/DALY) are less cost-effective options. We recommend both Costa Rica and Mexico to engage in MAR, CBE or mammography screening programs, depending on their budget. The results of this study should be interpreted with caution however, as the evidence on the intervention effectiveness is uncertain. Also, these programs require several organizational, budgetary and human resources, and the accessibility of breast cancer diagnostic, referral, treatment and palliative care facilities should be improved simultaneously. A gradual implementation of early detection programs should give the respective Ministries of Health the time to negotiate the required budget, train the required human resources and understand possible socioeconomic barriers. [ABSTRACT FROM AUTHOR]

ABSTRACT Interpreting the outcomes of cost utility analyses requires an appropriately defined threshold for costs per quality-adjusted life year (QALY). A common view is that the threshold should represent the (consumption) value a society attaches to a QALY. So far, individual valuations of personal health gains have mainly been studied rather than potentially relevant social values. In this study, we present the first direct empirical estimates of the willingness to pay for a QALY from a societal perspective. We used the contingent valuation approach, valuing QALYs under uncertainty and correcting for probability weighting. The estimates obtained in a representative sample of the Dutch population ( n = 1004) range from €52,000 to €83,000, depending on the specification of the societal perspective. The scale sensitivity was weak, however. Copyright © 2012 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Objectives: In 2000, the first “Dutch Manual for Costing: Methods and Reference Prices for Economic Evaluations in Healthcare” was published, followed by an updated version in 2004. The purpose of the Manual is to facilitate the implementation and assessment of costing studies in economic evaluations. New developments necessitated the publication of a thoroughly updated version of the Manual in 2010. The present study aims to describe the main changes of the 2010 Manual compared with earlier editions of the Manual.Methods: New and updated topics of the Manual were identified. The recommendations of the Manual were compared with the health economic guidelines of other countries, eliciting strengths and limitations of alternative methods.Results: New topics in the Manual concern medical costs in life-years gained, the database of the Diagnosis Treatment Combination (DBC) casemix System, reference prices for the mental healthcare sector and the costs borne by informal care-givers. Updated topics relate to the friction cost method, discounting future effects and options for transferring cost results from international studies to the Dutch situation.Conclusions: The Action Plan is quite similar to many health economic guidelines in healthcare. However, the recommendations on particular aspects may differ between national guidelines in some respects. Although the Manual may serve as an example to countries intending to develop a manual of this kind, it should always be kept in mind that preferred methods predominantly depend on a country's specific context. [ABSTRACT FROM PUBLISHER]

Rationale, aims and objectives The consideration of economic evidence in guideline development may be particularly important in health care management when different (drug) therapies show similar efficacy on clinical endpoints, such as in cardiovascular diseases. This article investigates to what extent the Dutch guideline 'cardiovascular risk management' (2006) considers cost-effectiveness and budget impact according to the most recent economic evidence. Method We carried out a systematic review of economic evaluations on cholesterol-lowering drugs and antihypertensives followed by an assessment of guideline recommendations. Results The guideline does not consider the most recent economic evidence but does consider cost-effectiveness based on economic evaluations performed in conjunction with clinical trials. Their conclusions are largely in agreement with the most recent economic evidence. An innovative aspect in the guideline is the application of a budget impact analysis to take accessibility and affordability constraints into account when considering cost-effectiveness. Conclusions Based on the most recent economic evidence, the guideline could be improved by more firmly formulating recommendations in favour of cost-effective drug therapies (simvastatin, pravastatin and low-dose diuretics) to stimulate compliance to the guideline in clinical practice. [ABSTRACT FROM AUTHOR]

Background: For the treatment of depression in diabetes patients, it is important that depression is recognized at an early stage. A screening method for depression is the patient health questionnaire (PHQ-9). The aim of this study is to validate the 9-item Patient Health Questionnaire (PHQ-9) as a screening instrument for depression in diabetes patients in outpatient clinics. Methods: 197 diabetes patients from outpatient clinics in the Netherlands filled in the PHQ-9. Within 2 weeks they were approached for an interview with the Mini Neuropsychiatric Interview. DSM-IV diagnoses of Major Depressive Disorder (MDD) were the criterion for which the sensitivity, specificity, positive- and negative predictive values and Receiver Operator Curves (ROC) for the PHQ-9 were calculated. Results: The cut-off point of a summed score of 12 on the PHQ-9 resulted in a sensitivity of 75.7% and a specificity of 80.0%. Predictive values for negative and positive test results were respectively 93.4% and 46.7%. The ROC showed an area under the curve of 0.77. Conclusions: The PHQ-9 proved to be an efficient and well-received screening instrument for MDD in this sample of diabetes patients in a specialized outpatient clinic. The higher cut-off point of 12 that was needed and somewhat lower sensitivity than had been reported elsewhere may be due to the fact that the patients from a specialized diabetes clinic have more severe pathology and more complications, which could be recognized by the PHQ-9 as depression symptoms, while instead being diabetes symptoms. [ABSTRACT FROM AUTHOR]

OBJECTIVES: To estimate the long-term impact of treatment with perindopril on costs and health effects in patients with stable coronary artery disease in Poland. METHODS: The cost-effectiveness analysis was based on data from a randomized double-blind, placebo-controlled trial. A decision-tree analysis was employed, including Monte Carlo and bootstrapping techniques. This study was a sub-study of the EUROPA (European Trial on Reduction of Cardiac Events with Perindopril in Stable Coronary Artery Disease) trial (n = 12 218; mean follow-up 4.2 years). Resource use was based on data from Polish EUROPA study patients (n = 1251), while effectiveness was based on the whole EUROPA study. The health gain of perindopril in life-years was based on overall EUROPA study results, and the adapted Polish life expectancy of patients not dying during the trial. Costs were calculated in new Polish zloty (PLN), year 2003 values; €1 = PLN4.053. Only direct healthcare costs related to cardiovascular events and medication use were studied. RESULTS: When observed mortality was combined with life expectancy beyond the end of the study, perindopril use showed a gain in life expectancy of 0.182 life-years (SD +/- 0.129) at a cost of PLN1983 (SD +/- 103) with discounting of 5% per annum on costs and no discounting on effects. This resulted in an incremental cost-effectiveness ratio (ICER) of PLN10 896 per life-year gained. The probability that the ICER for perindopril was below the threshold of PLN60 000 was 88%. The overall results were insensitive to discount rates for costs and life-years. CONCLUSIONS: Perindopril leads to a reduction in the risk of coronary events among patients with stable heart disease. When the expected improvement in life expectancy is combined with associated medical costs, there is a high probability that perindopril is cost effective, given the threshold of PLN60 000 per life-year gained. [ABSTRACT FROM AUTHOR]

Which costs and benefits to consider in economic evaluations of healthcare interventions remains an area of much controversy. Unrelated medical costs in life-years gained is an important cost category that is normally ignored in economic evaluations, irrespective of the perspective chosen for the analysis. National guidelines for pharmacoeconomic research largely endorse this practice, either by explicitly requiring researchers to exclude these costs from the analysis or by leaving inclusion or exclusion up to the discretion of the analyst. However, the inclusion of unrelated medical costs in life-years gained appears to be gaining support in the literature.This article provides an overview of the discussions to date. The inclusion of unrelated medical costs in life-years gained seems warranted, in terms of both optimality and internal and external consistency. We use an example of a smoking-cessation intervention to highlight the consequences of different practices of accounting for costs and effects in economic evaluations. Only inclusion of all costs and effects of unrelated medical care in life-years gained can be considered both internally and externally consistent. Including or excluding unrelated future medical costs may have important distributional consequences, especially for interventions that substantially increase length of life. Regarding practical objections against inclusion of future costs, it is important to note that it is becoming increasingly possible to accurately estimate unrelated medical costs in life-years gained. We therefore conclude that the inclusion of unrelated medical costs should become the new standard. [ABSTRACT FROM AUTHOR]

Which costs and benefits to consider in economic evaluations of healthcare interventions remains an area of much controversy. Unrelated medical costs in life-years gained is an important cost category that is normally ignored in economic evaluations, irrespective of the perspective chosen for the analysis. National guidelines for pharmacoeconomic research largely endorse this practice, either by explicitly requiring researchers to exclude these costs from the analysis or by leaving inclusion or exclusion up to the discretion of the analyst. However, the inclusion of unrelated medical costs in life-years gained appears to be gaining support in the literature.This article provides an overview of the discussions to date. The inclusion of unrelated medical costs in life-years gained seems warranted, in terms of both optimality and internal and external consistency. We use an example of a smoking-cessation intervention to highlight the consequences of different practices of accounting for costs and effects in economic evaluations. Only inclusion of all costs and effects of unrelated medical care in life-years gained can be considered both internally and externally consistent. Including or excluding unrelated future medical costs may have important distributional consequences, especially for interventions that substantially increase length of life. Regarding practical objections against inclusion of future costs, it is important to note that it is becoming increasingly possible to accurately estimate unrelated medical costs in life-years gained. We therefore conclude that the inclusion of unrelated medical costs should become the new standard. [ABSTRACT FROM AUTHOR]

Mortality rates in neonatal surgery have dropped markedly, illustrating the enormous progress made. Yet, new questions have arisen. To mention one, health care budgets have tightened. It follows that the effects of medical interventions should be weighted against their costs. As evidence was particularly sparse, we set out to analyse cost-effectiveness of neonatal surgery. The purpose of this article is to summarise our findings and to review recent studies. Moreover, this article explains the relevance of cost-effectiveness analysis and explores how cost-effectiveness interacts with other determinants of health care priority setting. Our research revealed that treatments for two common diagnostic categories in neonatal surgery (congenital anorectal malformations and congenital diaphragmatic hernia) produce good cost-effectiveness. Other groups also published cost-effectiveness studies in the field of neonatal surgery, although their number is still small. Contemporaneously, the economic aspects of health care have captured the interest of policy makers. Importantly, this is not to say that there are no other factors playing a role in priority setting, foremost among which are ethical questions and arguments of equity. This article concludes that, according to present evidence, neonatal surgery yields good value for money and contributes to equity in health. [ABSTRACT FROM AUTHOR]

Background: Major depressive disorder (MDD) has major consequences for both patients and society, particularly in terms of needlessly long sick leave and reduced functioning. Although evidence-based treatments for MDD are available, they show disappointing results when implemented in daily practice. A focus on work is also lacking in the treatment of depressive disorder as well as communication of general practitioners (GPs) and other health care professionals with occupational physicians (OPs). The OP may play a more important role in the recovery of patients with MDD. Purpose of the present study is to tackle these obstacles by applying a collaborative care model, which has proven to be effective in the USA, with a focus on return to work (RTW). From a societal perspective, the (cost)effectiveness of this collaborative care treatment, as a way of transmural care, will be evaluated in depressed patients on sick leave in the occupational health setting. Methods/Design: A randomised controlled trial in which the treatment of MDD in the occupational health setting will be evaluated in the Netherlands. A transmural collaborative care model, including Problem Solving Treatment (PST), a workplace intervention, antidepressant medication and manual guided self-help will be compared with care as usual (CAU). 126 Patients with MDD on sick leave between 4 and 12 weeks will be included in the study. Care in the intervention group will be provided by a multidisciplinary team of a trained OP-care manager and a consultant psychiatrist. The treatment is separated from the sickness certification. Data will be collected by means of questionnaires at baseline and at 3, 6, 9 and 12 months after baseline. Primary outcome measure is reduction of depressive symptoms, secondary outcome measure is time to RTW, tertiary outcome measure is the cost effectiveness. Discussion: The high burden of MDD and the high level of sickness absence among people with MDD contribute to the relevance of this study. The intervention is an innovative approach, with trained OPs in a new role as care managers in the treatment of MDD. If this intervention proves to be cost-effective, implementation will be very relevant for individual patients as well as for society. Trial registration: ISRCTN78462860 [ABSTRACT FROM AUTHOR]

Aim: To quantify the lifetime health and economic consequences of preventing and treating obesity with lifestyle intervention in Switzerland.Methods: A Markov model was developed comparing lifestyle intervention and standard care in overweight and obese people. Changes in weight and cardiovascular risk factors over time were modeled from reduction in body mass index, systolic blood pressure, total cholesterol and high density lipoprotein in three-year active treatment period. A probabilistic sensitivity analysis was performed. Three groups of people were followed in the analysis: overweight, borderline and moderate obese. The cost-effectiveness of interventions was compared using incremental cost-effectiveness ratio.Results: Lifestyle intervention resulted in increased survival duration and quality of life over lifetime. Compared with standard care, the average incremental cost of lifestyle intervention was lower in borderline and obese and higher in overweight. Lifestyle intervention dominated standard care in borderline female age 35 to 55 years, borderline male age 25 to 60 years, obese female age 45 years and obese male age 55 years.Conclusion: Our economic analysis suggests that lifestyle intervention is cost-effective in the long-term prevention and treatment of obesity. [ABSTRACT FROM AUTHOR]

Background: Depressive disorder is currently one of the most burdensome disorders worldwide. Evidence-based treatments for depressive disorder are already available, but these are used insufficiently, and with less positive results than possible. Earlier research in the USA has shown good results in the treatment of depressive disorder based on a collaborative care approach with Problem Solving Treatment and an antidepressant treatment algorithm, and research in the UK has also shown good results with Problem Solving Treatment. These treatment strategies may also work very well in the Netherlands too, even though health care systems differ between countries. Methods/design: This study is a two-armed randomised clinical trial, with randomization on patient-level. The aim of the trial is to evaluate the treatment of depressive disorder in primary care in the Netherlands by means of an adapted collaborative care framework, including contracting and adherence-improving strategies, combined with Problem Solving Treatment and antidepressant medication according to a treatment algorithm. Forty general practices will be randomised to either the intervention group or the control group. Included will be patients who are diagnosed with moderate to severe depression, based on DSM-IV criteria, and stratified according to comorbid chronic physical illness. Patients in the intervention group will receive treatment based on the collaborative care approach, and patients in the control group will receive care as usual. Baseline measurements and follow up measures (3, 6, 9 and 12 months) are assessed using questionnaires and an interview. The primary outcome measure is severity of depressive symptoms, according to the PHQ9. Secondary outcome measures are remission as measured with the PHQ9 and the IDS-SR, and cost-effectiveness measured with the TiC-P, the EQ-5D and the SF-36. Discussion: In this study, an American model to enhance care for patients with a depressive disorder, the collaborative care model, will be evaluated for effectiveness in the primary care setting. If effective across the Atlantic and across different health care systems, it is also likely to be an effective strategy to implement in the treatment of major depressive disorder in the Netherlands. [ABSTRACT FROM AUTHOR]

Background: Depressive disorder is one of the most common disorders, and is highly prevalent in chronically ill patients. The presence of comorbid depression has a negative influence on quality of life, health care costs, selfcare, morbidity, and mortality. Early diagnosis and well-organized treatment of depression has a positive influence on these aspects. Earlier research in the USA has reported good results with regard to the treatment of depression with a collaborative care approach and an antidepressant algorithm. In the UK 'Problem Solving Treatment' has proved to be feasible. However, in the general hospital setting this approach has not yet been evaluated. Methods/Design: CC: DIM (Collaborative Care: Depression Initiative in the Medical setting) is a two-armed randomised controlled trial with randomisation at patient level. The aim of the trial is to evaluate the treatment of depressive disorder in general hospitals in the Netherlands based on a collaborative care framework, including contracting, 'Problem Solving Treatment', antidepressant algorithm, and manual-guided self-help. 126 outpatients with diabetes mellitus, chronic obstructive pulmonary disease, or cardiovascular diseases will be randomised to either the intervention group or the control group. Patients will be included if they have been diagnosed with moderate to severe depression, based on the DSM-IV criteria in a two-step screening method. The intervention group will receive treatment based on the collaborative care approach; the control group will receive 'care as usual'. Baseline and follow-up measurements (after 3, 6, 9, and 12 months) will be performed by means of questionnaires. The primary outcome measure is severity of depressive symptoms, as measured with the PHQ-9. The secondary outcome measure is the cost-effectiveness of these treatments according to the TiC-P, the EuroQol and the SF-36. Discussion: Earlier research has indicated that depressive disorder is a chronic, mostly recurrent illness, which tends to cluster with physical comorbidity. Even though the treatment of depressive disorder based on the guidelines for depression is proven effective, these guidelines are often insufficiently adhered to. Collaborative care and 'Problem Solving Treatment' will be specifically tailored to patients with depressive disorders and evaluated in a general hospital setting in the Netherlands. [ABSTRACT FROM AUTHOR]

This contribution describes the entitlements in Dutch health care and explores how these entitlements are determined and to whom they apply. The focus is on services of curative care. No comprehensive positive or negative list of individual services is included in formal laws. Instead, the legislation states only what general types of medical services are covered and generally the “usual care” criterion determines to which interventions patients are entitled. This criterion is not very restrictive and yields local variations in service provision, which are moderated by practice guidelines. It is conceivable, however, that the recent introduction of the DBC financing system will change the reimbursement and therefore benefit-setting policy. [ABSTRACT FROM AUTHOR]

Background: Costs of inpatient days in hospitals are frequently the main drivers of total treatment costs, and their unit cost can markedly affect the outcomes of an economic evaluation. In many countries, the availability of unit cost data is limited and unit costs are often based on data from hospitals participating in clinical trials.Objective: To provide data about unit costs of inpatient hospital days in The Netherlands from a healthcare provider's perspective and to give an insight into the extent to which cost categories and total costs differ between hospitals.Design: Unit costs were collected from 22 wards and 11 intensive care units (ICUs) of general and university hospitals involved in clinical trials with 'piggybacked' economic evaluations. Direct costs, such as costs of nursing and medical materials, were calculated by dividing the annual cost per category of the nursing department by the annual number of inpatient days. Indirect costs, such as overheads and accommodation, were allocated to the nursing departments by applying direct allocation. All costs were expressed in 1998 euros (EUR).Results: The mean costs per inpatient day were EUR230 (range: EUR154-EUR311) in general hospitals and EUR323 (range: EUR209-EUR400) in university hospitals. The mean costs per inpatient day in an ICU were EUR1125 (EUR919-EUR1560). Between 38-48% of the total costs were made up of nursing costs. All cost categories showed wide variations between hospitals.Conclusions: The results of this study were used to develop standard costs for inpatient days in The Netherlands and may contribute to the comparability and generalisability of economic evaluations. [ABSTRACT FROM AUTHOR]

The lack of a uniform costing methodology is often considered a weakness of economic evaluations that hinders the interpretation and comparison of studies. Standardisation is therefore an important topic within the methodology of economic evaluations and in national guidelines that formulate the formal requirements for studies to be considered when deciding on the reimbursement of new medical therapies. Recently, the Dutch Manual for Costing: Methods and Standard Costs for Economic Evaluations in Health Care (further referred to as ‘the manual’) has been published, in addition to the Dutch guidelines for pharmacoeconomic research. The objectives of this article are to describe the main content of the manual and to discuss some key issues of the manual in relation to the standardisation of costs. The manual introduces a six-step procedure for costing. These steps concern: the scope of the study; the choice of cost categories; the identification of units; the measurement of resource use; the monetary valuation of units; and the calculation of unit costs. Each step consists of a number of choices and these together define the approach taken. In addition to a description of the costing process, five key issues regarding the standardisation of costs are distinguished. These are the use of basic principles, methods for measurement and valuation, standard costs (average prices of healthcare services), standard values (values that can be used within unit cost calculations), and the reporting of outcomes. The use of the basic principles, standard values and minimal requirements for reporting outcomes, as defined in the manual, are obligatory in studies that support submissions to acquire reimbursement for new pharmaceuticals. Whether to use standard costs, and the choice of a particular method to measure or value costs, is left mainly to the investigator, depending on the specific study setting. In conclusion, several instruments are available to increase standardisation in costing methodology among studies. These instruments have to be used in such a way that a balance is found between standardisation and the specific setting in which a study is performed. The way in which the Dutch manual tries to reach this balance can serve as an illustration for other countries. [ABSTRACT FROM AUTHOR]

Background: Estimating the probability of pregnancy leading to delivery and the influence of clinical factors on that probability is of fundamental importance in the treatment counselling of infertile couples. A variety of statistical techniques have been used to analyse fertility data, many borrowed from survival analysis.Methods and Results: We propose an alternative method of analysis which is based on a discrete time Markov chain approach, with states 'pregnancy (leading to a delivery)', 'not pregnant', and 'censored' and in which the transition probabilities are dependent both on the clinical characteristics of the patient and the treatment given.Conclusions: We believe that the method of analysis presented here may be preferable to standard analyses in that it better reflects the clinical situation, it is a truly discrete time analysis applied to a discrete time situation, it explicitly models the censoring process (a process which in itself provides information of interest to the physician) and can be readily extended to a variety of clinical situations. [ABSTRACT FROM AUTHOR]

Looks at the decision by the National Institute for Health and Clinical Excellence to abandon differential discounting of future health. Author's view that the decision is a step backwards and will impact funding decisions; Discussion of how discounting can have strong influence on cost effectiveness ratios for priority setting, especially in preventive interventions; Debate surrounding the current practice of equal discounting.

Background: Major depressive disorder (MDD) has major consequences for both patients and society, particularly in terms of needlessly long sick leave and reduced functioning. Although evidence-based treatments for MDD are available, they show disappointing results when implemented in daily practice. A focus on work is also lacking in the treatment of depressive disorder as well as communication of general practitioners (GPs) and other health care professionals with occupational physicians (OPs). The OP may play a more important role in the recovery of patients with MDD. Purpose of the present study is to tackle these obstacles by applying a collaborative care model, which has proven to be effective in the USA, with a focus on return to work (RTW). From a societal perspective, the (cost)effectiveness of this collaborative care treatment, as a way of transmural care, will be evaluated in depressed patients on sick leave in the occupational health setting.Methods/design: A randomised controlled trial in which the treatment of MDD in the occupational health setting will be evaluated in the Netherlands. A transmural collaborative care model, including Problem Solving Treatment (PST), a workplace intervention, antidepressant medication and manual guided self-help will be compared with care as usual (CAU). 126 Patients with MDD on sick leave between 4 and 12 weeks will be included in the study. Care in the intervention group will be provided by a multidisciplinary team of a trained OP-care manager and a consultant psychiatrist. The treatment is separated from the sickness certification. Data will be collected by means of questionnaires at baseline and at 3, 6, 9 and 12 months after baseline. Primary outcome measure is reduction of depressive symptoms, secondary outcome measure is time to RTW, tertiary outcome measure is the cost effectiveness.Discussion: The high burden of MDD and the high level of sickness absence among people with MDD contribute to the relevance of this study. The intervention is an innovative approach, with trained OPs in a new role as care managers in the treatment of MDD. If this intervention proves to be cost-effective, implementation will be very relevant for individual patients as well as for society.Trial Registration: ISRCTN78462860. [ABSTRACT FROM AUTHOR]