CYP2C19 genotype-guided antithrombotic treatment versus conventional clopidogrel therapy in peripheral arterial disease: study design of a randomized controlled trial (GENPAD).

BACKGROUND: Clopidogrel is recommended in international guidelines to prevent arterial thrombotic events in patients with peripheral arterial disease (PAD). Clopidogrel itself is inactive and metabolism is dependent on the CYP2C19 enzyme. About 30% of Caucasian PAD patients receiving clopidogrel carry 1 or 2 CYP2C19 loss-of-function allele(s) and do not or to a limited extent convert the prodrug into its active metabolite. As a result, platelet inhibition may be inadequate which could lead to an increased risk of adverse clinical events related to arterial thrombosis. A CYP2C19 genotype-guided antithrombotic treatment might be beneficial for PAD patients. METHODS: GENPAD is a multicenter randomized controlled trial involving 2,276 PAD patients with an indication for clopidogrel monotherapy. Patients with a separate indication for dual antiplatelet therapy or stronger antithrombotic therapy are not eligible for study participation. Patients randomized to the control group will receive clopidogrel 75 mg once daily without pharmacogenetic guidance. Patients randomized to the intervention group will be tested for carriage of CYP2C19 *2 and *3 loss-of-function alleles, followed by a genotype-guided antithrombotic treatment with either clopidogrel 75 mg once daily for normal metabolizers, clopidogrel 150 mg once daily for intermediate metabolizers, or acetylsalicylic acid 80 mg once daily plus rivaroxaban 2.5 mg twice daily for poor metabolizers. The primary outcome is a composite of myocardial infarction, ischemic stroke, cardiovascular death, acute or chronic limb ischemia, peripheral vascular interventions, or death. The secondary outcomes are the individual elements of the primary composite outcome and clinically relevant bleeding complications. CONCLUSION: The aim of the GENPAD study is to evaluate the efficacy, safety, and cost-effectiveness of a genotype-guided antithrombotic treatment strategy compared to conventional clopidogrel treatment in PAD patients.

Biopsy outperforms reflectance confocal microscopy in diagnosing and subtyping basal cell carcinoma: results and experiences from a randomized controlled multicentre trial.

BACKGROUND: Reflectance confocal microscopy (RCM) is a noninvasive method for skin assessment, allowing entire lesion evaluation up to the papillary dermis. RCM is a potentially attractive alternative to punch biopsy (PB) in basal cell carcinoma (BCC). OBJECTIVES: To determine the diagnostic accuracy of RCM vs. PB in diagnosing and subtyping BCC, and to study patient satisfaction and preferences. METHODS: Patients with a clinically suspected primary BCC were randomized between RCM and biopsy. Conventional surgical excision or follow-up were used as reference. Sensitivity and specificity for BCC diagnosis and subtyping were calculated for both methods. BCC subtype was stratified based on clinical relevance: aggressive (infiltrative/micronodular) vs. nonaggressive (superficial/nodular) histopathological subtype and superficial vs. nonsuperficial BCC. Data on patient satisfaction and preferences were collected using a questionnaire and a contingent valuation method. RESULTS: Sensitivity for BCC diagnosis was high and similar for both methods (RCM 99·0% vs. biopsy 99·0%; P = 1·0). Specificity for BCC diagnosis was lower for RCM (59·1% vs. 100·0%; P < 0·001). Sensitivity for aggressive BCC subtypes was lower for RCM (33·3% vs. 77·3%; P = 0·003). Sensitivity for nonsuperficial BCC was not significantly different (RCM 88·9% vs. biopsy 91·0%; P = 0·724). Patient satisfaction and preferences were good and highly comparable for both methods. CONCLUSIONS: Biopsy outperforms RCM in diagnosing and subtyping clinically suspected primary BCC. This outcome does not support routine clinical implementation of RCM, as a replacement for PBs in this patient group.

Subtypes of Sport-Related Concussion: a Systematic Review and Meta-cluster Analysis.

OBJECTIVE: Current clinical guidelines provide a unitary approach to manage sport-related concussion (SRC), while heterogeneity in the presentation of symptoms suggests that subtypes of SRC may exist. We systematically reviewed the available evidence on SRC subtypes and associated clinical outcomes. DATA SOURCES: Ovid Medline, Embase, PsycINFO, and SPORTDiscus ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Electronic databases were searched for studies: (i) identifying SRC symptom clusters using classification methodology; or (ii) associating symptom clusters to clinical outcome variables. A total of 6,146 unique studies were identified, of which 75 full texts were independently assessed by two authors for eligibility. A total of 22 articles were included for systematic review. DATA EXTRACTION: Two independent authors performed data extraction and risk of bias analysis using the Cochrane Collaboration tool. DATA SYNTHESIS: Six studies found evidence for existence of SRC symptom clusters. Combining the available literature through Multiple Correspondence Analysis (MCA) provided evidence for the existence of a migraine cluster, a cognitive-emotional cluster, a sleep-emotional cluster, a neurological cluster, and an undefined feelings cluster. Nineteen studies found meaningful associations between SRC symptom clusters and clinical outcomes. Clusters mapping to the migraine cluster were most frequently reported in the literature and were most strongly related to aspects of clinical outcome. CONCLUSIONS: The available literature provides evidence for the existence of at least five subtypes in SRC symptomatology, with clear relevance to clinical outcome. Systematically embedding the differentiation of SRC subtypes into prognosis, clinical management, and intervention strategies may optimize the recovery from SRC.

Is there a volume-quality relationship within the independent treatment centre sector? A longitudinal analysis.

BACKGROUND: The number of independent treatment centres (ITCs) has grown substantially. However, little is known as to whether the volume-quality relationship exists within this sector and whether other possible organisational factors mediate this relationship. The aim of this study is to gain a better understanding of such possible relationships. METHODS: Data originate from the Dutch Health and Youth Care Inspectorate (IGJ) and the Dutch Patients Association. We used longitudinal data from 4 years (2014-2017) including three different quality measures: 1) composite of structural and process indicators, 2) postoperative infections, and 3) patient satisfaction. We measured volume by the number of invasive treatments. We adjusted for three important organisational characteristics: (1) size of workforce, (2) chain membership, and (3) ownership status. For statistical inference, random effects analysis was used. We also ran several robustness checks for the volume-quality relationship, including a fractional logit model. RESULTS: ITCs with higher volumes scored better on structure, process and outcome (i.e. postoperative infections) indicators compared to the low-volume ITCs - although only marginally on outcome. However, ITCs with higher volumes do not have higher patient satisfaction. There is a decreasing marginal effect of volume - in other words, an L-shaped curve. The effect of the intermediating structural factors on the volume-quality relationship (i.e. workforce size, chain membership and ownership status) is less clear. Our findings suggest that chain membership has a negative influence on patient satisfaction. Furthermore, for-profit providers scored better on the Net Promoter Score. CONCLUSIONS: Our study shows with some certainty that the quality of care in low-volume ITCs is lower than in high-volume ITCs as measured by structural, process and outcome (i.e. postoperative infection) indicators. However, the size of the effect of volume on postoperative infections is small, and at higher volumes the marginal benefits (in terms of lower postoperative infections) decrease. In addition, volume is not related to patient satisfaction. Furthermore, the association between the structural intermediating factors and quality are tenuous.

Health-related quality of life analysis in stage III melanoma patients treated with adjuvant dendritic cell therapy.

BACKGROUND: Health-related quality of life (HRQoL) is an important issue in the rapidly evolving field of adjuvant treatment for stage III melanoma. Dendritic cell vaccination is one of the adjuvant forms of therapy currently investigated. METHODS: We enrolled adults with stage III melanoma to receive adjuvant dendritic cell vaccination after a complete radical lymph node dissection. HRQoL assessment was one of the secondary endpoints of this trial and investigated with the EORTC-QLQ-C30 questionnaire at baseline and week 26. RESULTS: Fifteen patients with a median age of 50 years were included in the study, with twelve evaluable patients on study at time of the second questionnaire. Global health status and role functioning improved clinically relevant with a mean difference of 15 (p = 0.010) and 26 points (p = 0.005), respectively. DISCUSSION: Despite the small number of patients, we found a clinically relevant improved global health status. Besides, compared to the other investigated therapies, toxicity of dendritic cell vaccination is low, which supports our finding. CONCLUSION: This is the first description of HRQoL in melanoma patients receiving dendritic cell vaccination. We show the expected improvement in global health status after surgical treatment of stage III melanoma. Thus, adjuvant dendritic cell vaccination does not seem to hamper this improvement, as shown in our small explorative study.

Exploring associations between psychiatric disorder, psychological distress, and health care utilization in cancer patients.

OBJECTIVE: The mental burden of cancer might elicit additional health care utilization. However, it is unclear how psychiatric disorder and psychological distress relate to health care utilization. Therefore, this study explores associations between psychiatric disorder, psychological distress, and health care utilization. It was hypothesized that presence of psychiatric disorder and psychological distress was associated with increased health care utilization and costs. METHODS: The current study consisted of secondary analyses of baseline data of a larger randomized controlled trial. Two hundred forty-five mixed-cancer patients with at least mild symptoms of psychological distress (Hospital Anxiety and Depression Scale-T ≥ 11) were mainly recruited via online media, participating centers and patient associations. Patients were assessed with Structured Clinical Interview for DSM-IV-TR Axis I Disorders (SCID-I) for depressive, anxiety, and/or adjustment disorder. Psychological distress was measured by the Hospital Anxiety and Depression Scale. Retrospective self-reported health care utilization in the past 3 months was collected. Associations between predictors and health care utilization in terms of incidence rate ratios (IRR) and costs per category (mental, primary, somatic, and complementary) were assessed by negative binomial, logistic, and gamma regression. RESULTS: Eighty-nine (36.3%) patients suffered from psychiatric disorder, which was associated with mental health care utilization (IRR = 1.63) and costs (OR = 3.11). We observed a nonsignificant trend of somatic health care utilization in patients with psychiatric disorder. Psychological distress was associated with mental health care utilization (IRR = 1.09) and costs (OR = 1.09). Psychological distress was also associated with complementary health care utilization (IRR = 1.03). CONCLUSION: Psychiatric disorder and psychological distress were associated with mental health care use and costs. Psychological distress was associated with complementary health care use. Adequate assessment and referral to mental health care might prevent unnecessary health care utilization.

Study protocol of a multicenter randomized controlled trial comparing the effectiveness of group and individual internet-based Mindfulness-Based Cognitive Therapy with treatment as usual in reducing psychological distress in cancer patients: the BeMind study.

BACKGROUND: Mindfulness-based interventions have shown to reduce psychological distress in cancer patients. The accessibility of mindfulness-based interventions for cancer patients could be further improved by providing mindfulness using an individual internet-based format. The aim of this study is to test the effectiveness of a Mindfulness-Based Cognitive Therapy (MBCT) group intervention for cancer patients in comparison with individual internet-based MBCT and treatment as usual (TAU). METHODS/DESIGN: A three-armed multicenter randomized controlled trial comparing group-based MBCT to individual internet-based MBCT and TAU in cancer patients who suffer from at least mild psychological distress (Hospital Anxiety and Depression Scale (HADS) ≥ 11). Measurements will be conducted prior to randomization (baseline), post-treatment and at 3 months and 9 months post-treatment. Participants initially allocated to TAU are subsequently randomized to either group- or individual internet-based MBCT and will receive a second baseline measurement after 3 months. Thus, the three-armed comparison will have a time span of approximately 3 months. The two-armed intervention comparison includes a 9-month follow-up and will also consist of participants randomized to the intervention after TAU. Primary outcome will be post-treatment psychological distress (HADS). Secondary outcomes are fear of cancer recurrence (Fear of Cancer Recurrence Inventory), rumination (Rumination and Reflection Questionnaire), positive mental health (Mental Health Continuum - Short Form), and cost-effectiveness (health-related quality of life (EuroQol -5D and Short Form-12) and health care usage (Trimbos and iMTA questionnaire on Costs associated with Psychiatric illness). Potential predictors: DSM-IV-TR mood/anxiety disorders (SCID-I) and neuroticism (NEO-Five Factor Inventory) will be measured. Mediators of treatment effect: mindfulness skills, (Five-Facets of Mindfulness Questionnaire- Short Form), working alliance (Working Alliance Inventory) and group cohesion (Group Cohesion Questionnaire) will also be measured. DISCUSSION: This trial will provide valuable information on the clinical and cost-effectiveness of group versus internet-based MBCT versus TAU for distressed cancer patients. TRIAL REGISTRATION: Clinicaltrials.gov NCT02138513. Registered 6 May 2014.

Fourfold increased detection of Lynch syndrome by raising age limit for tumour genetic testing from 50 to 70 years is cost-effective.

BACKGROUND: Recognising colorectal cancer (CRC) patients with Lynch syndrome (LS) can increase life expectancy of these patients and their close relatives. To improve identification of this under-diagnosed disease, experts suggested raising the age limit for CRC tumour genetic testing from 50 to 70 years. The present study evaluates the efficacy and cost-effectiveness of this strategy. METHODS: Probabilistic efficacy and cost-effectiveness analyses were carried out comparing tumour genetic testing of CRC diagnosed at age 70 or below (experimental strategy) versus CRC diagnosed at age 50 or below (current practice). The proportions of LS patients identified and cost-effectiveness including cascade screening of relatives, were calculated by decision analytic models based on real-life data. RESULTS: Using the experimental strategy, four times more LS patients can be identified among CRC patients when compared with current practice. Both the costs to detect one LS patient (€9437/carrier versus €4837/carrier), and the number needed to test for detecting one LS patient (42 versus 19) doubled. When family cascade screening was included, the experimental strategy was found to be highly cost-effective according to Dutch standards, resulting in an overall ratio of €2703 per extra life-year gained in additionally tested patients. CONCLUSION: Testing all CRC tumours diagnosed at or below age 70 for LS is cost-effective. Implementation is important as relatives from the large number of LS patients that are missed by current practice, can benefit from life-saving surveillance.

Cost-effectiveness of FDG-PET/CT for cytologically indeterminate thyroid nodules: a decision analytic approach.

CONTEXT: Patients with thyroid nodules of indeterminate cytology undergo diagnostic surgery according to current guidelines. In 75% of patients, the nodule is benign. In these patients, surgery was unnecessary and unbeneficial because complications may occur. Preoperative fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) was found to have a very high negative predictive value (96%) and might therefore avoid futile surgery, complications, and costs. In the United States, two molecular tests of cytology material are routinely used for this purpose. OBJECTIVE: Five-year cost-effectiveness for routine implementation of FDG-PET/CT was evaluated in adult patients with indeterminate fine-needle aspiration cytology and compared with surgery in all patients and both molecular tests. DESIGN: A Markov decision model was developed to synthesize the evidence on cost-effectiveness about the four alternative strategies. The model was probabilistically analyzed. One-way sensitivity analyses of deterministic input variables likely to influence outcome were performed. SETTING AND SUBJECTS: The model was representative for adult patients with cytologically indeterminate thyroid nodules. MAIN OUTCOME MEASURES: The discounted incremental net monetary benefit (iNMB), the efficiency decision rule containing outcomes as quality-adjusted life-years and (direct) medical cost, of implementation of FDG-PET/CT is displayed. RESULTS: Full implementation of FDG-PET/CT resulted in 40% surgery for benign nodules, compared with 75% in the conventional approach, without a difference in recurrence free and overall survival. The FDG-PET/CT modality is the more efficient technology, with a mean iNMB of €3684 compared with surgery in all. Also, compared with a gene expression classifier test and a molecular marker panel, the mean iNMB of FDG-PET/CT was €1030 and €3851, respectively, and consequently the more efficient alternative. CONCLUSION: Full implementation of preoperative FDG-PET/CT in patients with indeterminate thyroid nodules could prevent up to 47% of current unnecessary surgery leading to lower costs and a modest increase of health-related quality of life. Compared with an approach with diagnostic surgery in all patients and both molecular tests, it is the least expensive alternative with similar effectiveness as the gene-expression classifier.

TIPP and Lichtenstein modalities for inguinal hernia repair: a cost minimisation analysis alongside a randomised trial.

The transinguinal preperitoneal (TIPP) technique using a soft mesh with a memory ring was developed recently for inguinal hernia repair. To compare TIPP with the Lichtenstein method, a randomised trial was conducted (ISRCTN93798494). The aim of this study was to perform an economic evaluation of the TIPP modality compared to the Lichtenstein modality from both a hospital and societal perspective alongside the clinical trial. The TULIP study was a double-blind randomised clinical trial comparing two techniques for inguinal hernia repair (TIPP and Lichtenstein). Correct generation of the allocation sequence, allocation concealment, blinding, and follow-up were used/applied according to the recommendations of the Cochrane Handbook. Next to the cost drivers, the short-form-36 health survey (SF-36) data from the TULIP trial was used to determine utility. The SF-36 data from the TULIP trial were revised using the SF-6D algorithm according to Brazier. Two scenarios-a hospital and a societal perspective-were presented. If the analyses showed no difference in effects (on the SF-6D) the cost effectiveness decision rule to cost minimisation was altered. No significant difference in SF-6D utility between both modalities was found (mean difference: 0.888, 95% CI -1.02 to 1.23); consequently, the economic decision rule became cost minimisation. For the hospital perspective no significant differences in costs were found (mean difference: euro -13, 95% CI euro -130 to euro 104). However, when including productivity gains in the analysis, significant differences (P = 0.037) in costs favouring the TIPP modality (mean saving: euro 1,472, 95% CI euro 463- euro 2,714) were found. The results show that TIPP is a cost-saving inguinal hernia repair technique compared to the Lichtenstein modality against equal effectiveness expressed as quality adjusted life week at 1 year given a societal perspective. In the trial, TIPP patients showed on average a quicker recovery of 6.5 days compared to Lichtenstein patients.

Guideline adherence is worth the effort: a cost-effectiveness analysis in intrauterine insemination care.

STUDY QUESTION: Is optimal adherence to guideline recommendations in intrauterine insemination (IUI) care cost-effective from a societal perspective when compared with suboptimal adherence to guideline recommendations? SUMMARY ANSWER: Optimal guideline adherence in IUI care has substantial economic benefits when compared with suboptimal guideline adherence. WHAT IS KNOWN ALREADY: Fertility guidelines are tools to help health-care professionals, and patients make better decisions about clinically effective, safe and cost-effective care. Up to now, there has been limited published evidence about the association between guideline adherence and cost-effectiveness in fertility care. STUDY DESIGN, SIZE, DURATION: In a retrospective cohort study involving medical record analysis and a patient survey (n = 415), interviews with staff members (n = 13) and a review of hospitals' financial department reports and literature, data were obtained about patient characteristics, process aspects and clinical outcomes of IUI care and resources consumed. In the cost-effectiveness analyses, restricted to four relevant guideline recommendations, the ongoing pregnancy rate per couple (effectiveness), the average medical and non-medical costs of IUI care, possible additional IVF treatment, pregnancy, delivery and period from birth up to 6 weeks after birth for both mother and offspring per couple (costs) and the incremental net monetary benefits were calculated to investigate if optimal guideline adherence is cost-effective from a societal perspective when compared with suboptimal guideline adherence. PARTICIPANTS/MATERIALS, SETTING, METHODS: Seven hundred and sixty five of 1100 randomly selected infertile couples from the databases of the fertility laboratories of 10 Dutch hospitals, including 1 large university hospital providing tertiary care and 9 public hospitals providing secondary care, were willing to participate, but 350 couples were excluded because of ovulatory disorders or the use of donated spermatozoa (n = 184), still ongoing IUI treatment (n = 143) or no access to their medical records (n = 23). As a result, 415 infertile couples who started a total of 1803 IUI cycles were eligible for the cost-effectiveness analyses. MAIN RESULTS AND THE ROLE OF CHANCE: Optimal adherence to the guideline recommendations about sperm quality, the total number of IUI cycles and dose of human chorionic gonadotrophin was cost-effective with an incremental net monetary benefit between € 645 and over € 7500 per couple, depending on the recommendation and assuming a willingness to pay € 20 000 for an ongoing pregnancy. LIMITATIONS, REASONS FOR CAUTION: Because not all recommendations applied to all 415 included couples, smaller groups were left for some of the cost-effectiveness analyses, and one integrated analysis with all recommendations within one model was impossible. WIDER IMPLICATIONS OF THE FINDINGS: Optimal guideline adherence in IUI care has substantial economic benefits when compared with suboptimal guideline adherence. For Europe, where over 144,000 IUI cycles are initiated each year to treat ≈ 32 000 infertile couples, this could mean a possible cost saving of at least 20 million euro yearly. Therefore, it is valuable to make an effort to improve guideline development and implementation.

Relevant impact of central pathology review on nodal classification in individual breast cancer patients.

BACKGROUND: In the MIRROR study, pN0(i + ) and pN1mi were associated with reduced 5-year disease-free survival (DFS) compared with pN0. Nodal status (N-status) was assessed after central pathology review and restaging according to the sixth AJCC classification. We addressed the impact of pathology review. PATIENTS AND METHODS: Early favorable primary breast cancer patients, classified pN0, pN0(i + ), or pN1(mi) by local pathologists after sentinel node procedure, were included. We assessed the impact of pathology review on N-status (n = 2842) and 5-year DFS for those without adjuvant therapy (n = 1712). RESULTS: In all, 22% of the 1082 original pN0 patients was upstaged. Of the 623 original pN0(i + ) patients, 1% was downstaged, 26% was upstaged. Of 1137 patients staged pN1mi, 15% was downstaged, 11% upstaged. Originally, 5-year DFS was 85% for pN0, 74% for pN0(i + ), and 73% for pN1mi; HR 1.70 [95% confidence interval (CI) 1.27-2.27] and HR 1.57 (95% CI 1.16-2.13), respectively, compared with pN0. By review staging, 5-year DFS was 86% for pN0, 77% for pN0(i + ), 77% for pN1mi, and 74% for pN1 + . CONCLUSION: Pathology review changed the N-classification in 24%, mainly upstaging, with potentially clinical relevance for individual patients. The association of isolated tumor cells and micrometastases with outcome remained unchanged. Quality control should include nodal breast cancer staging.

Cost-effectiveness of adjuvant systemic therapy in low-risk breast cancer patients with nodal isolated tumor cells or micrometastases.

BACKGROUND: The cost-effectiveness of adjuvant systemic therapy in patients with low-risk breast cancer and nodal isolated tumor cells or micrometastases is unknown. PATIENTS AND METHODS: A cost-effectiveness analysis of adjuvant systemic therapy was carried out using the costs per 1% event prevented after 5 years of follow-up as incremental cost-effectiveness ratio (ICER). Secondary objective was to establish when adjuvant systemic therapy becomes cost saving. Patients included in the MIRROR study with isolated tumor cells or micrometastases who had a complete 5-year follow-up and who either did or did not receive systemic therapy were eligible. Sensitivity analyses were carried out. RESULTS: In the no adjuvant therapy cohort (N = 366), 24.9% of patients had an event within 5 years versus 16.8% of patients in the adjuvant therapy cohort (N = 483) (P < 0.01). The ICER was €363 per 1% event prevented. Beyond 18 years after diagnosis, the extrapolated mean cumulative costs per patient in the no adjuvant therapy cohort exceeded those of the adjuvant therapy cohort. CONCLUSIONS: In this population of breast cancer patients with isolated tumor cells or micrometastases, €36 300 had to be invested to prevent one event in 5 years of follow-up. Adjuvant systemic therapy was cost saving beyond 18 years after diagnosis.

Long-term global quality of life in patients treated for colorectal liver metastases.

BACKGROUND: Surgical treatment of colorectal liver metastases has become increasingly aggressive. The influence of this more active surgical approach on patients' health-related quality of life (HRQoL) has hardly been evaluated. This study investigated the impact of surgical and systemic treatment on HRQoL in patients undergoing hepatic resection for colorectal metastases. METHODS: A total of 145 patients with colorectal liver metastases were entered prospectively into the study. Based on HRQoL values derived from the EuroQol-5D, health summary measures were calculated to express the overall impact on four distinct clinical states. The HRQoL instrument was used at baseline, 3 and 6 weeks after surgery, and every 3 months thereafter for up to 3 years. RESULTS: Patients showed a clear deterioration in HRQoL in the first weeks after surgery, followed by a recovery to baseline levels at 3 months after potentially curative surgery. In contrast, a sustained decline was noted when initial surgery for colorectal liver metastases was considered futile and palliative chemotherapy was started immediately. Three years after initial surgery, there were distinct differences in HRQoL between patients with or without recurrence. The latter group still had HRQoL scores at baseline levels, whereas patients with tumour recurrence showed a significant deterioration in HRQoL. Remarkably, there was no decline in HRQoL in patients with recurrent disease who could be treated by secondary surgical intervention. CONCLUSION: Superior overall HRQoL in the first 3 years after initial successful surgical intervention merits an aggressive surgical approach and intensive follow-up to detect recurrence early.

A multi-faceted strategy to improve the use of national fertility guidelines; a cluster-randomized controlled trial.

BACKGROUND Proper use of clinical practice guidelines can decrease variation in care between settings. However, actual use of fertility guidelines is suboptimal and in need of improvement. Hence, a cluster-randomized controlled trial was designed to study the effects of two strategies to implement national Dutch guidelines on comprehensive fertility care. METHODS Sixteen fertility clinics participated in the trial. A minimal, professional-oriented implementation strategy of audit and feedback was tested versus a maximal multi-faceted strategy that was both professional and patient oriented. The extent of adherence to guideline recommendations, reflected in quality indicator scores, was the primary outcome measure. To gain an insight into unwanted side effects, patient anxiety and depression scores were gathered as secondary outcomes. Data collection encompassed medical record search, patient and professional questionnaires. RESULTS A total of 1499 couples were included at baseline and 1396 at the after-measurement. No overall significant improvement in indicator scores was found for either strategy [odds ratios ranging from 0.23 (95% confidence interval (CI): 0.06-0.95) to 6.66 (95% CI: 0.33-132.8]. Secondary outcomes did not differ significantly for both groups, although selected anxiety scores appeared lower in the maximal intervention group. Process evaluation of the trial revealed positive patient experiences with the intervention material [e.g. an increased understanding of their doctor's treatment policy (61%), an increased ability to ask questions about the treatment (61%)]. Professionals' appreciation of intervention elements varied, and execution of the multi-faceted strategy appeared incomplete. DISCUSSION Absence of an intervention effect may be due to the nature of the strategies, incomplete execution or flaws in study design. Process evaluation data raise the question of whether professionals should be the only stakeholder responsible for guideline implementation. This study therefore contributes to an increased understanding of fertility guideline implementation in general, and the role of patients in particular.

Electronic reminders for pathologists promote recognition of patients at risk for Lynch syndrome: cluster-randomised controlled trial.

We investigated success factors for the introduction of a guideline on recognition of Lynch syndrome in patients recently diagnosed with colorectal cancer (CRC) below age 50 or a second CRC below age 70. Pathologists were asked to start microsatellite instability (MSI) testing and report to surgeons with the advice to consider genetic counselling when MSI test or family history was positive. A multicentre cluster-randomised controlled trial (ClinicalTrials.gov, number NCT00141466) was performed in 12 pathology laboratories (clusters), serving 29 community hospitals. All received an introduction to the new guideline. In the intervention group, surgeons received education and tumour test result reminders; pathologists were provided with inclusion criteria cards, an electronic patient inclusion reminder system and feedback on inclusion. Two hundred sixty-six CRC patients were eligible for recognition as at risk for Lynch syndrome. The actual recognition was 18% more successful in the intervention as compared to the control arm (77% (120 of 156) compared to 59% (65 of 110)), with an adjusted odds ratio (OR) = 2.8 (95% confidence interval (CI) 1.1-7.0). The electronic reminder system for pathologists was most strongly associated with recognition of high-risk patients, OR = 4.2 (95% CI 1.7-10.1). An electronic reminder system for pathologists appeared effective for adherence to a new complex guideline and will enhance the recognition of Lynch syndrome.

The economic impact of high-need psoriasis in daily clinical practice before and after the introduction of biologics.

BACKGROUND: Although costs of biologics are high, effective treatment of patients with psoriasis may reduce the total health care costs, as it may limit the need for hospitalization. OBJECTIVES: To investigate the economic impact of psoriasis, including direct costs, before and after the introduction of biologics, with special focus on hospitalized patients, treatment effectiveness and patient satisfaction with medication. PATIENTS AND METHODS: A descriptive retrospective cohort study including 67 patients with high-need psoriasis was done. Direct costs were investigated for the biologic and pre-biologic period. Direct costs for a subgroup of hospitalized patients were analysed separately. Patient satisfaction with biologic treatment was measured using the Treatment Satisfaction Questionnaire for Medication (TSQM) version II. Effectiveness of biologic therapy was investigated by means of the Psoriasis Area and Severity Index (PASI). RESULTS: Mean total direct costs were €10,146 per patient per year (PPPY) in the pre-biologic treatment period, compared with €17,712 PPPY in the biologic treatment period. For six patients in the cohort, introduction of biologics led to a reduction of direct costs, as these patients did not need long hospitalizations. Treatment with biologics led to a decrease in PASI from 19·0 at the start of biologic therapy to 6·4 at analysis (66·4%). Patient satisfaction with biologics was high, indicated by a mean TSQM score of 77·8. CONCLUSIONS: Introduction of biologic therapies may have cost-neutral or cost-saving effects for patients who otherwise require long hospitalization periods. Treatment with biologics proved effective and was accompanied by high satisfaction for the patients.

Cost-effectiveness of post-diagnosis treatment in dementia coordinated by Multidisciplinary Memory Clinics in comparison to treatment coordinated by general practitioners: an example of a pragmatic trial.

BACKGROUND: With the rising number of dementia patients with associated costs and the recognition that there is room for improvement in the provision of dementia care, the question arises on how to efficiently provide high quality dementia care. OBJECTIVE: To describe the design of a study to determine multidisciplinary memory clinics' (MMC) effectiveness and cost-effectiveness in post-diagnosis treatment and care-coordination of dementia patients and their caregivers compared to the post-diagnosis treatment and care-coordination by general practitioners (GP). Next, this article provides the theoretical background of pragmatic trials, often needed in complex interventions, with the AD- Euro study as an example of such a pragmatic approach in a clinical trial. METHOD: The study is a pragmatic multicentre, randomised clinical trial with an economic evaluation alongside, which aims to recruit 220 independently living patients with a new dementia diagnosis and their informal caregivers. After baseline measurements, patient and caregiver are allocated to the treatment arm MMC or GP and are visited for follow up measurements at 6 and 12 months. Primary outcome measures are Health Related Quality of Life of the patient as rated by the caregiver using the Quality of Life in Alzheimer's Disease instrument (Qol-AD) and self-perceived caregiving burden of the informal caregiver measured using the Sense of Competence Questionnaire (SCQ). To establish cost-effectiveness a cost-utility analysis using utilities generated by the EuroQol instrument (EQ-5D) will be conducted from a societal perspective. Analyses will be done in an intention-to-treat fashion. RESULTS: The inclusion period started in January 2008 and will commence until at least December 2008. After finalising follow up the results of the study are expected to be available halfway through 2010. DISCUSSION: The study will provide an answer to whether follow-up of dementia patients can best be done in specialised outpatient memory clinics or in primary care settings with regard to quality and costs. It will enable decision making on how to provide good and efficient health care services in dementia. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT00554047.

Evaluating guidelines on continuation of anti-tumour necrosis factor treatment after 3 months: clinical effectiveness and costs of observed care and different alternative strategies.

OBJECTIVE: To study the adherence of rheumatologists to the Dutch guidelines for anti-tumour necrosis factor alpha (TNF-alpha) treatment. The secondary objective was to evaluate alternatives to the present guidelines with regard to the percentage of responders and costs. METHODS: The response (>1.2 DAS28 decrease) in patients who started on anti-TNF-alpha treatment for the first time was evaluated at 3 and 6 months after initiation. How many patients continued or discontinued their initial anti-TNF-alpha treatment was evaluated. Possible alternative guidelines were evaluated by means of a decision tree, with regard to the expected percentage of successfully (responders) and unsuccessfully treated patients and expected costs. RESULTS: At 3 months 56% (N = 306) and 44% (N = 233) of all 539 evaluable patients were classified as responders or non-responders, respectively. Despite the guidelines, most (81%) (N = 189) of the non-responders continued treatment. 37% of the non-responders who continued anti-TNF-alpha treatment were eventually classified as responders at 6 months. Decision analytical modelling showed that with equal expected costs all alternative strategies would result in more responders than according to theoretical full adherence with the guidelines. "Continuation in case of partial response" had the best trade-off between successfully treated patients (64%) and unsuccessfully treated patients (17%). CONCLUSION: There was suboptimal adherence to the Dutch guidelines for treatment with anti-TNF-alpha for rheumatoid arthritis patients. This seemed to be justified by the fact that a delayed response up to 6 months was shown. If treatment is continued despite a non-response at 3 months, this is only recommended in patients with at least a partial response (at least 0.6 DAS28 improvement).

The diagnostic accuracy of CT and MRI in the staging of pelvic lymph nodes in patients with prostate cancer: a meta-analysis.

AIM: To compare the diagnostic accuracy of computed tomography (CT) and magnetic resonance imaging (MRI) in the diagnosis of lymph node metastases in prostate cancer. METHODS: After a comprehensive literature search, studies were included that allowed construction of contingency tables for detection of lymph node metastases using CT or MRI. In addition, a summary receiver-operating characteristic (ROC) analysis was performed. RESULTS: A total of 24 studies were included. For CT, pooled sensitivity was 0.42 (0.26-0.56 95% CI) and pooled specificity was 0.82 (0.8-0.83 95% CI). For MRI, the pooled sensitivity was 0.39 (0.22-0.56 95% CI) and pooled specificity was 0.82 (0.79-0.83 95% CI). The differences in performance of CT and MRI were not statistically significant. CONCLUSION: CT and MRI demonstrate an equally poor performance in the detection of lymph node metastases from prostate cancer. Reliance on either CT or MRI will misrepresent the patient's true status regarding nodal metastases, and thus misdirect the therapeutic strategies offered to the patient.