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. (Am Heart J 2022;254:141-148.)

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 center dot 0% vs. biopsy 99 center dot 0%;P= 1 center dot 0). Specificity for BCC diagnosis was lower for RCM (59 center dot 1% vs. 100 center dot 0%;P< 0 center dot 001). Sensitivity for aggressive BCC subtypes was lower for RCM (33 center dot 3% vs. 77 center dot 3%;P= 0 center dot 003). Sensitivity for nonsuperficial BCC was not significantly different (RCM 88 center dot 9% vs. biopsy 91 center dot 0%;P= 0 center dot 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.

Background With biological patents expiring, biosimilars are becoming a realistic, less costly alternative to their originator. The data from numerous randomised clinical trials support that it is safe, effective and cost saving to switch to a biosimilar. However, real world data about efficacy, safety, and cost-effectiveness of such a switch are lacking. Since shared decision making (SDM) is a key factor in the treatment of rheumatic diseases, a non-mandatory open label transitioning from Etanercept originator to its biosimilar was performed at the rheumatology department of Bernhoven. Objectives The first goal of this study was to investigate the effect of switching from Etanercept originator to its biosimilar on the effectiveness of treatment. The second aim was to analyse the effect of SDM on the 1 year retention rates and reasons for withdrawal in daily clinical practice. Methods All patients with rheumatoid arthritis (RA), axial spondyloarthritis (SpA) and psoriatic arthritis (PsA) that were using Etanercept originator between 01–06–2016 and 23–10–2017 were informed by letter of the possibility to switch to its biosimilar. During the next outpatient visit with their rheumatologist the possibility to switch was discussed. Patients had the opportunity to ask questions regarding biosimilars and the switch to a biosimilar. If patients agreed the switch was made, with the reservation that they could switch back to the originator if they encountered difficulties with the biosimilar. Using the registry of the rheumatology department at Bernhoven data were collected on disease activity (DA), medication use and adverse events from the moment of switch till 23–10–2017. As measure for DA the DAS28 was used for RA and PsA, the ASDAS was used for SpA. Stop reasons for biosimilars were verified using the health record system of the hospital. Reasons for change in disease activity and discontinuation of biosimilar treatment were assessed. Results Between 01–06–2016 and 23–10%–2017 80% (69 patients) of the Etanercept originator users switched to its biosimilar. These patients switched to biosimilar after a median time of 5.1 (IQR 2.8–8.3) years. By 23–10–2017, median follow-up of 307 (IQR 196–357) days, the mean DA did not significantly differ from the DA at baseline, 3.1 (95%>CI 2.5–3.7) vs. 2.8 (95%>CI 2.5–3.1). At end of follow-up 25% of the patients had discontinued there treatment and either switched back to originator (18%), switched to another biological (3%) or stopped treatment with biologicals (4%). Reasons for switching back to originator were adverse events (58%), lack of effect (17%) and "adverse event and lack of effect" (25%). Only one serious adverse event was reported. This was a drug hypersensitivity reaction. After the patient was recovered, the originator was restarted without any difficulties. Conclusions An open label non-mandatory switch from Etanercept originator to its biosimilar showed that around 80% of the patients is willing to perform this switch. Switching did not affect effectiveness of treatment during one year follow-up. 75% of the patients were able to continue biosimilar therapy. In the 69 patients that switched only one serious adverse effect occurred. Disclosure of Interest None declared

Background Current guidelines say that there should be a prominent place for patient participation and shared decision making in rheumatic care. To achieve this Bernhoven introduced an online patient health record (OPHR) for patients with rheumatoid arthritis (RA) aiming to facilitate self management and giving insight in the individual disease course in April 2014. This platform enables patients to monitor their disease by completing questionnaires about for instance pain, fatigue and quality of life. It also gives access to their medication history and offers patients information in the form of an online library. Objectives This study analyses how the introduction of an OPHR, aiming to promote patient participation, influences the prescription of DMARD’s and the disease activity (DAS28) in daily clinical practice. A distinction was made between the effects of the PHR on patients recently diagnosed with RA (study A) and the RA population as a whole (study B). Methods In April 2014 anan OPHR for patients with RA was introduced at the rheumatology department of Bernhoven. Using data from the rheumatology department registry, two analyses were performed to evalute this implementation. Study A compared the treatment and course of DAS28 of patients diagnosed in the period three years prior to the implementation (“prior group”) with those diagnosed in the period three years after the implementation (“after group”). Study B was an observational study that examined yearly trends for DMARD use and DAS28 for the whole RA population between April 2011 and April 2017 Results Study A A total of 287 patients were diagnosed with RA of which 127 were in the prior group and 171 in the after group. CsDMARD’s were given 160 days [95%>CI 123–198] after diagnosis in the “prior group” versus (vs.) 32 days [95%>CI 22–43] in the after group. Next to that there was an increase in cumulative time csDMARD’s were used during follow-up, 54% vs. 74% (p-value<0.001). Also, more patients received csDMARD combination therapy, 49% vs. 64% (p-value=0.001). There was no difference in number of patients that started a bDMARD, 7% vs. 14% (p-value=0.059). However, a significant larger group started with a bDMARD in the first year after start of csDMARD therapy in the after group, 3.1% vs. 9.9% (p-value 0.024). 39% of the prior group vs. 69% in the after group achieved either remission or LDA within the first year of DMARD therapy (p-value<0.001). Study B The trend analysis of DMARD use in the RA population is plotted in figure 1. Between 2011 and 2017 a change in trend can be observed for the use of csDMARD’s, the use of csDMARD combination and the use of bDMARD csDMARD combination therapy. The usage of bDMARD therapy did not change. Conclusions After the introduction of the OPHR patients recently diagnosed with RA got earlier and more intense treatment, with a more prominent role for biologicals. Next to that a bigger proportion of patients recently diagnosed with RA achieved remission and LDA within the first year of DMARD therapy. When looking for trends in the total RA population, an increase of the use of csDMARD’s, the use of csDMARD combination and the use of bDMARD csDMARD combination therapy was observed after April 2014. Disclosure of Interest None declared

Background Evidence on cost-effectiveness is lacking for the comparison of biological treatments after failure of the first TNFi treatment in patients with Rheumatoid Arthritis (RA). Objectives The objective of this study was to compare the cost-effectiveness of three biological treatment options, abatacept, rituximab or a second TNFi, after failure of the first TNFi treatment in patients suffering from RA. Methods The inclusion criteria for this pragmatic randomized controlled trial were: failure of the first TNFi, a DAS28 >3.2, not treated before with abatacept or rituximab and no contraindications for these medications. The utility was based on the EQ5D questionnaire and was used to calculate QALYs. All medication costs in one year were taken into account. Incremental cost-utility evaluation was preformed to analyze the cost-effectiveness over one year corrected for possible confounders. Uncertainty in the cost-utility ratio was analyzed using the non-parametrical bootstrap technique. Cost-effectiveness was presented by Cost-Effectiveness Acceptability Curves (CEAC). Results Of 144 randomized patients, 8 did not start the treatment due to infections, withdrawn from the study or waive the medication. 136 started in one of the three treatment arms: 42 on abatacept (mean age=56.2 yrs, female=88.1%, median disease duration=7.1 yrs, rheumatoid factor (RF) positive=51.4%, mean baseline DAS28=4.7), 44 on rituximab (mean age=56.7 yrs, female=63.6%, median disease duration=7.6 yrs, RF positive=79.1% mean baseline DAS28=4.9) and 50 on a second TNFi (mean age=56.2 yrs, female=74.0%, median disease duration=5.6 yrs, RF positive=55.8% mean baseline DAS28=4.9). Gender and RF were significantly different between the groups (p=0.032 and p=0.020 respectively). The mean QALY and costs in euro9s were respectively 0.58 (sd=0.17) and €15.024 (sd=€11353) for patients in the abatacept group; 0.63 (sd=0.17) and €9385 (sd=€3814) for patients in the rituximab group and 0.61 (sd=0.18) and €11041 (sd=€7923) for the TNF alpha blocker group after 12 month. The corrected difference in costs between abatacept and rituximab was significant (β=4723; CI=892-8623; p=0.040). The corrected differences in costs between TNFi and abatacept and rituximab were not significant (β=-3326; CI=-8686-1031; p=0.200 and β=1397; CI=-1873-4333; p=0.394, respectively). If the Willingness To Pay is €80000, the chance rituximab is cost-effective is 85% compared to another TNFi and 98% compared to abatacept, see Figure. Conclusions In this multi-centered pragmatic randomized controlled study in patients which their first TNFi failed, it was shown that after one year follow-up, rituximab is more cost-effective than abatacept and another TNFi. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.3253

Background The most effective biological treatment option after the failure of a first TNFi treatment in a patient with rheumatoid arthritis (RA) is still unknown. Objectives The objective of this study was to compare the effectiveness of three treatment options: abatacept, rituximab and a second TNFi, after the failure of a TNFi treatment, in patients with RA. Methods The inclusion criteria for this pragmatic randomized controlled trial were: failing of the first TNFi, a DAS28 >3.2, not treated before with abatacept or rituximab and no contraindications for these medications. Primary outcome, the DAS28 and the secondary outcomes, HAQ-DI and SF36, were analyzed by linear mixed models to find differences over time. We corrected for possible confounders. Suspected Unexpected Serious Adverse Reactions (SUSAR) and Serious Adverse Reactions (SAR) were collected. Results Of 144 randomized patients, 8 did not start the treatment due to infections, withdrawn from the study or did not want to start the medication. 136 started in one of the three treatment arms; 42 on abatacept (mean age=56.2 yrs, female=88.1%, median disease duration=7.1 yrs, rheumatoid factor (RF) positive=51.4%, mean baseline DAS28=4.7); 44 on rituximab (mean age=56.7 yrs, female=63.6%, median disease duration=7.6 yrs, RF positive=79.1% mean baseline DAS28=4.9); and 50 on a second TNFi (mean age=56.2 yrs, female=74.0%, median disease duration=5.6 yrs, RF positive=55.8% mean baseline DAS28=4.9). Gender and RF are significantly different between the groups (p=0.032 and p=0.020 respectively). The mean DAS28 at 6 and 12 month respectively were 4.05 and 3.85 for abatacept, 3.85 and 3.40 for rituximab and 3.70 and 3.50 for a second TNFi. No significant differences in effectiveness between the three treatment options over time (mixed models) were found in one of the outcome variables. The figure shows the DAS28 and HAQ-DI over time. One SUSAR occurred during one year follow-up. A patient in the abatacept group got a psychosis four months after the start of the study. Three SARs occurred within one year after start of the study: one salmonella infection and one pneumonia in the rituximab group and one pneumonia in the TNFi group. However, these SARs were no reason to change or stop medication. Conclusions Although during a follow up of 1 year some small differences in DAS28, HAQ-DI and SF36 were seen between abatacept, rituximab, and a second TNFi after failure of the first TNFi, these differences were not significant. So if effectiveness is the only interest, abatacept, rituximab and TNFi seem probably equally effective after failure of the first TNFi. No substantial differences with respect to safety were observed between these three treatment groups. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.1635

Background. Live kidney donation has a clear economical benefit over dialysis and deceased-donor transplantation. Compared with mini-incision open donor nephrectomy, laparoscopic donor nephrectomy (LDN) is considered cost-effective. However, little is known on the cost-effectiveness of hand-assisted retroperitoneoscopic donor nephrectomy (HARP). This study evaluated the cost-effectiveness of HARP versus LDN.Methods. Alongside a randomized controlled trial, the cost-effectiveness of HARP versus LDN was assessed. Eighty-six donors were included in the LDN group and 82 in the HARP group. All in-hospital costs were recorded. During follow-up, return-to-work and other societal costs were documented up to 1 year. The EuroQol-5D questionnaire was administered up to 1 year postoperatively to calculate quality-adjusted life years (QALYs).Results. Mean total costs from a healthcare perspective were $ 8935 for HARP and $ 8650 for LDN (P=0.25). Mean total costs from a societal perspective were $ 16,357 for HARP and $ 16,286 for LDN (P=0.79). On average, donors completely resumed their daytime jobs on day 54 in the HARP group and on day 52 in the LDN group (P=0.65). LDN resulted in a gain of 0.005 QALYs.Conclusions. Absolute costs of both procedures are very low and the differences in costs and QALYs between LDN and HARP are very small. Other arguments, such as donor safety and pain, should determine the choice between HARP and LDN.

Objective: To evaluate the influence of adherence to the Systematic Care Program for Dementia (SCPD) intervention protocol on patient and caregiver outcomes. Design: Data were drawn from the SCPD study-a single-blind, multicenter, cluster-randomized, controlled trial. Multivariate regression analyses were used to assess the influence of adherence on patient and caregiver outcomes. Setting: Six community mental health services (CMHSs) across the Netherlands. Participants: Forty-eight mental health professionals treating 125 patient-caregiver dyads who were referred to the CMHS because of suspected patient dementia. Intervention: Training of professionals in the SCPD and its subsequent use. The SCPD consists of a systematic assessment of caregiver problems and consequent interventions. Measurements: The dependent variables were caregiver's sense of competence, caregiver's depressive symptoms, caregiver's distress due to the patient's behavioral problems, and the severity of patient's behavioral problems. The main independent variables were adherence to the SCPD intervention protocol and the intensity of the SCPD interventions. The follow-up lasted 12 months. Results: Caregivers treated by adhering professionals had a better sense of competence than caregivers treated by nonadhering professionals at follow-up. No differences between intervention groups and controls were found for the other outcomes. Conclusion: Nonadherence to the intervention protocol might be a reason for the difference found in the sense of competence between the intervention groups. Furthermore, the intensity of the SCPD might have been too low. Moreover, it might be that overburdened caregivers found it difficult to make effective use of the help offered to them. A qualitative process analysis should be executed to explore more in-depth clarifications. (Am J Geriatr Psychiatry 2013; 21:26-36)

BACKGROUND In this study, the potential impact of a new national guideline for adjuvant systemic therapy in breast cancer (introduced in The Netherlands in 1998) was assessed, as well as the modifications of this guideline, issued in 2001. Both the change in total number of patients eligible for adjuvant therapy, as well as the cost-effectiveness of the changed clinical management of these patients were analysed. PATIENTS AND METHODS Percentages of patients who would be eligible for adjuvant therapy in 1994, 1998 and 2001 were estimated, based on clinical data from 127 patients, who were operated on in 1994. Ten-year overall survival rates were used as a measure of effectiveness, based on the two most recent EBCTCG meta-analyses. Actual resource costs were calculated. With a decision analytic model, the incremental cost-effectiveness ratios (1998 versus 1994, and 2001 versus 1998) were calculated. RESULTS The introduction of the 1998 guideline resulted in a relative increase of 80% in the total number of patients eligible for adjuvant therapy, compared with 1994 (from 40% to 72% of all patients with primary breast cancer). With an estimated absolute increase of 10-year overall survival of 2%, the 1998 guideline was found to have an expected incremental cost-effectiveness ratio of about 4837 per life-year gained. CONCLUSIONS Introduction of the new guideline considerably affected the number of patients eligible for adjuvant systemic therapy for breast cancer. The associated incremental cost-effectiveness ratio is well within the range of values that are generally considered acceptable.

BACKGROUND In order to reduce protein-energy malnutrition in older people during hospitalisation an early interdisciplinary intervention is needed. We developed a protocol which includes screening for malnutrition, dysphagia and dehydration on admission, followed by immediate interventions. OBJECTIVE To assess effectiveness of the protocol on nutritional status, hospital-acquired infections and pressure sores, and to evaluate the protocol s economical feasibility. DESIGN Prospective, controlled study. SETTING The inpatient geriatric service of a university hospital (UMC Nijmegen) and a geriatric ward of a non-academic teaching hospital (Rijnstate Hospital, Arnhem). SUBJECTS 298 older patients (>60 years). METHODS One of the geriatric wards applied the protocol (N=140) while the other provided standard care (N=158). All non-terminally ill patients admitted for more than two days were included. Body mass was measured on admittance and discharge and hospital-acquired infections and pressure sores were scored and costs related to nutrition, infections and length of hospital stay were assessed. RESULTS There was a 0.8 kg loss (SEM 0.3 kg) in average weight in the standard care group and a 0.9 kg gain (SEM 0.2 kg) in the intervention group (p<0.001). The number of hospital acquired infections was significantly lower in the intervention group (33/140 versus 58/158, p=0.01) but no significant difference in number of patients with pressure sores (23/140 versus 33/158) was found. Costs were not significantly different: 7516 versus 7908 Euro/patient for intervention versus controls, respectively. CONCLUSION An early interdisciplinary intervention approach can be effective in reducing protein-energy malnutrition and related hospital-acquired infections and appears to be economically feasible.