Discontinuation of the PACE Plus trial: problems in patient recruitment in general practice.

BACKGROUND: The PACE Plus trial was a multi-center, double-blinded, superiority randomized controlled trial (RCT) conducted in patients from Dutch general practice to investigate the efficacy of paracetamol and NSAIDs in acute non-specific low back pain (LBP). Because insufficient numbers of patients could be recruited (only four out of the required 800 patients could be recruited over a period of 6 months), the trial was prematurely terminated in February 2017, 6 months after the start of recruitment. This article aims to transparently communicate the discontinuation of PACE Plus and to make recommendations for future studies. METHODS: General Practitioners (GPs) from 36 participating practices received a one-question survey in which they were asked to give the three most important factors that in their opinion contributed to failure of patient recruitment. RESULTS: GPs of 33 out of 36 (92%) participating practices sent a response. A total of 81 factors were reported. These have been categorized into patient factors (26 out of 81 comments, 32%), GP factors (39 out of 81 comments, 48%) and research factors (16 out of 81 comments, 20%). DISCUSSION: Patient recruitment in the PACE Plus trial may have failed due to inefficient medication distribution, recruitment of incident rather than prevalent cases, a design that was too complicated, adequate self-management of LBP, patient expectations different from the trial's scope and lack of time of participating GPs. Substantial differences in design may explain why the preceding PACE trial did manage to successfully complete patient recruitment. CONCLUSION: Although the PACE Plus trial was terminated as a result of insufficient patient inclusion, the research questions addressed in this trial remain relevant but unanswered. We hope that lessons learned from the discontinuation of PACE Plus and corresponding recommendations may be helpful in the design of upcoming research projects in LBP in general practice. TRIAL REGISTRATION: Dutch Trial Registration NTR6089, registered September 14th 2016.

Efficacy of paracetamol, diclofenac and advice for acute low back pain in general practice: design of a randomized controlled trial (PACE Plus).

BACKGROUND: Low back pain is common and associated with a considerable burden to patients and society. There is uncertainty regarding the relative benefit of paracetamol and diclofenac and regarding the additional effect of pain medication compared with advice only in patients with acute low back pain. This trial will assess the effectiveness of paracetamol, diclofenac and placebo for acute low back pain over a period of 4 weeks. Furthermore, this trial will assess the additional effectiveness of paracetamol, diclofenac and placebo compared with advice only for acute low back pain over a period of 4 weeks. METHODS: The PACE Plus trial is a multi-center, placebo-blinded, superiority randomized controlled trial in primary care, with a follow-up of 12 weeks. Patients with acute low back pain aged 18-60 years presenting in general practice will be included. Patients are randomized into four groups: 1) Advice only (usual care conforming with the clinical guideline of the Dutch College of General Practitioners); 2) Advice and paracetamol; 3) Advice and diclofenac; 4) Advice and placebo. The primary outcome is low back pain intensity measured with a numerical rating scale (0-10). Secondary outcomes include compliance to treatment, disability, perceived recovery, costs, adverse reactions, satisfaction, sleep quality, co-interventions and adequacy of blinding. Between group differences for low back pain intensity will be evaluated using a repeated measurements analysis with linear effects models. An economic evaluation will be performed using a cost-effectiveness analysis with low back pain intensity and a cost-utility analysis with quality of life. Explorative analyses will be performed to assess effect modification by predefined variables. Ethical approval has been granted. Trial results will be released to an appropriate peer-viewed journal. DISCUSSION: This paper presents the design of the PACE Plus trial: a multi-center, placebo-blinded, superiority randomized controlled trial in primary care that will assess the effectiveness of advice only, paracetamol, diclofenac and placebo for acute low back pain. TRIAL REGISTRATION: Dutch Trial Registration NTR6089 , registered September 14th, 2016. PROTOCOL: Version 4, June 2016.

Cost-utility of exercise therapy in patients with hip osteoarthritis in primary care.

OBJECTIVE: To determine the cost-effectiveness (CE) of exercise therapy (intervention group) compared to 'general practitioner (GP) care' (control group) in patients with hip osteoarthritis (OA) in primary care. METHOD: This cost-utility analysis was conducted with 120 GPs in the Netherlands from the societal and healthcare perspective. Data on direct medical costs, productivity costs and quality of life (QoL) was collected using standardised questionnaires which were sent to the patients at baseline and at 6, 13, 26, 39 and 52 weeks follow-up. All costs were based on Euro 2011 cost data. RESULTS: A total of 203 patients were included. The annual direct medical costs per patient were significantly lower for the intervention group (€ 1233) compared to the control group (€ 1331). The average annual societal costs per patient were lower in the intervention group (€ 2634 vs € 3241). Productivity costs were higher than direct medical costs. There was a very small adjusted difference in QoL of 0.006 in favour of the control group (95% CI: -0.04 to +0.02). CONCLUSION: Our study revealed that exercise therapy is probably cost saving, without the risk of noteworthy negative health effects. TRIAL REGISTRATION NUMBER: NTR1462.

Effectiveness of exercise therapy added to general practitioner care in patients with hip osteoarthritis: a pragmatic randomized controlled trial.

OBJECTIVE: To assess the effectiveness of exercise therapy added to general practitioner (GP) care compared with GP care alone, in patients with hip osteoarthritis (OA) during 12 months follow-up. METHODS: We performed a multi-center parallel pragmatic randomized controlled trial in 120 general practices in the Netherlands. 203 patients, aged ≥45 years, with a new episode of hip complaints, complying with the ACR criteria for hip OA were randomized to the intervention group (n = 101; GP care with additional exercise therapy) or the control group (n = 102; GP care only). GP care was given by patient's own GP. The intervention group received, in addition, a maximum of 12 exercise therapy sessions in the first 3 months and hereafter three booster sessions. Blinding was not possible. Primary outcomes were hip pain and hip-related function measured with the HOOS questionnaire (score 0-100). RESULTS: The overall estimates on hip pain and function during the 12-month follow-up showed no between-group difference (intention-to-treat). At 3-months follow-up there was a statistically significant between-group difference for HOOS pain -3.7 (95% CI: -7.3; -0.2), effect size -0.23 and HOOS function -5.3 (95% CI: -8.9; -1.6), effect size -0.31. No adverse events were reported. CONCLUSIONS: No differences were found during 12-months follow-up on pain and function. At 3-months follow-up, pain and function scores differed in favor of patients allocated to the additional exercise therapy compared with GP care alone. TRIAL REGISTRATION: The Netherlands Trial Registry NTR1462.

The view of European experts regarding health economics for medical nutrition in disease-related malnutrition.

Health-care systems are currently facing tremendous budget constraints resulting in growing pressure on decision makers and health-care providers to obtain the maximum possible health benefits of the resources available. Choices have to be made, and health economics can help in allocating limited health-care resources among unlimited wants and needs. Attempts to achieve cost reductions often focus on severe pathologies and chronic diseases as they commonly represent high health-care expenditures. In this context, awareness of the considerable financial burden caused by disease-related malnutrition (DRM) is lacking. Possibilities of reducing costs by optimising the management of DRM through medical nutrition will mostly not even be taken into account. During a European expert meeting, the total evaluation of medical nutrition was viewed and discussed. The aim of this meeting was to gain an experts' outline of the key issues relating to the health economic assessment of the use of medical nutrition. This article provides a summary of the observations per discussed item and describes the next steps suggested.

The cost-effectiveness of periodic safety update reports for biologicals in Europe.

We analyzed the cost-effectiveness of all Periodic Safety Update Reports (PSURs) submitted for biologicals in Europe from 1995 to 2009 by comparing two regulatory scenarios: full regulation (PSUR reporting) and limited regulation (no PSUR reporting, but all other parts of the pharmacovigilance framework remain in place). During this period, PSUR reporting resulted in the detection of 2 out of a total of 24 urgent safety issues for biologicals: (i) distant spread of botulinum toxin and (ii) edema/fluid collection associated with off-label use of dibotermin-alfa. We used Markov-chain life tables to calculate costs and health effects of PSURs. The incremental cost-effectiveness ratio (ICER) of full regulation (PSUR reporting) vs. limited regulation (no PSUR reporting) for the base-case scenario was \[euro]342,110 per quality-adjusted life year (QALY) gained. It is possible to assess the cost-effectiveness of regulatory requirements using the same methods as those used in assessing the cost-effectiveness of medical interventions.

Cost-effectiveness of two endovascular treatment strategies vs intravenous thrombolysis.

OBJECTIVE: To assess the cost-effectiveness of endovascular treatment against intravenous thrombolysis (IVT) when varying assumptions concerning its effectiveness. METHODS: We developed a health economic model including a hypothetical population consisting of patients with ischemic stroke, admitted within 4.5 h from onset, without contraindications for IVT or intra-arterial treatment (IAT). A decision tree and life table were used to assess 6-month and lifetime costs (in Euros) and effects in quality-adjusted life years treatment with IVT alone, IAT alone, and IVT followed by IAT if the patient did not respond to treatment. Several analyses were performed to explore the impact of considerable uncertainty concerning the clinical effectiveness of endovascular treatment. RESULTS: Probabilistic sensitivity analysis demonstrated a 54% probability of positive incremental lifetime effectiveness of IVT-IAT vs IVT alone. Sensitivity analyses showed significant variation in outcomes and cost-effectiveness of the included treatment strategies at different model assumptions. CONCLUSIONS: Acceptable cost-effectiveness of IVT-IAT compared to IVT will only be possible if recanalization rates are sufficiently high (>50%), treatment costs of IVT-IAT do not increase, and complication rates remain similar to those reported in the few randomized studies published to date. Large randomized studies are needed to reduce the uncertainty concerning the effects of endovascular treatment.

The cost-effectiveness of drug regulation: the example of thorough QT/QTc studies.

We analyzed the cost-effectiveness of the International Conference on Harmonisation (ICH) E14 guideline that requires a thorough QT/QTc (TQT) study for all drugs under development. We compared two pharmacoeconomic scenarios: the health effects and costs resulting from implementing ICH E14 ("regulation" scenario) vs. not implementing ICH E14 ("no regulation" scenario). We used a dynamic population model to calculate the cost-effectiveness of ICH E14 for a prototype QT-prolonging antipsychotic drug entering the US and European markets. The incremental cost-effectiveness ratios of regulation vs. no regulation were ~€2.4 million per sudden cardiac death prevented and ~€187,000 per quality-adjusted life year (QALY) gained in users of antipsychotic drugs. The main driver of cost was the requirement for electrocardiogram (ECG) monitoring of users of QTc-prolonging drugs. Even when several of the assumptions in the model were varied, there were no results in favor of regulation. Our study shows that cost-effectiveness analysis of drug regulatory measures is feasible and should be considered before developing such measures.

Cost-utility of exercise therapy in adolescents and young adults suffering from the patellofemoral pain syndrome.

The objective of this paper was to determine the cost effectiveness of exercise therapy (intervention group) compared with "usual care" (control group) in adolescents and young adults with the patellofemoral pain syndrome in primary care. This multicenter prospective randomized clinical trial with cost-utility analysis was conducted at 38 general practices and three sport medical advice centers in the Netherlands for 2007. A total of 131 patients were included. The annual direct medical costs per patient were significantly higher for the intervention group (euro 434) compared with the control group (euro 299) mainly caused by additional physiotherapy visits. The average annual societal costs per patient were significantly lower in the intervention group (euro 1011 vs euro 1.166). Productivity costs were the largest cost component, in particular costs due to reduced efficiency at paid work which were responsible for 47% and 56% of the total costs in the intervention and control group respectively. Patients in the intervention group experienced a slightly, but not significantly, higher quality of life (0.8722 vs 0.8617). With a cost effectiveness ratio of -euro 14,738 per quality adjusted life year, exercise therapy appears to be cost effective as compared with "usual care."

Medical consumption and costs during a one-year follow-up of patients with LUTS suggestive of BPH in six european countries: report of the TRIUMPH study.

OBJECTIVE: To determine the medical consumption and associated treatment costs of patients with LUTS suggestive of BPH. METHODS: A prospective, cross-sectional, observational survey in six European countries: France, Germany, Italy, Poland, Spain and the United Kingdom, with a one-year follow-up of incident and prevalent patients. RESULTS: Treatment costs were estimated for 5,057 patients with a mean age of 66 years and a mean IPSS score at inclusion of 11.5. In 30% of patients watchful waiting was the therapy of choice for the full follow-up period, 57% were prescribed alpha-lockers, 11% finasteride and 10% phytotherapy at any moment during the follow-up (including switches and combination of treatment). Surgery rate was 4.9%. Mean one-year treatment costs were 858 per patient, three quarters of which concerned medication costs. Multivariate regression analysis showed that medication choice, complications and undergoing surgery were associated with higher costs. CONCLUSIONS: Treatment costs for patients with LUTS suggestive of BPH were moderate and largely consisted of medication costs. Daily practice and associated costs varied considerably across the six countries.

Cost-effectiveness of integrated stroke services.

BACKGROUND: Randomized trials have shown that integrating services for acute stroke care may lead to organizational improvements, higher efficiency and better patient outcomes in the acute phase. AIM: To compare the costs and effects of stroke services in an experimental group of patients compared to a group of patients receiving conventional care. DESIGN: Prospective non-randomized controlled trial. METHODS: We compared all consecutively hospitalized stroke patients in three experimental stroke service settings (Delft, Haarlem and Nijmegen, n = 411) with concurrent patients receiving conventional stroke care (n = 187) over 6 months follow-up. Main end-points were total costs per patient and total health-adjusted days per 100 patients as measured by the EuroQol-5D score during follow-up. RESULTS: Mean total costs per patient were 16,000 Euro (95%CI 14,670 Euro-16,930 Euro): 13,160 Euro in Delft, 16,790 Euro in Haarlem, 20,230 Euro in Nijmegen, and 13,810 Euro in the control regions. Early discharge in Delft saved about 2500 Euro hospital costs per patient. General patient health in Delft was significantly better than in the control regions; Haarlem and Nijmegen showed no difference in health. DISCUSSION: Our study confirms the potential to improve stroke outcomes in a cost-effective way in Dutch settings. This was seen in the group of patients in Delft, a complete and relatively simple stroke service, but not in two other regions with more complex stroke services. Important factors are reduction of hospital days and, most likely, adequate multidisciplinary rehabilitation.

Influence of waiting time on cost-effectiveness.

Economic evaluations of health care programs are intended to support policy decisions and therefore should incorporate elements of the health care environment such as waiting lists. We explore possible relationships between waiting time and the cost-effectiveness of health care programs. The impact of waiting on cost-effectiveness is very scenario dependent and may be substantial, especially if health loss while waiting is partly or completely non-reversible. We argue that economic evaluations of health care programs in countries with waiting lists should consider the possible impact of waiting on costs and health effects.

Health problems lead to considerable productivity loss at work among workers with high physical load jobs.

OBJECTIVE: To assess the feasibility and validity of two instruments for the measurement of health-related productivity loss at work. STUDY DESIGN AND SETTING: A cross-sectional study was conducted in two occupational populations with a high prevalence of health problems: industrial workers (n=388) and construction workers (n=182). We collected information on self-reported productivity during the previous 2 weeks and during the last work day with the Health and Labor Questionnaire (HLQ) and the Quantity and Quality instrument (QQ), with added data on job characteristics, general health, presence of musculoskeletal complaints, sick leave, and health-care consumption. For construction workers, we validated self-reported productivity with objective information on daily work output from 19 work site observations. RESULTS: About half the workers with health problems on the last working day reported reduced work productivity (QQ), or 10.7% of all industrial workers and 11.8% of all construction workers, resulting in a mean loss of 2.0 hr/day per worker with reduced work productivity. The proportion of workers with reduced productivity was significantly lower on the HLQ: 5.3% of industrial workers and 6.5% of construction workers. Reduced work productivity on the HLQ and the QQ was significantly associated with musculoskeletal complaints, worse physical, mental and general health, and recent absenteeism. The QQ and HLQ questionnaires demonstrated poor agreement on the reporting of reduced productivity. Self-reported productivity on the QQ correlated significantly with objective work output (r=.48). CONCLUSION: Health problems may lead to considerable sickness presenteeism. The QQ measurement instrument is better understandable, and more feasible for jobs with low opportunities for catching up on backlogs.

Burden of informal caregiving for stroke patients. Identification of caregivers at risk of adverse health effects.

BACKGROUND: We assessed the objective and subjective burden of caregiving for stroke patients and investigated which characteristics of the patient, the informal caregiver and the objective burden contribute most to subjective burden and to the condition of feeling substantially burdened. METHODS: We studied a sample of 151 stroke survivors and their primary informal caregivers. We collected data through patient and caregiver interviews 6 months after stroke. RESULTS: Both the level of subjective burden and the condition of feeling substantially burdened were associated with both caregiver's and patient's health-related quality of life, patient's age, and the number of caregiving tasks performed. CONCLUSIONS: These conditions can be used in clinical practice to identify potentially vulnerable caregivers in need of support and at risk of adverse health effects. Monitoring stroke survivors as well as their family caregivers at discharge may help to prevent or alleviate caregiver burden.

What really matters: an inquiry into the relative importance of dimensions of informal caregiver burden.

OBJECTIVE: Prevailing measures of subjective caregiver burden either have no overall summary score or do not consider the relative importance caregivers attach to different dimensions of burden. Our aim was to assess which dimensions informal caregivers perceive as being important to their overall burden from care giving. DESIGN: Cross-sectional. SUBJECTS: Data were pooled from two Dutch samples of primary informal caregivers covering a wide range of chronic care-giving situations: caregivers for stroke survivors (n = 196) and caregivers for individuals with rheumatoid arthritis (RA) (n = 131). MAIN MEASURES: Subjective burden of care giving was assessed using the Caregiver Reaction Assessment (CRA) and the Self-Rated Burden scale (SRB). RESULTS: In the total sample four of the five dimensions of the CRA were found to contribute to the overall subjective burden experienced by informal caregivers. In the individual stroke and RA samples only two of the five dimensions emerged as relevant. SRB scores were significantly higher for caregivers of stroke patients, but no differences were found for the five dimensions of the CRA between the two samples. CONCLUSIONS: The dimensions of CRA are not equally important to the overall subjective burden of informal caregivers. To assess overall subjective burden, a measure based on a caregiver's own assessment of burden such as SRB needs to be used in addition to prevailing measures.

The desire for support and respite care: preferences of Dutch informal caregivers.

Informal care is an indispensable element in the care for many patients. In order to maintain a sustainable input of informal care, it seems important to identify measures to alleviate the burden of care giving for caregivers at risk of burn out or other serious health problems, such as support and respite care. Thus, far research has focused on the burden of caregiving and on the supply of respite care. The demand side: what type of care is preferred by informal caregivers and what determines their preferences, is virtually unknown. We analysed the preferences and the underlying determinants for several types of support and respite care in a sample of 950 Dutch informal caregivers. Almost 80% of the respondents desire support or respite care in general, 42-47% would prefer more communication with other informal caregivers or more information of professional caregivers. Some time off is preferred by 40% of the respondents. The results show that caregiver characteristics, care recipient characteristics, elements of the caregiving situation and institutional variables determine the desire for support and respite care. Especially, the subjective burden of caregiving is important, whereas the number of caregiving tasks and the time invested (objective burden) hardly affect the desire for support and respite care.

Assessment of post-stroke quality of life in cost-effectiveness studies: the usefulness of the Barthel Index and the EuroQoL-5D.

Stroke is a major cause of death and long-term disability in Western societies and constitutes a major claim on health care budgets. We address the problem of estimating quality adjusted life years (QALYs) for use in cost-effectiveness studies of stroke interventions. In the acute phase after stroke--at stroke onset and during rehabilitation--many patients are physically or mentally not able to (self-)report their quality of life. Missing values may obviously bias cost-effectiveness results. We have examined the direct relationship between a conventional clinical scale of functional status that is suited for proxy-assessment (Barthel Index (BI)) and a measure of health related quality of life (EuroQoL-5D). Based on data collected within the framework of an evaluation of three stroke-service experiments in The Netherlands (n = 598, 6 month follow-up), we established a plausible and significant relationship between the measures. Health related quality of life (HRQoL) is -0.25 for patients with a BI of 0, and with each additional point HRQoL increases with 0.05. Independent patients (BI 20) get a HRQoL is 0.75, which corresponds to the general population reference score for our sample. BI scores may be used as proxy for HRQoL in case of missing values on EuroQoL-5D.

Productivity costs before and after absence from work: as important as common?

Traditionally, production losses are estimated using the human capital or friction cost method. These methods base estimations of productivity costs on data on absence from work. For some diseases, like migraine, productivity losses without absence are occasionally calculated by estimating the production losses from reduced productivity at work. However, diseases typically only associated with absence may also be expected to cause reduced productivity before and after absence. In a previous study, Brouwer et al. concluded that productivity losses without absence are also very relevant in common diseases, like influenza, common cold or neck-problems. Studying a new sample of employees of a Dutch trade-firm (n = 51), who completed the questionnaire 'Ill and Recovered' upon return to work after absence due to illness, it was revealed that about 25% of the respondents experienced production losses before absence and about 20% of the respondents experience production losses after absence. This leads to an increase in estimated production losses of about 16% compared with only considering absence data. Current productivity costs estimates based solely on absence data may, therefore, underestimate real productivity costs. Compensation mechanisms in firms may reduce the underestimation.

Resource consumption and costs in Dutch patients with type 2 diabetes mellitus. Results from 29 general practices.

AIMS: The aims of this study were to estimate the costs incurred by Dutch patients with Type 2 diabetes, examine which patient and/or treatment characteristics are associated with costs, and estimate the medical and non-medical costs of patients with Type 2 diabetes in The Netherlands. METHODS: Twenty-nine Dutch general practitioners provided information on all Type 2 diabetes patients in their practice (n = 1371), information on demography, clinical characteristics, treatment type, the presence of complications and the type and amount of medical consumption during the previous 6 months. Medical costs were analysed using multivariate linear regression. Estimates of costs seen in The Netherlands were based on these results plus information from other sources regarding costs of end-stage renal disease, appliances, travel and productivity loss. RESULTS: Although only 9% of patients were hospitalized within the previous 6 months, hospitalization costs represented one-third of the medical costs, drug costs 40% and ambulatory costs 26%. Patients using insulin, patients with macrovascular complications only or in combination with microvascular complications incurred higher medical costs than other patients. Age and hyperlipidaemia were also positively related to medical costs. When these results were combined with other data sources, we estimated that patients with Type 2 diabetes are responsible for pound365 500 000 (1 271 000 000 guilders) or 3.4% of the relevant parts of health care costs in 1998. The non-medical costs (travel costs, productivity costs) are limited: 52 500 000 (183 000 000 guilders). CONCLUSIONS: Independent determinants of the medical costs of Type 2 diabetes in The Netherlands include age, complications, insulin use and hyperlipidaemia.