Committed to Safety: Ten Case Studies on Reducing Harm to Patients

Presents case studies of healthcare organizations, clinical teams, and learning collaborations to illustrate successful innovations for improving patient safety nationwide. Includes actions taken, results achieved, lessons learned, and recommendations

Understanding and Improving Malaria Diagnosis in Health Facilities in Dar es Salaam, Tanzania

In Tanzania, as in most settings of sub-Saharan Africa, malaria is the first reported cause of attendance in health facilities. The National Bureau of Statistics estimates that a total of 16 million cases and 100,000 deaths (mainly in children) are due to malaria each year. In Dar es Salaam, the main city, approximately 3 million attendances are recorded, of which about one third are due to fever, mostly considered as presumptive malaria. Recent data show that transmission intensity is much lower in urban settings than in rural lowland areas. This is especially true for Dar es Salaam where only a small fraction of all fever episodes in children and adults are actually associated with Plasmodium parasitaemia. Clinical presentation of malaria is largely unspecific. No reliable clinical predictor that allows including or excluding the diagnosis of malaria has been identified. In this context, and in the absence of diagnostic test, WHO recommended in the past all fever episodes to be treated with antimalarials. Such blanket treatment leads first to substantial over-treatment with malaria drugs (in Dar es Salaam up to 95% of all treatments are unnecessary) and second to increased risk of missing alternative diagnoses with potentially fatal outcome. To address this issue of high public health relevance, we undertook a project called IMALDIA (Improving Malaria Diagnosis) aimed at improving the management of febrile patients in health facilities in Dar es Salaam, mainly through the implementation of Rapid Diagnostic Tests for malaria (mRDT). The project had 3 major components: (1) Evaluating the safety of withholding antimalarials in febrile children with a negative mRDT living in a moderate and a highly endemic area (2) Introducing laboratory diagnosis for malaria in the routine management of fever cases, using mRDT. The focus of this operational research was to document how feasible and effective the introduction of these tests is in the context of the routine management of fever cases. (3) Understanding the aetiologies of fever cases in children by screening a group of 1000 children with detailed clinical assessments and a range of laboratory tests in order to better identify the diversity of the causes of fever in small children living in an urban and a rural area. The overall aim of the IMALDIA project was to improve the diagnostic approach and management of fever cases in health facilities in Dar es Salaam, contribute to a more efficient and effective health sector, and help Tanzania on its way to reducing infant and child mortality.In a first step, we assessed the diagnostic performance of mRDT when used by health workers in routine practice. For this purpose, a quality assurance system both at central and peripheral level was set up. This system did not detect major problem and showed that the final result of mRDT by health workers was reliable. Summary X The purpose of the second step was to better estimate the pre-test probability of malaria in populations targeted by mRDT (febrile patients of all age groups attending a health facility of any type). To this end we undertook a systematic review of the studies giving the proportion of patients with associated P. falciparum parasitemia (PFPf) in Sub-Saharan Africa. We found that the median PFPf was 35%, and that it had decreased by half when comparing the period before with the period after the year 2000 (44% versus 22%). This relatively low pre-test probability nowadays is another reason to implement mRDT in Africa. In Dar es Salaam the PFPf was very low (below 10%) hence it was even more urgent to start using a reliable malaria test. Microscopy was available in almost all public health facilities of the city but its performance was extremely low, with an overall sensitivity of 71% and a specificity of only 47%. On the request of several Tanzanian stake-holders, in particular clinicians working routinely with patients, we assessed the safety of withholding antimalarials in children under five years with a negative malaria test. We did not observe any complication or death due to a missed diagnosis of malaria in our cohort of 1000 children, of which 60% were negative by mRDT. We concluded that the strategy of withholding antimalarials in negative children is safe and does not expose the child to an increased risk. The results of the systematic review coupled with the findings of the safety study led us to question the appropriateness of the previous WHO recommendation of treating all fevers with antimalarials in children less than five years living in highly endemic areas. WHO has now changed its policy, confirming that the IMALDIA findings were very relevant to the changed situation of many African countries, including Tanzania. The core of this thesis, and the main objective of the IMALDIA project, was to investigate the feasibility and value of implementing mRDT in the management of fever episodes in an urban malaria setting. Using 2 different designs and 2 independent data sources, we found a three quarter reduction in antimalarial consumption following RDT implementation. This massive reduction was due to the higher accuracy of routine mRDT compared to routine microscopy (that led to a dramatic reduction in the number of positive patients) and to the confidence of health workers in mRDT results (the proportion of negative patients treated with antimalarials dropped from 53% to 7%). The impact was maintained up to the end of the observation period (18 months). Not surprisingly, mRDT implementation increased the prescription of antibiotics by 50% and unfortunately did not have a major impact on the quality of the medical consultation. We took the opportunity of our near-to-program implementation of mRDT to perform a cost-saving analysis in a real situation and in a setting representative of many moderate endemic places in Africa. The conclusion was that costs can be saved on drugs, from both the provider and from the client’s perspective. For this reason, the overall expenditure for the patient was lower in health facilities using mRDT (by 0.31 USD per patient). However, the overall expenditure for the health Summary XI system was higher (by 1.31 USD per patient) when using mRDT instead of routine microscopy, mainly because of the relatively high price of the device. The aim of the last study was to explore the other causes of fever (beside malaria), in order to generate evidence for a revision of the existing clinical decision-charts for the management of patients, in particular the Integrated Management of Childhood Illness (IMCI). Half of the fever episodes in children were due to acute respiratory infections (ARI), of which 2/3 were probably of viral origin. Only 5% of all ARI were documented pneumonia. Gastroenteritis contributed to 9% of all fevers, of which at least 1/3 were due to a virus. In 1/5 of the children, no aetiology of high probability could be found but most of them recovered without treatment. Most of the children with acute fever thus do not need to receive an antibiotic. Based on these findings, we proposed a limited series of modifications to the IMCI chart and concluded that new point-of-care laboratory tests for the main infectious diseases are urgently needed. In conclusion, the IMALDIA project provided a deep insight into many aspects of the implementation of mRDT in near-to-programme conditions in Tanzania. Our findings show that the introduction of mRDT is safe, feasible and useful for the routine management of fever cases in all age groups and at all levels of the health system. Implementation at large scale will require flexibility on the part of the health care provider in order to be able to change his/her behaviour and a strong commitment of all persons involved. As malaria diagnosis is only one aspect of the management of patients presenting with fever, this will not solve all obstacles for making a proper differential diagnosis and prescribing the appropriate treatment for fever episodes. To really improve the quality of care it will be essential to develop new improved guidelines for clinicians. These decision charts should be based on the new available evidence and could include novel point-of-care tests for the key diseases, once these become availabl

Implementing the EffTox dose-finding design in the Matchpoint trial

Background: The Matchpoint trial aims to identify the optimal dose of ponatinib to give with conventional chemotherapy consisting of fludarabine, cytarabine and idarubicin to chronic myeloid leukaemia patients in blastic transformation phase. The dose should be both tolerable and efficacious. This paper describes our experience implementing EffTox in the Matchpoint trial. Methods: EffTox is a Bayesian adaptive dose-finding trial design that jointly scrutinises binary efficacy and toxicity outcomes. We describe a nomenclature for succinctly describing outcomes in phase I/II dose-finding trials. We use dose-transition pathways, where doses are calculated for each feasible set of outcomes in future cohorts. We introduce the phenomenon of dose ambivalence, where EffTox can recommend different doses after observing the same outcomes. We also describe our experiences with outcome ambiguity, where the categorical evaluation of some primary outcomes is temporarily delayed. Results: We arrived at an EffTox parameterisation that is simulated to perform well over a range of scenarios. In scenarios where dose ambivalence manifested, we were guided by the dose-transition pathways. This technique facilitates planning, and also helped us overcome short-term outcome ambiguity. Conclusions: EffTox is an efficient and powerful design, but not without its challenges. Joint phase I/II clinical trial designs will likely become increasingly important in coming years as we further investigate non-cytotoxic treatments and streamline the drug approval process. We hope this account of the problems we faced and the solutions we used will help others implement this dose-finding clinical trial design. Trial registration: Matchpoint was added to the European Clinical Trials Database (2012-005629-65) on 2013-12-30