Forschungs- & Entwicklungsinformationsdienst der Gemeinschaft - CORDIS

Periodic Report Summary 2 - PRIMA-EDS (Polypharmacy in chronic diseases: Reduction of Inappropriate Medication and Adverse drug events in elderly populations by electronic Decision Support)

Project Context and Objectives:
The objective of PRIMA-eDS is to tackle the growing problem of polypharmacy in older multimorbid patients. The prevalence of polypharmacy in the population >75 years has been found to be between 25 and 50%. While there exists only limited evidence regarding the benefit of polypharmacy, the evidence regarding potential harm of polypharmacy and inappropriate medication is increasing. Thus polypharmacy and inappropriate prescription have been shown to increase the risk of adverse drug events, and contribute substantially to morbidity, hospitalization, and mortality. A study carried out in Austria found that 10% of hospitalizations of patients >70 years are directly related to an adverse drug event. This clearly indicates that there is a strong need to reduce inappropriate drug therapy and polypragmatic drug prescription. Diverse heterogeneous approaches to reduce polypharmacy and inappropriate prescribing have been proposed, but none of these have been evaluated regarding practicability in primary care and clinically relevant endpoints within a sufficiently powered randomized controlled trial. The most popular approach to reduce inappropriate prescribing is at present the implementation of Potentially Inappropriate Medication (PIM)-lists as have been first introduced by Beers in the 1990s. These lists are based on Delphi-rounds of experts (mostly pharmacologists and geriatricians) and not on evidence derived from clinical studies, and they never have been shown to have any effect on clinical outcome. Other approaches include the STOPP-criteria of Gallagher or the Medication Appropriateness Index (MAI). None of these tools have been sufficiently evaluated regarding clinical outcome, and they are hardly applicable in every day practice. Physicians and especially general practitioners (GPs) are unable to do thorough medication reviews with their patients in every day practice due to knowledge gaps and limited time. Therefore, PRIMA-eDS sets out to develop an electronic decision support (eDS) tool to assist physicians and patients to avoid inappropriate medication and polypharmacy, and to identify prescriptions where risks outweigh possible benefits of the drug treatment. This tool will be based on current best evidence to optimize treatment of those diseases that are most common in elderly patients like cardiovascular disease, heart failure, hypertension, atrial fibrillation, diabetes mellitus type 2, musculoskeletal disorders, COPD, and mental diseases. In several systematic reviews this evidence is collated and transformed into recommendations to optimize drug treatment of multimorbid older patients. A further objective of PRIMA-eDS is to prove in a randomized controlled trial that the implementation of the PRIMA-eDS-tool will not only lead to a reduction of inappropriate prescribing but also to a reduction of hospitalisation, morbidity and mortality. Finally, the main objective of PRIMA-eDS is to implement the eDS-tool in everyday practice thus optimizing the management of chronic diseases and improving health care for older multimorbid patients.

Project Results:
In the second project period we completed the systematic review started during period 1 on currently available strategies to reduce polypharmacy (work package 2, task 2) and presented the results of the review at several conferences. We prepared a publishable manuscript of the main results which is currently under review with the British Journal of Clinical Pharmacology.
We also completed the set of systematic reviews of WP2, task 1, initiated in period 1. We performed 21 systematic reviews including 17 drug classes and covering 15 chronic conditions in older people. The report on WP2, task 1, has been submitted to the EU commission as deliverable D3 on June 23, 2015. The methodology of the systematic reviews and six systematic reviews are currently being prepared for publication in a special issue of BMC geriatrics.
The set of systematic reviews led to the development of 40 recommendations covering 17 drug classes and 15 chronic conditions. The complete set of recommendations has been submitted to the EU-commission as deliverable D4 on June 23, 2015. Additional recommendations keep arising after the submission of the deliverable through continuous updating and further processing of results, making a total of 46 recommendations used in the PRIMA-eDS-tool at the moment.
The stop-recommendations developed in WP2, task 1, were incorporated into the PRIMA-eDS-tool along with a number of other resources to prevent inappropriate prescribing (WP3). These sources include the EBMeDS-database of DMP, the RENBASE database on renal dosing, the SFINX database on drug-drug-interactions, an indication- and contraindication-check based on EMA drug information, and the PHARAO decision support software on adverse drug reactions. A summarizing description of the complete PRIMA-eDS-tool will be submitted to the EU-commission with this report as deliverable D5.
The programming and designing of the electronic case report form (eCRF) of WP4 was completed in June 2015 after extensive pilot testing, and submitted to the EU-commission as deliverable D6 on June 23, 2015. While the tool was already in use for the randomized controlled trial, optimization for easy usage and high data quality went on and is still ongoing.
In WP5, the PRIMA-eDS randomized controlled trial was registered with Current Controlled Trials ltd. on July 31, 2014 (DOI 10.1186/ISRCTN10137559). The finalized study protocol, the trial registration, and all ethics approvals of the five PRIMA-eDS study sites were submitted to the EU-commission as deliverable D7 on June 23, 2015. The study protocol was submitted to BMC Trials for publication and accepted for publication on January 14, 2016.
Recruitment of GP-practices and patients had been started in project period 1 and was completed on September 30, 2015. We recruited 3940 patients in 360 GP-practices. The recruitment goal aimed at according to our power and sample size calculation was thus reached. Recruitment of patients was delayed for various reasons (see detailed report). The last GP-practices were randomized on Oct 5, 2015 (official end of recruitment and randomization, with a delay of 12 months). GP-training on eCRF and eDS-tool (only intervention practices) was completed in October 2015.
The multicentre clinical trial evaluating the effectiveness of the PRIMA-eDS tool regarding the primary combined endpoint of first hospitalization or death is currently ongoing (WP6). Due to the delayed development of the eCRF and the eDS-tool the trial started with a delay of 10 months. Due to slow recruitment, the trial is delayed by 12 months. No further delays are expected.
In WP7 we developed a final statistical analysis plan and set up an independent safety and data monitoring committee (SDMC) in accordance with WP9. A final report on statistical issues and safety monitoring will be submitted to the EU-commission as deliverable D11 with this report.
Technical support regarding proper use of the eCRF in all GP-practices and the eDS-tool in the intervention group is provided by DMP/Avain and local hotlines in all study centres (WP8). Due to the delay of the randomized controlled trial, D12 (mid-term report on technical support) will be submitted with delay.
In WP9 we developed a safety and monitoring manual which was approved by the consortium and the SDMC. As part of the monitoring activities the SDMC with the help of local monitors is continuously checking and assuring that data protection measures are accurately followed and in place. Monitoring of all patient data assured that signed informed consent forms have been obtained from all patients. The monitoring plan will be submitted to the EU-commission as deliverable D14 with this report. The first interim report of WP9 (D15) will be submitted with delay in month 40 due to the delay of the randomized controlled trial. Accordingly D16 and D17 will also be delayed.
WP10 has not started yet. In WP11 the eDS tool is continuously optimized, especially if new evidence arises regarding the stopping rules. Quarterly updates of the incorporated data bases (RENBASE, SFINX, PHARAO) are implemented in the eDS-tool without delay.
In WP12 we presented the PRIMA-eDS tool and the protocol of the randomized trial at various national and international conferences. Publications of the systematic reviews have been submitted to the British Journal of Clinical Pharmacology and to BMC Geriatrics. The study protocol has been accepted for publication in BMC Trials.

Potential Impact:
After an observation period of 24 months (work package 6), the effects of the eDS-tool will be evaluated regarding the primary composite outcome of hospitalisation and death as well as various secondary outcomes (work package 10). We expect a risk reduction of 20% regarding our composite endpoint of hospitalisation and mortality, on which sample size calculation has been based. After the end of the trial the tool will be optimized using the trial results (work package 11), and implementation in daily practice will be pursued by widespread dissemination of the eDS-tool and the trial results (work package 12). In case of the anticipated positive trial result, PRIMA-eDS will have a substantial impact on health care and health policy. We expect that the new state-of-the-art in chronic care of older multimorbid patients will be to abandon the current practice of treating single diseases, and to turn towards treating multimorbidity in a standardized way, taking limited life expectancy, large numbers needed to treat regarding drug treatment to improve prognosis, risks and possible harms of polypharmacy, and drug-drug as well as drug-disease-interactions into account. The multifaceted multimorbidity treatment algorithm developed in PRIMA-eDS will be incorporated into guidelines for the drug treatment of older patients with multiple diseases, and the PRIMA-eDS decision support tool will be made available to healthcare providers in and outside of Europe. PRIMA-eDS will thus have a large beneficial effect on patient outcome. The intervention will also have a considerably important impact on health economics, not only reducing medication costs but also costs due to hospitalization and treatment of adverse drug events and their consequences. In a small randomized controlled trial it could be shown that the reduction of polypharmacy by medication review would reduce monthly medication costs by a mean of 27$ per patient. The result was significant even though the trial was underpowered and had an observation period of only six weeks. We expect to achieve a much larger effect by the implementation of the PRIMA-eDS-tool, with the advantage of being widely applicable and much less time-consuming than a medication review for the physician or pharmacist. Even a small saving of 27$ per patient per month would lead to a large effect on health economics if the aging population of Europe and the high prevalence of polypharmacy are taken into account.

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Private Universitaet Witten/Herdecke gGmbH


Scientific Research
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