Drug-drug interactions : from knowledge base to clinical impact

Drug usage has increased steadily, and the more drugs used, the higher the risk for adverse effects or loss of effect due to drug-drug interactions. For drug prescribers it is difficult to know what drugs a patient is taking and whether they interact. Computerizing of health care records has made it possible to connect patients’ drug lists to clinical decision support systems giving the prescriber information about e.g. drug-drug interactions, duplicated prescriptions and drugs in pregnancy. The aim of this thesis is to create a knowledge base suitable for usage in decision support systems, to evaluate the database in clinical practice, and to use existing clinical databases to create new knowledge about possible drug-drug interactions and their mechanisms. Paper I is a description of how the knowledge base SFINX was created. The publication describes handling of substances and drug formulations. Standardization of literature searches and text formulations, classification of interactions, structuring of interaction texts, basis for recommendations and the process of approval is also discussed. In paper II, the interaction between lamotrigine and quetiapine was studied using therapeutic drug monitoring data. Patients exposed to both quetiapine and lamotrigine were matched with controls exposed to quetiapine alone. The dose-corrected quetiapine concentration was 58% lower in patients co-treated with lamotrigine than in patients treated with quetiapine alone, possibly due to induction of quetiapine metabolism by lamotrigine. In paper III, the influence of mutations in the CYP2C9 gene on the interaction between simvastatin and warfarin was studied. In patients with a CYP2C9*3 allele, the warfarin maintenance dose was 25% lower if treated with simvastatin, according to the results from multiple regression. No significant interaction could be observed in patients lacking the *3 allele. Paper IV was a questionnaire study where we collected information about how SFINX is used and how the database is perceived by the users of the web version. We found that the database is often used when the prescriber/pharmacist sees the patient, that the information influences the treatment of the patient, and that the database is used to learn more about interactions. In paper V, we investigated if integration of SFINX into electronic health care records prevented the prescribing of drug combinations leading to potentially serious drug-drug interactions in primary health care. When comparing prescriptions between a period before integration of SFINX and a period after integration, we found that the prevalence of potentially serious drug-drug interactions decreased significantly by 17%

Evaluation of usage patterns and user perception of the drug-drug interaction database SFINX

Purpose: The aim of the present study was to investigate how prescribers and pharmacists use and perceive the drug-drug interaction database SFINX in their clinical work. Methods: A questionnaire was developed with questions aimed at the usage of SFINX, and the perceptions of the database. The questionnaire was sent out to all registered users of the web application of SFINX. The anonymous answers from the target users, prescribers and pharmacists were summarized using descriptive statistics. Statistical analysis was performed on age and gender differences for some questions regarding different usage patterns. Results: The questionnaire was sent to 11,763 registered SFINX users. The response rate was 23%, including 1871 answers from prescribers or pharmacists. SFINX was reported to be used at least weekly or more often by 45% of the prescribers and 51% of the pharmacists. Many prescribers reported using the database during the patient consultation (60%) or directly before or after (56%). Among the prescribers, 74% reported that the information received made them change their action at least sometimes. About 20% of the prescribers and 25% of the pharmacists considered the information as irrelevant sometimes or more often. Conclusion: Most prescribers and pharmacists reported using SFINX in direct association with a patient consultation. Information received by using SFINX makes prescribers and pharmacists change their handling of patients. DDI databases with relevant information about patient handling might improve drug treatment outcome. (C) 2015 Elsevier Ireland Ltd. All rights reserved

Reseptilääkkeiden kliinisesti merkittävät interaktiot avohoidossa ja farmasistin rooli niiden ehkäisyssä

Adverse drug events (ADE) are a major problem which deteriorates the quality of drug therapy. They cause significant morbidity and mortality each year. ADEs are often caused by incompatible drug combinations, drug-drug interactions (DDIs). Interprosessional collaboration between health care professionals is important in improving medication safety and preventig drug interactions. The aim of this study was to investigate the most common clinically significant drug-drug interactions in outpatient care and the role of pharmacist in preventing them. The study material was an interaction data which was collected in Helsinki University Pharmacy during August 2015. DDIs and the action needed by presecribers or pharmacists to handle them were collected. Only clinically significant interactions of the SFINX interaction database i.e. D- and C-interactions were recorded. The most common D-interactions (interactions to be avoided) were fluoroquinolones or tetracyclines combined with metal ions (calcium, iron, magnesium, aluminium) (14.7 % of D-interactions) and codeine or tramadol combined with CYP2D6 enzyme inhibiting antidepressants (12.6 %). C-interactions concerned most commonly interactions between antihypertensive drugs and NSAIDs (26.2 % of C-interactions). 59.6 % of D-interactions were interactions that might result in adverse drug reactions and 40.4 % were interactions that might result in therapeutic failure. For C-interactions numbers were 49.4 % and 50.6 %, respectively. Only a few interactions (1.6 %) led to contact with the prescriber from the pharmacy, and more often (1.8 %) the pharmacist advised the patient to contact the prescriber. 32.6 % of the interactions led to pharmacist's advice. The most typical interactions which can be prevented by pharmacist's advice were chelation interactions which can be prevented by taking drugs many hours apart from each other. 59.7 % of the interactions produced no action in pharmacy. Those concerned situations where the prescriber had planned the treatment and weighed up the benefits and risks of the medication, or interactions where the drugs had been in contemporary use for a long time, and thus the pharmacist assumed that the prescriber had planned the treatment. Pharmacists should intervene in drug-drug interactions easier. To avoid unnecessary calls, communication between prescribers and community pharmacies should be developed. Pharmacists' role in preventing DDIs could be improved for example by education and by updating the operations models in collaboration with other health care. Safe and efficient drug treatment should be ensured with interprofessional collaboration, and the responsibility should not be shifted to the patient alone.Lääkehaittatapahtumat ovat keskeinen lääkehoidon ongelma aiheuttaen vuosittain merkittävää sairastuvuutta ja kuolleisuutta. Lääkehaittojen taustalla voi olla yhteensopimaton lääkeyhdistelmä eli lääkeinteraktio. Lääkitysturvallisuuden edistämisessä ja lääkeinteraktioiden ehkäisyssä on keskeistä moniammatillinen yhteistyö terveydenhuollon ammattilaisten kesken. Tässä tutkimuksessa selvitettiin, mitkä ovat reseptilääkkeiden tyypillisimpiä kliinisesti merkittäviä interaktioita avohoidossa ja millainen rooli farmasisteilla on niiden ehkäisyssä. Aineistona oli Yliopiston Apteekin toimipisteissä elokuun 2015 aikana kerätty interaktiotiedosto. Farmasistit kirjasivat reseptintoimituksen yhteydessä ylös, millaista lääkärin tai farmasistin toimintaa asiakkaiden reseptilääkityksessä havaittujen interaktioiden käsittely on edellyttänyt. Aineistoon tallennettiin ainoastaan SFINX-interaktiotietokannan kliinisesti merkittävät eli D- ja C-luokan interaktiot, joiden lääkkeet olivat potilaalla samanaikaisesti käytössä. Yleisimmät vakavimman eli D-luokan interaktiot olivat fluorokinoloni- tai tetrasykliiniantibiootin ja metalli-ionin (kalkki, rauta, magnesium, alumiini) väliset interaktiot (14,7 % D-interaktioista) sekä kodeiinin tai tramadolin interaktio CYP2D6-entsyymiä estävän masennuslääkkeen kanssa (12,6 %). C-luokan interaktioista tyypillisimpiä olivat verenpainelääkkeiden interaktiot tulehduskipulääkkeiden kanssa (26,2 % C-interakioista). D-interaktioista 59,6 % altisti haittavaikutuksille ja 40,4 % lääkkeen tehon alenemiselle; C-interaktioiden kohdalla vastaavat luvut olivat 49,4 % ja 50,6 %. Vain pieni osa interaktioista (1,6 %) johti yhteydenottoon lääkäriin apteekista, ja useamman interaktion kohdalla (1,8 %) farmasisti kehotti asiakasta itseään keskustelemaan interaktiosta lääkärin kanssa. Interaktioista 32,6 % johti farmasistin antamaan neuvontaan. Tyypillisimpiä farmasistin neuvonnalla ehkäistävissä olevia interaktioita olivat imeytymisvaiheen kelaatiointeraktiot, joita voidaan ehkäistä ottamalla lääkkeet riittävän monta tuntia erillään toisistaan. 59,7 % interaktioista ei johtanut toimenpiteisiin apteekissa. Nämä koskivat tilanteita, joissa lääkäri oli suunnitellut hoidon ja punninnut lääkityksen hyödyt ja riskit tai sellaisia interaktioita, joissa lääkkeet olivat olleet asiakkaalla pitkään yhtäaikaisessa käytössä, minkä perusteella apteekissa oletettiin, että kyseessä oli suunniteltu hoito. Lääkeinteraktioihin tulisi puuttua apteekissa herkemmin. Turhien puhelinsoittojen välttämiseksi lääkärien ja apteekkien välistä viestintää pitäisi kehittää. Farmasistien roolia interaktioiden ehkäisyssä voitaisiin parantaa esimerkiksi koulutuksen avulla ja päivittämällä interaktioiden käsittelyyn liittyviä toimintamalleja yhteistyössä muun terveydenhuollon kanssa. Turvallinen ja tehokas lääkehoito tulee varmistaa moniammatillisella yhteistyöllä, eikä vastuuta sen toteutumisesta tule siirtää yksin potilaalle

Selectively decentralized reinforcement learning

Indiana University-Purdue University Indianapolis (IUPUI)The main contributions in this thesis include the selectively decentralized method in solving multi-agent reinforcement learning problems and the discretized Markov-decision-process (MDP) algorithm to compute the sub-optimal learning policy in completely unknown learning and control problems. These contributions tackle several challenges in multi-agent reinforcement learning: the unknown and dynamic nature of the learning environment, the difficulty in computing the closed-form solution of the learning problem, the slow learning performance in large-scale systems, and the questions of how/when/to whom the learning agents should communicate among themselves. Through this thesis, the selectively decentralized method, which evaluates all of the possible communicative strategies, not only increases the learning speed, achieves better learning goals but also could learn the communicative policy for each learning agent. Compared to the other state-of-the-art approaches, this thesis’s contributions offer two advantages. First, the selectively decentralized method could incorporate a wide range of well-known algorithms, including the discretized MDP, in single-agent reinforcement learning; meanwhile, the state-of-the-art approaches usually could be applied for one class of algorithms. Second, the discretized MDP algorithm could compute the sub-optimal learning policy when the environment is described in general nonlinear format; meanwhile, the other state-of-the-art approaches often assume that the environment is in limited format, particularly in feedback-linearization form. This thesis also discusses several alternative approaches for multi-agent learning, including Multidisciplinary Optimization. In addition, this thesis shows how the selectively decentralized method could successfully solve several real-worlds problems, particularly in mechanical and biological systems

Avohoidon lääkitysturvallisuus : tehostettu lääkehoidon koordinaatio ja riskien hallinta apteekin ja kotihoidon yhteistyönä

Over the last decade, a great deal of research has described the medication safety risks in hospitals and institutional care both in Finland as well as globally. Less attention has been paid to the safety of medicine use in outpatient care, even though majority of the use occurs at home. The aim of this study was to enhance prospective medication risk management in outpatient care, by enhancing coordination of care with community pharmacists’ participation and use of risk management screening tools available. Specific objectives of studies I–III were: I) to demonstrate how community pharmacies can utilize their prospective surveillance system for screening clinically significant drug-drug interactions (DDIs) in outpatients and assess the rate of DDIs in a large national prescription sample. II) To integrate risk assessment tools, procedures and databases available in Finland to form a coordinated medication management model (CoMM) for older home clients involving home care nurses and practical nurses (PNs), physicians and community pharmacists. III) To assess the impact of the CoMM on medication risks identified in drug regimens of older home care clients over a one-year period. Medication risks assessed related to potentially inappropriate medications (PIMs), excessive use of psychotropics, anticholinergic and serotonergic load, as well as clinically significant DDIs. In study I, all DDI alerts issued by the online surveillance system were collected during a one-month period in 16 out of 17 University Pharmacy outlets in Finland, covering approximately 10% of the national outpatient prescription volume. The surveillance system was based on the FASS database, which categorizes DDIs into four classes (A–D) according to their clinical significance. Potential DDIs were analyzed for 276,891 dispensed prescriptions and they were associated with 11.2% of the prescriptions. Clinically significant DDIs categorized as FASS classes D (most severe, should be avoided) and C (clinically significant but controllable) were associated with 0.5% and 7.2% of the prescriptions, respectively. Studies II–III were conducted in primary care in the city of Lohja, Southern Finland. Health care units involved were the home care, public primary healthcare center and a private community pharmacy. System-based risk management theory and the action research method were applied to construct the collaborative procedure utilizing each profession’s existing resources in medication risk management of older (>65 years, n=191) home care clients. Study II produced a 5-stage medication management model (CoMM) suitable for screening medications of a high number of home care clients and identifying clients with potential clinically significant drug-related problems (DRPs). The core of the model was the triage meetings that proved to be a feasible method for customizing comprehensiveness of collaborative medication reviews, according to their clinical needs while minimizing physicians’ time demands. In study III, an RCT study design was used to assess the impact of the CoMM on medication risks identified in drug regimens of older home care clients over a one-year period. Participants’ (n=129) mean age was 82.8 years, 69.8% were female and mean number of prescription medicines in use was 13.1. The intervention did not show an impact on the medication risks between the original intervention group and the control group in the intention to treat analysis, but the per protocol analysis indicated a tendency for effectiveness, particularly in optimizing central nervous system medication use (benzodiazepines). Half (50.0%) of the participants with a potential need for medication changes, agreed on in the triage meeting, had none of the changes actually implemented. Study I demonstrated that community pharmacists can actively contribute to DDI risk management and systematically use their surveillance systems for identifying patients with clinically significant DDIs. In study II, the developed care coordination model (CoMM) was feasible for screening and reviewing medications of a high number of older home care clients in order to identify clients with severe DRPs and provide interventions to solve them, utilizing existing primary care resources. In study III, the CoMM intervention indicated a tendency for effectiveness when implemented as planned, particularly in optimizing CNS medication use during a 12-month follow-up. Our study revealed that organizations and health care units involved in home care clients’ medication therapy are currently working independently in silos, where no specific team membertakes holistic responsibility for medications. This study demonstrated the challenges to overcome when trying to change clinical practice and improve coordination between units involved in medication management of home care clients. Even though the outcomes of the intervention were not optimal, the value of the study is in discussing the real-world experiences and challenges of implementing new practices in home care. This study indicated that practitioners in Finnish health care are not well acquainted with systems thinking, a fact which needs to be addressed in the future. Further studies are needed on care culture and other contributing factors to high prevalence of PIM use and other risks for clinically significant DRPs identified in this study. Particularly, further investigation is needed on system-based factors contributing to situations where identified preventable clinically significant medication risks are left unsolved, as well as the relationship between inappropriate medication use and medication errors. A need for the organizational and national development of medication safety in primary care was identified in this thesis, which is line with the national and international publications, policy documents and recommendations. Furthermore, community pharmacists’ contribution to medication safety, particularly in older adults, should be better utilized in the future, as this thesis shows promising demonstrations. KEYWORDS: Medication risk management, medication-related risk, drug-drug interaction, primary care, home care, older adult, community pharmacy  Avohoidossa toteutetaan valtaosa lääkehoidosta. Väitöstutkimuksessa tutkittiin avohoidon lääkitysturvallisuutta ennakoivan riskienhallinnan näkökulmasta. Tutkimus koostuu kolmesta osatyöstä, jotka ajoittuvat suomalaisen järjestelmälähtöisen lääkitysturvallisuustyön eri vaiheisiin. Osatyössä I tutkittiin apteekissa tunnistettujen lääkeyhteisvaikutusten yleisyyttä. Osatyössä II kehitettiin koordinoitu, moniammatillinen toimintamalli iäkkäiden kotihoidon asiakkaiden lääkitysriskien tunnistamiseen ja selvittämiseen. Osatyössä III tutkittiin toimintamallin vaikuttavuutta. Osatyön I aineisto kerättiin 2004, jolloin ensimmäinen sähköinen tietokanta lääkeyhteisvaikutusten tunnistamiseen oli juuri otettu käyttöön Suomessa. Yliopiston Apteekki (YA) kehitti tietokannan käyttöönottoon toimintamallin paikallisten lääkäreiden kanssa. Lääkeyhteisvaikutusten yleisyys tutkittiin kuukauden aikana YA:n toimipisteistä toimitetuista resepteistä (n=280 000). Lääkeyhteisvaikutusten riski liittyi 11,2 % resepteistä, vakavimpien riski löytyi 0,5 % resepteistä. Yleisimmin nämä koskivat tulehduskipulääkkeiden yhteiskäyttöä varfariinin tai metotreksaatin kanssa. Osatyöt II-III toteutettiin Lohjan kotihoidossa. Työssä II kehitettiin toimintatutkimusta käyttäen koordinoitu toimintamalli iäkkäiden (>65 vuotta) kotihoidon asiakkaiden lääkitysriskien tunnistamiseen ja ratkaisemiseen hyödyntäen olemassa olevia kotihoidon, apteekin ja lääkäreiden resursseja. Toimintamallissa kotihoidon hoitajat seuloivat lääkehoidon riskejä riskimittarilla. Tunnistettujen riskien ja ajantasaisten lääkityslistojen perusteella arvioitiin tarkempien lääkehoidon arviointien tarve hyödyntämällä ns. triage-menettelyä. Tarkempaa arviointia tarvitsi 55 % tutkittavista. Apteekin (Lohjan 1. apteekki) farmasistit toteuttivat tarvittavat lääkehoidon arvioinnit ja tutkittavien omalääkärit päättivät mahdollisista lääkemuutoksista. Toimintamalliin kuului myös lääkitysmuutosten seuranta. Osatyössä III tutkittiin toimintamallin vaikuttavuutta vertaamalla lääkitysriskimuutoksia interventio- ja kontrolliryhmissä vuoden seuranta-ajalla. Tutkittavien (n=129) keski-ikä oli 83 vuotta, 70 % oli naisia ja käytössä oli keskimäärin 13 reseptilääkettä. Toimintamallin vaikuttavuutta ei pystytty osoittamaan ryhmien välisessä vertailussa, koska 50 %:ssa tunnistettuihin lääkehoidon ongelmiin ei puututtu. Tutkimus osoitti, että nykyisessä terveydenhuoltojärjestelmässä koordinaatiota on vaikea rakentaa. Tämä johtuu useista järjestelmälähtöisistä syistä, joita tulisi tutkia tarkemmin olemassa olevien resurssien, kuten apteekkien, tehokkaammaksi hyödyntämiseksi lääkehoitojen riskienhallinnassa

Evaluation of Effectiveness of Risk Minimisation Measures in Europe

Tesis Doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Medicina. Fecha de Lectura: 02-06-202