Datos de vida real para la mejora de la utilización y la efectividad de los medicamentos en el Sistema Nacional de Salud: contribuciones esenciales

Los estudios de utilización de medicamentos con datos de vida real permiten informar una serie de cuestiones fundamentales en cuatro ámbitos principales de la gestión sanitaria y farmacoterapéutica: ¿cómo se utilizan los fármacos en el día a día?, ¿cuál es el grado de adecuación de dicho uso?, ¿cuáles son los resultados de dicha utilización en términos de beneficios clínicos, de utilización de servicios sanitarios y costes?, y finalmente, ¿cuál es el impacto de las medidas de gestión de la prestación farmacéutica sobre todo lo anterior?. La presente tesis doctoral se presenta mediante un compendio de publicaciones que demuestran la contribución de los datos de vida real al conocimiento y mejora de la atención farmacoterapéutica en la Comunidad Valenciana. Dado el papel esencial de las fuentes de datos de vida real en la presente tesis, se presenta en primer lugar el sistema de información sanitaria y poblacional disponible en la Comunidad Valenciana, detallando las características de las diferentes bases de datos que lo conforman, su alcance, ventajas y limitaciones. De este modo se establece el marco de interpretación de los resultados obtenidos en los diferentes estudios presentados a continuación. A continuación, se analiza la calidad del control de la anticoagulación oral en pacientes con fibrilación atrial no valvular tratados con acenocumarol, así cómo los patrones de cambio a otras alternativas terapéuticas en el año 2015 en la Comunidad Valenciana. Se muestra que la calidad del control del índice internacional normalizado (INR) es subóptima, con alrededor de la mitad de los pacientes con valores de Tiempo en Rango Terapéutico (TRT) por debajo del 65%, indicando mal control. Sistemáticamente, las mujeres obtienen peores resultados de control del INR. Además, se hallan tasas muy bajas de cambio a terapias anticoagulantes alternativas indicadas en pacientes con mal control de INR, lo que sugiere la existencia de un potencial problema de inercia terapéutica. Estos resultados señalan áreas prioritarias de actuación y contribuyen a un mejor diseño de intervenciones de mejora de la calidad de la atención en estos pacientes. En el tercer artículo, se analiza la evolución dinámica del control de anticoagulación oral en pacientes con fibrilación atrial no valvular que inician tratamiento con acenocumarol en el período 2011 a 2015, utilizando el análisis de clases latentes que permite agrupar a los pacientes en diferentes trayectorias en función de su probabilidad de presentar valores de INR controlado (entre 2 y 3) a lo largo de su primer año de tratamiento. El análisis de trayectorias identifica cuatro trayectorias de control de INR (óptimo, al alza, a la baja, inadecuado) que resultan consistentes con las medidas tradicionales de TRT. Los pacientes clasificados en trayectorias de mal control o a la baja presentan mayor mortalidad que los pacientes clasificados en trayectorias de control óptimo o al alza. Esta técnica puede ser de utilidad en práctica clínica habitual complementando a las medidas tradicionales de control de INR. En el cuarto estudio, se demuestra la mayor precisión de los estimadores de adherencia a la medicación, calculados a partir de datos de vida real, cuando se utiliza información relacionada a nivel individual de prescripción y dispensación, en comparación con el diseño más comúnmente utilizado en los estudios de adherencia a la medicación, que se limita al uso de información de dispensación. Se analiza la adherencia a la medicación en una cohorte representativa de pacientes tratados (iniciadores y prevalentes) con medicación antiosteoporótica, comparando diferentes variantes metodológicas para el cálculo del Porcentaje de Días Cubiertos con medicación (PDC), y se establecen las ventajas de utilizar información de prescripción y dispensación, tales como una mejor definición del inicio de terapia, la captura de períodos iniciales de no adherencia o de los pacientes menos adherentes, o una mayor precisión en la atribución de los períodos sin medicación al paciente o al prescriptor. Finalmente, se analiza la evolución de la utilización de la medicación antiosteoporótica en la misma cohorte que en el estudio previo, en el período 2009 a 2015, así como el impacto de tres intervenciones de política sanitaria sobre dicho uso (dos alertas de la Agencia Española del Medicamento y Productos Sanitarios sobre bifosfonatos y riesgo de osteonecrosis mandibular y fracturas atípicas, así como el cambio en el sistema de copago de 2012), empleando un diseño de series temporales interrumpidas. Se observa una reducción a la mitad en la utilización de dichos fármacos a lo largo del período, y se aprecia que tanto la segunda alerta como el cambio de copago tienen un papel importante en dicho declive, aunque no la primera alerta. Dicha reducción se produce tanto en pacientes de bajo como de alto riesgo, lo que plantea dudas sobre la selectividad de dichas medidas sobre la adecuación de los tratamientos. El presente trabajo evalúa la capacidad de este tipo de medidas de política farmacéutica sobre la prescripción y aporta información que orienta el diseño de intervenciones de mejoras en este ámbito

Cost‐Sharing Increase, Medication Adherence, and Hospitalizations in Schizophrenia Patients: A Natural Experiment

Increases in medication cost-sharing rates remain a controversial system-wide cost-containment measure for chronic mental health patients. The objective was to investigate the effects of cost-sharing increases on adherence to prescribed antipsychotic medication and psychiatric hospitalizations among patients with schizophrenia. In July 2012, a Spanish National Law raised the cost-sharing rate from 0 to 10% for pensioner outpatient medication while cost-sharing remained at 0% for other socioeconomic groups. To estimate the effects of the reform, we analyzed the prevalent adult schizophrenic population of Valencia, Spain, followed up 1 year before and after the Law took effect. We used a quasi-experimental design with a patient fixed-effects difference-in-differences regression to evaluate the reform effects on antipsychotic medication adherence, prescription, and hospitalization rates. A total of 5,672 included patients were exposed to the reform, whereas 5,545 were not. There were no differences in adherence, prescription, or hospitalization rates between exposed and nonexposed patients prior to its implementation. The odds ratio of exposed patients remaining adherent to issued prescriptions after the reform took effect were 0.70 99% confidence interval (CI 0.66–0.75), in relation to the nonexposed group. Additionally, the reform was associated with a reduction in exposure to antipsychotic medication (odds ratio (OR) 0.85, 99%CI 0.83–0.88) and an increase in hospitalization risk (OR 1.13, 99% CI 1.05–1.23) during the first year after implementation. Policies raising the cost-sharing rate of medication for patients with schizophrenia are simultaneously associated with unintended effects. We report decreases in antipsychotic exposure and increases in hospitalization rates that lasted for 1 year after follow-up

A Multilevel Analysis of Real-World Variations in Oral Anticoagulation Initiation for Atrial Fibrillation in Valencia, a European Region

Introduction: Beyond clinical trials, clinical practice guidelines, and administrative regulation, treatment decision-making can be influenced by individual and contextual factors. Our goal was to describe variations in the patterns of initiation of anticoagulation therapy in patients with atrial fibrillation by Health Areas (HA) in the region of Valencia in Spain and to quantify the influence of the HAs on variations in treatment choice.Methods: We conducted a population-based retrospective cohort study of all atrial fibrillation patients who started treatment with oral anticoagulants between November 2011 and February 2014 in each of the region's 24 HAs. We described patient and utilization characteristics per HA and initiation patterns over time, and we identified contextual and individual factors associated with differences in initiation patterns.Results: 21,879 patients initiated treatment with an oral anticoagulant in the 24 HAs. Initiation with direct oral anticoagulants (DOAC) in the first year was 14.6%. In November 2013 the ratio was 25.4%, with HA ratios ranging from 3.8 to 57.1%. DOAC-initiating patients had less comorbidity but were more likely to present episodes of previous ischemic stroke, hemorrhagic stroke, or TIA when compared with patients initiating with VKA treatment. Variability among HAs was statistically significant, with the majority of HAs ranking above or below the regional initiation average (ICC ≈ 8%).Conclusion: There was high variability in the percentage of DOAC initiation and in the choice of DOAC among HAs. Interventions aimed to improve DOAC initiation decision-making and to reduce variations should take into account the Health Area component

Estimating Adherence Based on Prescription or Dispensation Information: Impact on Thresholds and Outcomes. A Real-World Study With Atrial Fibrillation Patients Treated With Oral Anticoagulants in Spain

Objective: To estimate drug exposure, Proportion of Days Covered (PDC) and percentage of patients with PDC ≥ 80% from a cohort of atrial fibrillation patients initiating oral anticoagulant (OAC) treatment. We employed three different approaches to estimate PDC, using either data from prescription and dispensing (PD cohort) or two common designs based on dispensing information only, requiring at least one (D1) or at least two (D2) refills for inclusion in the cohorts. Finally, we assessed the impact of adherence on health outcomes according to each method.Methods: Population-based retrospective cohort of all patients with Non Valvular Atrial Fibrillation (NVAF), who were newly prescribed acenocoumarol, apixaban, dabigatran or rivaroxaban from November 2011 to December 2015 in the region of Valencia (Spain). Patients were followed for 12 months to assess adherence using three different approaches (PD, D1 and D2 cohorts). To analyze the relationship between adherence (PDC ≥ 80) defined according to each method of calculation and health outcomes (death for any cause, stroke or bleeding) Cox regression models were used. For the identification of clinical events patients were followed from the end of the adherence assessment period to the end of the available follow-up period.Results: PD cohort included all patients with an OAC prescription (n = 38,802), D1 cohort excluded fully non-adherent patients (n = 265) and D2 cohort also excluded patients without two refills separated by 180 days (n = 2,614). PDC ≥ 80% ranged from 94% in the PD cohort to 75% in the D1 cohort. Drug exposure among adherent (PDC ≥ 80%) and non-adherent (PDC < 80%) patients was different between cohorts. In adjusted analysis, high adherence was associated with a reduced risk of death [Hazard Ratio (HR): from 0.82 to 0.86] and (except in the PD cohort) the risk for ischemic stroke (HR: from 0.61 to 0.64) without increasing the risk of bleeding.Conclusion: Common approaches to assess adherence using measures based on days’ supply exclude groups of non-adherent patients and, also, misattribute periods of doctors’ discontinuation to patient non-adherence, misestimating adherence overall. Physician-initiated discontinuation is a major contributor to reduced OAC exposure. When using the PDC80 threshold, very different groups of patients may be classified as adherent or non-adherent depending on the method used for the calculation of days’ supply measures. High adherence and high exposure to OAC treatment in NVAF patients is associated with better health outcomes

Impact of the 2018 revised Pregnancy Prevention Programme by the European Medicines Agency on the use of oral retinoids in females of childbearing age in Denmark, Italy, Netherlands, and Spain: an interrupted time series analysis

Background: In March 2018, the European pregnancy prevention programme for oral retinoids was updated as part of risk minimisation measures (RMM), emphasising their contraindication in pregnant women. Objective: To measure the impact of the 2018 revision of the RMMs in Europe by assessing the utilisation patterns of isotretinoin, alitretinoin and acitretin, contraceptive measures, pregnancy testing, discontinuation, and pregnancy occurrence concomitantly with a retinoid prescription. Methods: An interrupted time series (ITS) analysis to compare level and trend changes after the risk minimisation measures implementation was conducted on a cohort of females of childbearing age (12-55 years of age) from January 2010 to December 2020, derived from six electronic health data sources in four countries: Denmark, Netherlands, Spain, and Italy. Monthly utilisation figures (incidence rates [IR], prevalence rates [PR] and proportions) of oral retinoids were calculated, as well as discontinuation rates, contraception coverage, pregnancy testing, and rates of exposed pregnancies to oral retinoids, before and after the 2018 RMMs. Results: From 10,714,182 females of child-bearing age, 88,992 used an oral retinoid at any point during the study period (mean age 18.9-22.2 years old). We found non-significant level and trend changes in incidence or prevalence of retinoid use in females of child-bearing age after the 2018 RMMs. The reason of discontinuation was unknown in >95% of cases. Contraception use showed a significant increase trend in Spain; for other databases this information was limited. Pregnancy testing was hardly recorded thus was not possible to model ITS analyses. After the 2018 RMM, rates of pregnancy occurrence during retinoid use, and start of a retinoid during a pregnancy varied from 0.0 to 0.4, and from 0.2 to 0.8, respectively. Conclusion: This study shows a limited impact of the 2018 RMMs on oral retinoids utilisation patterns among females of child-bearing age in four European countries. Pregnancies still occur during retinoid use, and oral retinoids are still prescribed to pregnant women. Contraception and pregnancy testing information was limited in most databases. Regulators, policymakers, prescribers, and researchers must rethink implementation strategies to avoid any pregnancy becoming temporarily related to retinoid use

Impact of the 2018 revised Pregnancy Prevention Programme by the European Medicines Agency on the use of oral retinoids in females of childbearing age in Denmark, Italy, Netherlands, and Spain: an interrupted time series analysis

Background: In March 2018, the European pregnancy prevention programme for oral retinoids was updated as part of risk minimisation measures (RMM), emphasising their contraindication in pregnant women.Objective: To measure the impact of the 2018 revision of the RMMs in Europe by assessing the utilisation patterns of isotretinoin, alitretinoin and acitretin, contraceptive measures, pregnancy testing, discontinuation, and pregnancy occurrence concomitantly with a retinoid prescription.Methods: An interrupted time series (ITS) analysis to compare level and trend changes after the risk minimisation measures implementation was conducted on a cohort of females of childbearing age (12–55 years of age) from January 2010 to December 2020, derived from six electronic health data sources in four countries: Denmark, Netherlands, Spain, and Italy. Monthly utilisation figures (incidence rates [IR], prevalence rates [PR] and proportions) of oral retinoids were calculated, as well as discontinuation rates, contraception coverage, pregnancy testing, and rates of exposed pregnancies to oral retinoids, before and after the 2018 RMMs.Results: From 10,714,182 females of child-bearing age, 88,992 used an oral retinoid at any point during the study period (mean age 18.9–22.2 years old). We found non-significant level and trend changes in incidence or prevalence of retinoid use in females of child-bearing age after the 2018 RMMs. The reason of discontinuation was unknown in >95% of cases. Contraception use showed a significant increase trend in Spain; for other databases this information was limited. Pregnancy testing was hardly recorded thus was not possible to model ITS analyses. After the 2018 RMM, rates of pregnancy occurrence during retinoid use, and start of a retinoid during a pregnancy varied from 0.0 to 0.4, and from 0.2 to 0.8, respectively.Conclusion: This study shows a limited impact of the 2018 RMMs on oral retinoids utilisation patterns among females of child-bearing age in four European countries. Pregnancies still occur during retinoid use, and oral retinoids are still prescribed to pregnant women. Contraception and pregnancy testing information was limited in most databases. Regulators, policymakers, prescribers, and researchers must rethink implementation strategies to avoid any pregnancy becoming temporarily related to retinoid use

Cost‐sharing increase, medication adherence and hospitalizations in schizophrenia patients: a natural experiment

Increases in medication cost‐sharing rates remain a controversial system‐wide cost‐containment measure for chronic mental health patients. The objective was to investigate the effects of cost‐sharing increases on adherence to prescribed antipsychotic medication and psychiatric hospitalizations among patients with schizophrenia. In July 2012, a Spanish National Law raised the cost‐sharing rate from 0 to 10% for pensioner outpatient medication while cost‐sharing remained at 0% for other socioeconomic groups. To estimate the effects of the reform, we analyzed the prevalent adult schizophrenic population of Valencia, Spain, followed up 1 year before and after the Law took effect. We used a quasi‐experimental design with a patient fixed‐effects difference‐in‐differences regression to evaluate the reform effects on antipsychotic medication adherence, prescription, and hospitalization rates. A total of 5,672 included patients were exposed to the reform, whereas 5,545 were not. There were no differences in adherence, prescription, or hospitalization rates between exposed and nonexposed patients prior to its implementation. The odds ratio of exposed patients remaining adherent to issued prescriptions after the reform took effect were 0.70 99% confidence interval (CI 0.66–0.75), in relation to the nonexposed group. Additionally, the reform was associated with a reduction in exposure to antipsychotic medication (odds ratio (OR) 0.85, 99%CI 0.83–0.88) and an increase in hospitalization risk (OR 1.13, 99% CI 1.05–1.23) during the first year after implementation. Policies raising the cost‐sharing rate of medication for patients with schizophrenia are simultaneously associated with unintended effects. We report decreases in antipsychotic exposure and increases in hospitalization rates that lasted for 1 year after follow‐up

Variations in osteoporosis medication utilization. A population-based ecological cross-sectional study in the region of Valencia, Spain.

Little is known about the contextual variability in osteoporosis medication utilization. Our aims were 1) to describe variations in utilization and spending on osteoporotic medication between the Primary Care Health Zones (PHZ) of the Valencia region, Spain, 2) to analyze observed variations using Small Area Variation Analysis methods, and 3) to quantify the influence of the specialized care level on variations in utilization. We conducted a population-based cross-sectional ecological study of expenditure and utilization of five therapeutic groups marketed as osteoporosis treatments in Spain in 2009. The unit of analysis was the PHZ (in total 240) nested in the 23 Hospital Healthcare Departments (HHD) of the region of Valencia, covering a population of about 4.9 million inhabitants. Drug utilization was measured by dispensed Defined Daily Dose per 1000 women aged 50 years old and over and day (DID) per PHZ and cost was measured by the annual osteoporosis drug cost per woman aged 50 and older as well as the average price of DDD (Defined Daily Dose) in each PHZ. We calculated Indirect Standardized Drug Utilization Ratios (ISR) and we used Spearman's correlation to analyze associations between the ISRs of the different therapies. The average osteoporosis drug consumption was 119.1 DID, ranging from 77.6 to 171.3 DID (2.2 times higher) between PHZs in the 5th and 95th percentiles. Annual expenditure also showed a two-fold variation among PHZs. Average prices of the DDD by therapeutic group showed very low or no variation, although they differed substantially among therapeutic groups. Regarding the standardized consumption of osteoporotic drugs, HHDs explained a substantial part (39%) of the variance among PHZs. In conclusion, there is considerable variability in the volume and choice of anti-osteoporotic treatments between PHZs. with HHDs explaining an important proportion of the variation in utilization. Interventions aimed at reducing variation to improve appropriate care should take into account both the PHZ and HHD levels of care