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Use of Real-World Data (RWD) has gained the interest of different stakeholders in cancer care. The aim of this study was to identify and describe the use of RWD/RWE during the pre-authorization phase of products authorized by the EMA in 2018 and 2019 (n = 111), with the focus on oncology medicines (n = 24). Information was extracted from the European Public Assessment Report (EPAR) summaries and recorded for 5 stages (11 categories) of the drug development lifecycle (discovery, early development, clinical development, registration/market launch, lifecycle management). Specific chapters of full EPAR were reviewed to substantiate the findings on RWD/RWE use in clinical trial design, efficacy, safety, and effectiveness evaluation. RWD/RWE is present in all stages of the oncology drug development; 100.0 % in discovery, 37.5 % early development, 58.3 % in clinical development, 62.5 % in registration decision and 100.0 % in post-authorization lifecycle management. Examples showed that trial design supported by RWD/RWE included use of open label/single arm studies; efficacy was about using either comparison of results to historical controls, supplying survey data obtained outside the clinical trial or utilizing expert panel advice; safety about including literature findings in evidence; and effectiveness on comparison of trial results of the given product to historical data or existing standard of care. The findings of this study provide specific insights into how RWD/RWE is used in development of cancer therapeutics, how it contributes to regulatory decision making and can guide further policy developments in this field.
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Desarrollo de Medicamentos , Formulación de Políticas , Oncología Médica , RegistrosRESUMEN
AIM: Pain is increasingly treated with opioids. Potential harms of opioid therapy disproportionally affect older patients. This study aims to provide information on trends, nature and duration of opioid prescribing to older adults, in primary care and to explore differences between older patients from different ages. METHODS: Primary care data (2005-2017) were derived from routine electronic medical records of patients in Nivel Primary Care Database. All opioid prescriptions with Anatomical Therapeutic Chemical Classification (ATC) code N02A were selected (except for codeine). Diagnoses were recorded using the International Classification of Primary Care (ICPC). Patients were categorized in three age groups (65-74, 75-84, and ≥85 years). Descriptive analyses were used to describe the trend of opioid prescriptions for specific opioids, the duration of use and underlying diagnoses. RESULTS: 283,600 patients were included of which 32,287 had at least one opioid prescription in 2017. An increase in the number of older adults who received at least one opioid was seen between 2005 and 2017. The oldest patients were more likely to be prescribed an opioid, especially when it comes to strong opioids, the increase in the volume of prescribing was highest in this group. Moreover, over 40% of the oldest patients used strong opioids chronically. Strong opioids were mostly prescribed for musculoskeletal diagnoses. Cancer was the second most common diagnosis for strong opioids in the younger subgroups, whereas less specified diagnoses were as second in the oldest subgroup. CONCLUSION: Opioid prescription changes with increasing age in frequency, nature, and duration, despite higher harm risks among older patients. Because of the high prevalence of chronic use, it is important to monitor the patient throughout the treatment and to critically evaluate the initiation and continuation of opioid prescriptions.
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In the development process for new drugs, dose-finding studies are of major importance. Absence of these studies may lead to failed phase 3 trials and delayed marketing authorization. In our study we investigated to what extent dose-finding studies are performed in the case of orphan drugs for metabolic and oncologic indications. We identified all orphan drugs that were authorized until August 1, 2017. European Public Assessment Reports were used to extract the final dose used in the summary of product characteristics, involvement of healthy volunteers, study type, end points used, number of patients, number of doses, studies in special populations, and dose used for phase 3 studies. Each drug was checked for major objections and dose changes postmarketing. We included 49 orphan drugs, of which 28 were indicated for metabolic disorders and 21 for oncologic indications. Dose-finding studies were performed in 32 orphan drugs, and studies in healthy volunteers in 26. The absence of dose-finding studies was mostly due to the rarity of the disease. In this case the dose was determined based on factors such as animal studies or clinical experience. Dose-related major objections were raised for 9 orphan drugs. Postmarketing dose-finding studies were conducted in 18 orphan drugs, but dose changes were applied in only 2 drugs. In conclusion, dose-finding studies in the case of metabolic and oncologic orphan drugs were conducted in the development programs of two thirds of orphan drugs. Dose-finding studies performed postmarketing suggest that registered doses are not always optimal. It is thus important to perform more robust dose-finding studies both pre- and postmarketing.
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Producción de Medicamentos sin Interés Comercial , Preparaciones Farmacéuticas/administración & dosificación , Enfermedades Metabólicas/tratamiento farmacológico , Neoplasias/tratamiento farmacológico , Enfermedades Raras , Estudios RetrospectivosRESUMEN
Previous observational studies on statins have shown variable results based on the methodology used. Our objective was to study the association between statins and orthopedic implant failure and to explore the influence of methodological differences in study design. Our study base consisted of patients with a primary total joint replacement in Denmark and the United Kingdom (n = 189,286; 1987-2012). We used 4 study designs: 1) case-control (each patient with revision surgery matched to 4 controls), 2) time-dependent cohort (postoperative statin use as a time-varying exposure variable), 3) immortal time cohort (misclassifying the time postoperatively before statin use), and 4) time-exclusion cohort (excluding the time postoperatively before statin use). Cox proportional hazards models and logistic regression were used to estimate incidence rate ratios. In the time-dependent cohort design, statin use was associated with a decreased risk of revision surgery (adjusted incidence rate ratio (IRR) = 0.90, 95% confidence interval (CI): 0.85, 0.96), which was similar to our case-control results (IRR = 0.87, 95% CI: 0.81, 0.93). In contrast, both time-fixed cohort designs yielded substantially lower risk estimates (IRR = 0.36 (95% CI: 0.34, 0.38) and IRR = 0.65 (95% CI: 0.63, 0.68), respectively). We discourage the use of time-fixed cohort studies, which may falsely suggest protective effects. The simple choice of how to classify exposure can substantially change results from biologically plausible to implausible.
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Prótesis de Cadera , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Prótesis de la Rodilla , Extremidad Inferior/cirugía , Falla de Prótesis , Reoperación , Adulto , Anciano , Estudios de Casos y Controles , Estudios de Cohortes , Factores de Confusión Epidemiológicos , Dinamarca , Femenino , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Medición de Riesgo , Reino UnidoRESUMEN
INTRODUCTION: Responsible conduct of research implies that results of clinical trials should be completely and adequately reported. This article describes the design of a cohort study that aims to investigate the occurrence and the determinants of selective reporting in an inception cohort of all clinical drug trials that were reviewed by the Dutch Institutional Review Boards (IRBs) in 2007. It also describes the characteristics of the study cohort. METHODS AND ANALYSIS: In 2007, Dutch IRBs reviewed 622 clinical drug trials. For each trial, we assessed the stages of progress. We discriminated five intermediate stages and five definite stages. Intermediate stages of progress are: approved by an IRB; started inclusion; completed as planned; terminated early; published as article. The definite stages of progress are: rejected by an IRB; never started inclusion; not published as article; completely reported; selectively reported. We will use univariate and multivariate Cox regression models to identify trial characteristics associated with non-publication. We will identify seven trial-specific discrepancy items, including the objectives, inclusion and exclusion criteria, end points, sample size, additional analyses, type of population analysis and sponsor acknowledgement. The percentage of trials with discrepancies between the protocol and the publication will be scored. We will investigate the association between trial characteristics and the occurrence of discrepancies. ETHICS AND DISSEMINATION: No IRB-approval is required for this study. Access to confidential research protocols was provided by the Central Committee on Research Involving Human Subjects. We plan to finish data collection in June 2015, and expect to complete data cleaning, analysis and manuscript preparation within the next 3â months. Hence, a first draft of an article containing the results is expected before the end of October 2015.
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Ensayos Clínicos como Asunto/métodos , Preparaciones Farmacéuticas , Proyectos de Investigación , Ensayos Clínicos como Asunto/ética , Estudios de Cohortes , Ética en Investigación , Humanos , Difusión de la Información/ética , Sesgo de Publicación , Edición/éticaRESUMEN
OBJECTIVE: Total hip arthroplasty (THA) and total knee arthroplasty (TKA) are effective procedures for patients with moderate-to-severe osteoarthritis. Mortality rates after THA and TKA may have changed because of new surgical techniques, improvement of peri- and postoperative care, and performance of surgery in older patients having multiple comorbidities. However, data on secular mortality trends are scarce. We undertook this study to evaluate mortality patterns between 1989 and 2007 in patients undergoing elective THA and TKA. METHODS: In a Danish retrospective nationwide cohort study, 71,812 patients who underwent THA and 40,642 patients who underwent TKA were identified between January 1989 and December 2007. All-cause and disease-specific mortality was assessed, stratified by calendar periods. Using Cox proportional hazards models, relative risks (RRs) of mortality were calculated between different calendar periods, adjusted for age, sex, and comorbid diseases. RESULTS: Since the early 1990s, short-term survival following elective THA and TKA has greatly improved. Compared with the period between 1989 and 1991, 60-day mortality rates between 2004 and 2007 were substantially lower for patients undergoing THA (RR 0.40, 95% confidence interval [95% CI] 0.28-0.58) and for patients undergoing TKA (RR 0.37, 95% CI 0.21-0.67). This trend was far superior to what was seen in the general population. The decrease in mortality was greatest for deaths from myocardial infarction, venous thromboembolism, pneumonia, and stroke. Patients tended to have more presurgical comorbidity over time, and the duration of hospital stay was roughly halved. CONCLUSION: Mortality rates following elective THA and TKA have decreased substantially since the early 1990s, despite patients having more presurgical comorbidity. These findings are reassuring for patients undergoing elective THA or TKA.
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Artroplastia de Reemplazo de Cadera , Artroplastia de Reemplazo de Rodilla , Osteoartritis de la Cadera/cirugía , Osteoartritis de la Rodilla/cirugía , Complicaciones Posoperatorias/mortalidad , Anciano , Estudios de Cohortes , Dinamarca/epidemiología , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Infarto del Miocardio/mortalidad , Osteoartritis de la Cadera/epidemiología , Osteoartritis de la Rodilla/epidemiología , Neumonía/mortalidad , Complicaciones Posoperatorias/epidemiología , Estudios Retrospectivos , Accidente Cerebrovascular/mortalidad , Tromboembolia Venosa/mortalidadRESUMEN
BACKGROUND: There are concerns that metal-on-metal hip implants may cause cancer. The objective of this study was to evaluate patterns and timing of risk of cancer in patients with metal-on-metal total hip replacements (THR). METHODS: In a linkage study between the English National Joint Registry (NJR) and the Clinical Practice Research Datalink (CPRD), we selected all THR surgeries (NJR) between 2003 and 2010 (nâ=â11,540). THR patients were stratified by type of bearing surface. Patients were followed up for cancer and Poisson regression was used to derive adjusted relative rates (RR). RESULTS: The risk of cancer was similar in patients with hip resurfacing (RR 0.69; 95% Confidence Interval [CI] 0.39-1.22) or other types of bearing surfaces (RR 0.96; 95% CI 0.64-1.43) compared to individuals with stemmed metal-on-metal THR. The pattern of cancer risk over time did not support a detrimental effect of metal hip implants. There was substantial confounding: patients with metal-on-metal THRs used fewer drugs and had less comorbidity. CONCLUSIONS: Metal-on-metal THRs were not associated with an increased risk of cancer. There were substantial baseline differences between the different hip implants, indicating possibility of confounding in the comparisons between different types of THR implants.
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Artroplastia de Reemplazo de Cadera/estadística & datos numéricos , Registros Electrónicos de Salud/estadística & datos numéricos , Metales Pesados/uso terapéutico , Sistema de Registros , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Artroplastia de Reemplazo de Cadera/efectos adversos , Inglaterra , Femenino , Prótesis de Cadera/efectos adversos , Humanos , Masculino , Persona de Mediana Edad , Neoplasias/etiología , Análisis de Regresión , Estudios Retrospectivos , Riesgo , Sesgo de SelecciónRESUMEN
Regulatory science as a discipline has evolved over the past years with the object to boost and promote scientific rationale behind benefit/risk and decision making by regulatory authorities. The European Medicines Agency, EMA, the Food and Drug Administration, FDA, and the Japanese Pharmaceutical and Medical Devices Agency, PMDA, highlighted in their distinct ways the importance of regulatory science as a basis of good quality assessment in their strategic plans. The Medicines Evaluation Board, MEB, states: 'regulatory science is the science of developing and validating new standards and tools to evaluate and assess the benefit/risk of medicinal products, facilitating sound and transparent regulatory decision making'. Through analysis of regulatory frameworks itself and their effectiveness, however, regulatory science can also advance knowledge of these systems in general. The comprehensive guidance that is issued to complete an application dossier for regulatory product approval has seldomly been scrutinized for its efficiency. Since it is the task of regulatory authorities to protect and promote public health, it is understood that they take a cautious approach in regulating drugs prior to market access. In general, the authorities are among the first to be blamed if dangerous or useless drugs were allowed to the market. Yet, building a regulatory framework that is not challenged continuously in terms of deliverables for public health and cost-effectiveness, might be counterproductive in the end. Regulatory science and research can help understand how and why regulatory decisions are made, and where renewed discussions may be warranted. The MEB supports regulatory science as an R&D activity to fuel primary regulatory processes on product evaluation and vigilance, but also invests in a 'looking into the mirror' approach. Along the line of the drug life-cycle, publicly available data are reviewed and their regulatory impact highlighted. If made explicit, regulatory research can open the door to evidence based regulatory practice and serve the regulator's contribution to innovative drug licensing today.
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Preparaciones Farmacéuticas , Control Social Formal/métodos , Animales , Práctica Clínica Basada en la Evidencia , Agencias Gubernamentales , Humanos , SeguridadRESUMEN
OBJECTIVES: Gastrointestinal (GI) bleeding may impose a serious threat in patients undergoing total hip or knee replacement (THR/TKR). The objectives of this study are to evaluate the timing of GI bleeding following THR/TKR and to determine the effect modification by proton pump inhibitor (PPI) use. METHODS: In a nationwide Danish cohort study, we selected all patients with a primary THR/TKR between 1998 and 2007 (n=95,115). Three control subjects without THR/TKR were matched by age, sex, and region. We calculated disease and medication adjusted (adj.) Hazard ratios (HRs) for GI bleeding with THR/TKR vs. controls. PPI use was assessed in the previous 3 months (in a time-dependent manner). RESULTS: We identified a 6-fold increased risk of GI bleeding during the first 2 weeks following THR (adj. HR, 6.02; 95% confidence interval (CI), 4.06-8.92) and a 2.3-fold increased risk for TKR patients (adj. HR, 2.30; 95% CI, 1.17-4.54), both vs. matched controls. The elevated risk lasted longer in THR patients (12 weeks) as compared with TKR patients (6 weeks). PPI use lowered the HR for GI bleeding by 74% during the first 6 weeks following THR, but not TKR. CONCLUSIONS: This study demonstrated an increased risk of GI bleeding during the first 2 weeks following THR (6-fold) and TKR (2.3-fold), and remained increased for up to 6 (TKR) to 12 weeks (THR) after surgery. PPI use substantially lowered this elevated risk in THR patients, but not in TKR patients.
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Artroplastia de Reemplazo de Cadera , Artroplastia de Reemplazo de Rodilla , Hemorragia Gastrointestinal/prevención & control , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Complicaciones Posoperatorias/prevención & control , Anciano , Estudios de Casos y Controles , Estudios de Cohortes , Dinamarca/epidemiología , Femenino , Hemorragia Gastrointestinal/epidemiología , Humanos , Incidencia , Masculino , Complicaciones Posoperatorias/epidemiología , Modelos de Riesgos Proporcionales , Riesgo , Factores de RiesgoRESUMEN
BACKGROUND AND PURPOSE: Stroke is a potentially fatal complication of total hip replacements (THR). However, timing of stroke in THR patients compared with matched controls and influence of drug use remain unknown. The objective of this study was to determine timing of stroke in patients with THR compared with matched control subjects. METHODS: A nationwide cohort study was conducted within the Danish registers (1998-2007). Included patients were those with a primary THR in the study period (n=66,583) and were matched by age, sex, and region to three referent subjects without THR or total knee replacements. Time-dependent Cox models were used to derive hazard ratios and were adjusted for disease history and drug use. RESULTS: A 4.7-fold increased risk of ischemic stroke (adjusted hazard ratio, 4.69; 95% CI, 3.12-7.06), and a 4.4-fold increased risk of hemorrhagic stroke (adjusted hazard ratio, 4.40; 95% CI, 2.01-9.62) were found within 2 weeks following THR, compared with matched controls. The risk remained elevated during the first 6 postoperative weeks for ischemic stroke, and the first 12 weeks for hemorrhagic stroke. Outpatient antiplatelet drug use lowered the 6-week hazard ratios for ischemic stroke by 70%, although not affecting risk of hemorrhagic stroke. CONCLUSIONS: This study shows, that THR patients have a 4.7-fold increased risk of ischemic stroke, and a 4.4-fold increased risk of hemorrhagic stroke during the first 2 weeks postsurgery. Risk assessment of stroke in individual patients undergoing THR (ie, evaluate other risk factors for stroke) should be considered during the first 6 to 12 weeks.
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Artroplastia de Reemplazo de Cadera/estadística & datos numéricos , Isquemia Encefálica/epidemiología , Hemorragia Cerebral/epidemiología , Complicaciones Posoperatorias/epidemiología , Accidente Cerebrovascular/epidemiología , Anciano , Anciano de 80 o más Años , Anticoagulantes/uso terapéutico , Artroplastia de Reemplazo de Rodilla/estadística & datos numéricos , Isquemia Encefálica/tratamiento farmacológico , Hemorragia Cerebral/tratamiento farmacológico , Estudios de Cohortes , Comorbilidad , Dinamarca/epidemiología , Diuréticos/uso terapéutico , Femenino , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Masculino , Persona de Mediana Edad , Complicaciones Posoperatorias/tratamiento farmacológico , Modelos de Riesgos Proporcionales , Psicotrópicos/uso terapéutico , Sistema de Registros/estadística & datos numéricos , Estudios Retrospectivos , Factores de Riesgo , Accidente Cerebrovascular/tratamiento farmacológico , Factores de TiempoRESUMEN
BACKGROUND: Limited evidence suggests that the risk of acute myocardial infarction (AMI) may be increased shortly after total hip replacement (THR) and total knee replacement (TKR) surgery. However, risk of AMI in these patients has not been compared against matched controls who have not undergone surgery. The objective of this study was to evaluate the timing of AMI in patients undergoing THR or TKR surgery compared with matched controls. METHODS: Retrospective, nationwide cohort study within the Danish national registries. All patients who underwent a primary THR or TKR (n = 95,227) surgery from January 1, 1998, through December 31, 2007, were selected and matched to 3 controls (no THR or TKR) by age, sex, and geographic region. All study participants were followed up for AMI, and disease- and medication history-adjusted hazard ratios (HRs) were calculated. RESULTS: During the first 2 postoperative weeks, the risk of AMI was substantially increased in THR patients compared with controls (adjusted HR, 25.5; 95% CI, 17.1-37.9). The risk remained elevated for 2 to 6 weeks after surgery (adjusted HR, 5.05; 95% CI, 3.58-7.13) and then decreased to baseline levels. For TKR patients, AMI risk was also increased during the first 2 weeks (adjusted HR, 30.9; 95% CI, 11.1-85.5) but did not differ from controls after the first 2 weeks. The absolute 6-week risk of AMI was 0.51% in THR patients and 0.21% in TKR patients. CONCLUSIONS: Risk of AMI is substantially increased in the first 2 weeks after THR (25-fold) and TKR (31-fold) surgery compared with controls. Risk assessment of AMI should be considered during the first 6 weeks after THR surgery and during the first 2 weeks after TKR surgery.
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Artroplastia de Reemplazo de Cadera/efectos adversos , Artroplastia de Reemplazo de Rodilla/efectos adversos , Infarto del Miocardio/etiología , Anciano , Anciano de 80 o más Años , Dinamarca , Femenino , Humanos , Masculino , Persona de Mediana Edad , Sistema de Registros , Estudios Retrospectivos , RiesgoRESUMEN
The majority of knee arthroplasties (KAs) are performed in patients with osteoarthritis (OA). Although bone mass may be increased in these patients, subjects with knee OA may have an increased risk of hip fracture, possibly due to an increased severity of falls. However, in patients with KAs, risk of hip fracture has not been studied extensively. We evaluated the association between KAs and hip fracture risk in a population-based case-control study using the Dutch PHARMO Record Linkage System (1991-2002, n = 33,104). Cases were patients with a first admission for hip fracture; controls were matched by age, gender, and geographic location. Neither group had a previous history of fracture. Time since first KA was calculated. Analyses were adjusted for disease and drug history. A 54% increased hip fracture risk was found in patients who underwent KA (adjusted [adj.] OR = 1.54, 95% CI 1.19-2.00). We found a strong effect modification by age in these patients: the youngest patients (aged 18-70 years) were at more increased risk for hip fracture (adj. OR = 2.76, 95% CI 1.16-6.59), while we could not detect a statistical increase in patients aged >80 years. Furthermore, the association tended to be greater during the first few years after surgery, although it did not reach statistical significance. We found that KAs are associated with a 54% increased risk of hip fracture, in particular among adult patients aged <71 years old. Fracture risk assessment could be considered in patients who are about to undergo a KA.
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Artroplastia de Reemplazo de Rodilla , Fracturas de Cadera/complicaciones , Fracturas de Cadera/epidemiología , Adolescente , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Artroplastia de Reemplazo de Rodilla/efectos adversos , Estudios de Casos y Controles , Femenino , Humanos , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Osteoartritis/complicaciones , Osteoartritis/cirugía , Factores de Riesgo , Adulto JovenRESUMEN
OBJECTIVE: To investigate potential differences in the availability of medicines for chronic and acute conditions in low- and middle-income countries. METHODS: Data on the availability of 30 commonly-surveyed medicines - 15 for acute and 15 for chronic conditions - were obtained from facility-based surveys conducted in 40 developing countries. Results were aggregated by World Bank country income group and World Health Organization region. FINDINGS: The availability of medicines for both acute and chronic conditions was suboptimal across countries, particularly in the public sector. Generic medicines for chronic conditions were significantly less available than generic medicines for acute conditions in both the public sector (36.0% availability versus 53.5%; P = 0.001) and the private sector (54.7% versus 66.2%; P = 0.007). Antiasthmatics, antiepileptics and antidepressants, followed by antihypertensives, were the drivers of the observed differences. An inverse association was found between country income level and the availability gap between groups of medicines, particularly in the public sector. In low- and lower-middle income countries, drugs for acute conditions were 33.9% and 12.9% more available, respectively, in the public sector than medicines for chronic conditions. Differences in availability were smaller in the private sector than in the public sector in all country income groups. CONCLUSION: Current disease patterns do not explain the significant gaps observed in the availability of medicines for chronic and acute conditions. Measures are needed to better respond to the epidemiological transition towards chronic conditions in developing countries alongside current efforts to scale up treatment for communicable diseases.
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Países en Desarrollo , Accesibilidad a los Servicios de Salud/organización & administración , Necesidades y Demandas de Servicios de Salud/organización & administración , Medicamentos bajo Prescripción , Sector Privado , Sector Público , Enfermedad Aguda , Enfermedad Crónica , Recolección de Datos , Interpretación Estadística de Datos , Accesibilidad a los Servicios de Salud/estadística & datos numéricos , Necesidades y Demandas de Servicios de Salud/estadística & datos numéricos , Humanos , Estadística como AsuntoAsunto(s)
Enfermedad Coronaria/mortalidad , Enfermedad Coronaria/prevención & control , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Peptidil-Dipeptidasa A/genética , Polimorfismo Genético/genética , Anciano , Enfermedad Coronaria/genética , Femenino , Estudios de Seguimiento , Genotipo , Humanos , Masculino , Resultado del TratamientoRESUMEN
This study aimed to assess the potential cost-effectiveness of screening men for their angiotensin-converting enzyme (ACE)-genotype before starting statin therapy. We used a combination of decision-analytic and Markov modelling techniques to evaluate the long-term incremental clinical and economic effects associated with genetic testing of men with hypercholesterolemia before starting treatment with statins. The study was performed from a health care payer perspective. We used data from the Rotterdam study, a prospective population-based cohort study in the Netherlands, which was started in 1990 and included 7983 subjects aged 55 years and older. Men treated with cholesterol-lowering drugs at baseline or with a baseline total cholesterol > or = 6.5 mmol/l were included. The ratio of difference in lifelong costs between the screening strategy and the no screening strategy to difference in life expectancy between these strategies was calculated. We also performed a cost-utility analysis. The base case was a 55-year-old man with hypercholesterolemia who was initially untreated. Several univariate sensitivity analyses were performed. All costs were discounted with an annual rate of 5%. Screening men for their ACE-genotype was the dominant strategy for the base case analysis, because the screening strategy saved money (851 Euro), but life expectancy was not changed. Screening was the dominant strategy for all age-groups in our cohort. Even in 80-year-old subjects, with the shortest life-expectancy, it was cheaper to screen than to give lifelong treatment to men with a DD genotype without success. Even if all DD subjects were treated with other (non-statin) cholesterol-lowering drugs, screening remained the cost-effective strategy. The results of the cost-utility analysis were similar. Discounting the effects with 5% per year also had no major impact on the conclusions. If other studies confirm that men with the DD genotype do not benefit from treatment with statins, screening for ACE genotype in men most likely will be a cost-effective strategy before initiating statin therapy.
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Anticolesterolemiantes/uso terapéutico , Economía Farmacéutica , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Hipercolesterolemia/tratamiento farmacológico , Peptidil-Dipeptidasa A/genética , Genotipo , Humanos , Hipercolesterolemia/enzimología , Masculino , Persona de Mediana Edad , Calidad de VidaRESUMEN
BACKGROUND: Several studies have indicated that type 2 diabetes mellitus is more common among schizophrenic patients than in the general population. In this study, we investigated whether the use of antipsychotic drugs in patients with diabetes leads to worsening of glycemic control. METHOD: In this cohort study, patients with newly diagnosed type 2 diabetes were selected from the PHARMO Record Linkage System, which comprises pharmacy records for all 320000 residents of 6 Dutch cities. In total, we identified 2585 patients with incident cases of type 2 diabetes who began treatment with oral hypoglycemic agents between 1991 and 1997 and had a medication history of at least 2 years after diagnosis of diabetes. A change in treatment from oral hypoglycemic agents alone to insulin therapy (with or without continuation of oral hypoglycemic agents) was considered a proxy for deterioration of beta-cell function. We compared the incidence of initiation of insulin therapy between users and nonusers of antipsychotic drugs by performing a Cox proportional hazards model analysis. RESULTS: We found an increased risk for initiation of insulin therapy at 2 years after diagnosis of diabetes in users of antipsychotics compared with nonusers; the relative hazard (hazard ratio) was 2.0 (95% CI = 1.2 to 3.3), which did not change after adjustment for potential confounders. The risk decreased in the years after diagnosis of diabetes. CONCLUSION: It seems that use of antipsychotics by patients with type 2 diabetes mellitus is associated with initiation of insulin therapy (i.e., "secondary failure"), especially in the first 2 years of the disease.
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Antipsicóticos/efectos adversos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Antipsicóticos/farmacocinética , Antipsicóticos/uso terapéutico , Glucemia/efectos de los fármacos , Glucemia/metabolismo , Comorbilidad , Diabetes Mellitus Tipo 2/epidemiología , Femenino , Humanos , Hipoglucemiantes/uso terapéutico , Insulina/metabolismo , Insulina/uso terapéutico , Islotes Pancreáticos/efectos de los fármacos , Islotes Pancreáticos/metabolismo , Masculino , Persona de Mediana Edad , Países Bajos/epidemiología , Modelos de Riesgos Proporcionales , Trastornos Psicóticos/tratamiento farmacológico , Trastornos Psicóticos/epidemiología , Factores de Riesgo , Insuficiencia del TratamientoRESUMEN
OBJECTIVE: Estimates of efficacy of drugs from clinical trials may differ from estimates in observational studies. To obtain valid results, the definition of exposure in an observational study is critical. The objective of our study was to compare different exposure definitions for assessing the effectiveness of statins. STUDY DESIGN AND SETTING: The study was performed in the Rotterdam Study, a population-based cohort study that included 7983 subjects of > or =55 years of age. We selected 3806 subjects who received antihyperlipidemic drug treatment (n=179) or had a total cholesterol > or =6.5 mmol/L at baseline. We conducted analyses with two different exposure definitions. RESULTS: Treatment with statins was assessed at baseline. The adjusted relative risk (RR) of myocardial infarction (MI) and stroke was 0.75 (95% confidence interval [CI] 0.41-1.37) and of total mortality was 1.34 (95% CI 0.66-2.74) in subjects treated with statins. We used pharmacy data, which give insight into drug use on a continuous basis. The adjusted RR of MI and stroke after 2 years of cumulative treatment was 0.63 (95% CI 0.34-1.15) and of total mortality was 0.91 (95% CI 0.59-1.39). CONCLUSION: Our results suggest that use of a time-dependent exposure definition is more accurate because estimates of effectiveness were more in agreement with results from randomized controlled trials of statin treatment.
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Inhibidores de Hidroximetilglutaril-CoA Reductasas/administración & dosificación , Infarto del Miocardio/prevención & control , Accidente Cerebrovascular/prevención & control , Anciano , Esquema de Medicación , Métodos Epidemiológicos , Femenino , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Masculino , Persona de Mediana Edad , Mortalidad , Países Bajos/epidemiología , Resultado del TratamientoRESUMEN
OBJECTIVE: The objective of this study was to determine whether pharmacy records of nitrate prescriptions could be used as a marker of angina pectoris. METHOD: This study was conducted within the Rotterdam Study, a prospective follow-up study which started in 1991 and included 7983 elderly subjects. During follow-up, 1601 subjects filled a first prescription for a nitrate and later filled at least one other prescription for nitrates according to pharmacy records. After excluding subjects who started using nitrates in 1991 and who had less than one year of medication history, we took a random sample of 78 subjects (10%). We studied discharge and outpatient cardiologist letters and files from general practitioners for additional information on angina pectoris in these subjects, and allocated patients to one of three categories according to the possibility of the initial diagnosis of angina being correct. RESULTS: From the random sample of 78, additional information was available on 75 subjects. Definite angina pectoris was present in 33, probable angina pectoris in 18, and possible angina pectoris in 19 subjects. Five subjects had no angina pectoris. Therefore, 93% had at least a possible diagnosis while 68% had at least a probable diagnosis of angina pectoris. The positive predictive value of 2 nitrate prescriptions of which at least one was for rescue therapy was 94%. CONCLUSIONS: We conclude that the use of more than one nitrate prescription can be used as a marker for angina pectoris. This marker may be useful in epidemiological studies.
Asunto(s)
Angina de Pecho/tratamiento farmacológico , Registros Médicos/estadística & datos numéricos , Nitratos/uso terapéutico , Farmacia/estadística & datos numéricos , Vasodilatadores/uso terapéutico , Anciano , Angina de Pecho/epidemiología , Prescripciones de Medicamentos/estadística & datos numéricos , Utilización de Medicamentos/tendencias , Estudios de Seguimiento , Predicción , Humanos , Persona de Mediana Edad , Estudios ProspectivosRESUMEN
Discontinuation and poor adherence to therapy are major problems during long-term treatment, particularly with cholesterol lowering drugs. Several studies have indicated that the cholesterol lowering effect of statins differs according to apolipoprotein (apo)E genotypes. Low-density lipoprotein-cholesterol lowering capacity appears to be smaller in subjects with the epsilon(4) allele. To assess whether the use of statins in daily practice differs according to apoE genotypes, we used data from the Rotterdam Study, a population-based prospective cohort study in the Netherlands, which started in 1990 and included 7983 subjects aged 55 years or more. During follow-up, there were 798 subjects who started to use statins. We used a Cox proportional hazard model to determine the rate of discontinuation in the first 3 years of statin use. Subjects on statin therapy with epsilon(2)epsilon(2) and epsilon(4)epsilon(4) genotypes showed a trend towards higher dosages than subjects with the other genotypes. Relative to subjects with the epsilon(2)epsilon(3) genotype, those with the epsilon(4)epsilon(4) genotype had a risk of 2.28 [95% confidence interval (CI) 1.02-5.12] to discontinue statins within 3 years. In women, this relative risk was 1.70 (CI 0.53-5.42) versus 3.18 (CI 1.01-10.03) in men. The apoE genotype is associated with discontinuation of statins. This suggests that subjects who are genetically prone to develop hypercholesterolemia show the highest risk of discontinuation of treatment.
Asunto(s)
Apolipoproteínas E/genética , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Estudios de Cohortes , Relación Dosis-Respuesta a Droga , Femenino , Genotipo , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/administración & dosificación , Lípidos/sangre , Masculino , Persona de Mediana Edad , Países Bajos , Cooperación del Paciente , Mapeo RestrictivoRESUMEN
Coronary artery disease is among the leading causes of death worldwide. Clinical trials show a protective effect of statins against the sequelae of coronary artery disease. The mean risk reductions for subjects using statins compared with placebo found in these trials is about 30%. These are average reductions for all patients included in the trials. Important factors in interpreting the variability in the outcome of drug therapy include the patient's health profile, prognosis, disease severity, quality of drug prescribing, compliance with prescribed pharmacotherapy and the genetic profile of the patient. This review aims to give an overview of the known polymorphisms (Cholesteryl Ester Transfer Protein polymorphism, Stromelysin-1 polymorphism, -455G/A and TaqI polymorphisms of the beta-fibrinogen gene, apoE4, Asp(9)Asn mutation in the lipoprotein lipase gene, the -514 CT polymorphism in the hepatic lipase gene and the ACE deletion type gene) that have an influence on the effects of statins in the general population. The expectation is that in the future a subject's genotype may determine whether he will be treated with statins or not. Determining the genotype will not deny therapy to a subject, but will help in deciding the therapy that will suit the patient best.