The role of Real-World Data and evidence in oncology medicines approved in EU in 2018-2019.

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.

Use of Opioids Increases With Age in Older Adults: An Observational Study (2005-2017).

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.

Added therapeutic value of new drugs approved in Brazil from 2004 to 2016.

This study aimed to assess the level of therapeutic innovation of new drugs approved in Brazil over 13 years and whether they met public health needs. Comparative descriptive analysis of therapeutic value assessments performed by the Brazilian Chamber of Drug Market Regulation (CMED) and the French drug bulletin Prescrire for new drugs licensed in Brazil, from January 1st 2004 to December 31st 2016. The extent to which new drugs met public health needs was examined by: checking inclusions into government-funded drug lists and/or clinical guidelines; comparing Anatomical Therapeutic Chemical Classification (ATC) codes and drug indications with the list of conditions contributing the most to the national disease burden; and assessing new medicines aimed to treat neglected diseases. 253 new drugs were approved. Antineoplastics, immunossupressants, antidiabetics and antivirals were the most frequent. Thirty-three (14%) out of 236 drugs assessed by the Brazilian chamber and sixteen (8.2%) out of 195 assessed by the French bulletin Prescrire were considered innovative. Thirty-six drugs (14.2%) were selected for coverage by the Brazilian Unified National Health System (SUS), seven of which were therapeutically innovative, and none were aimed to treat neglected disease. About 1/3 of the drugs approved aimed to treat conditions among the top contributors to Brazil's disease burden. Few therapeutically innovative drugs entered the Brazilian market, from which only a small proportion was approved to be covered by the SUS. Our findings suggest a divergence between public health needs, research & development (R&D) and drug licensing procedures.

Dose-Finding Studies Among Orphan Drugs Approved in the EU: A Retrospective Analysis.

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.

Added therapeutic value of new drugs approved in Brazil from 2004 to 2016 / Valor terapêutico acrescentado de novos medicamentos aprovados no Brasil de 2004 a 2016 / Valor terapéutico añadido de los nuevos medicamentos aprobados en Brasil desde 2004 a 2016

Abstract: This study aimed to assess the level of therapeutic innovation of new drugs approved in Brazil over 13 years and whether they met public health needs. Comparative descriptive analysis of therapeutic value assessments performed by the Brazilian Chamber of Drug Market Regulation (CMED) and the French drug bulletin Prescrire for new drugs licensed in Brazil, from January 1st 2004 to December 31st 2016. The extent to which new drugs met public health needs was examined by: checking inclusions into government-funded drug lists and/or clinical guidelines; comparing Anatomical Therapeutic Chemical Classification (ATC) codes and drug indications with the list of conditions contributing the most to the national disease burden; and assessing new medicines aimed to treat neglected diseases. 253 new drugs were approved. Antineoplastics, immunossupressants, antidiabetics and antivirals were the most frequent. Thirty-three (14%) out of 236 drugs assessed by the Brazilian chamber and sixteen (8.2%) out of 195 assessed by the French bulletin Prescrire were considered innovative. Thirty-six drugs (14.2%) were selected for coverage by the Brazilian Unified National Health System (SUS), seven of which were therapeutically innovative, and none were aimed to treat neglected disease. About 1/3 of the drugs approved aimed to treat conditions among the top contributors to Brazil's disease burden. Few therapeutically innovative drugs entered the Brazilian market, from which only a small proportion was approved to be covered by the SUS. Our findings suggest a divergence between public health needs, research & development (R&D) and drug licensing procedures.

Resumo: O objetivo foi avaliar o nível de inovação terapêutica de novos medicamentos aprovados no Brasil ao longo de 13 anos e se eles atendem a necessidades de saúde pública. Foi feita uma análise comparativa descritiva da avaliação de valor terapêutico realizada pela Câmara de Regulação do Mercado de Medicamentos (CMED) e pelo boletim de medicamentos francês Prescrire para novos medicamentos licenciados no Brasil entre 1º de janeiro de 2004 e 31 de dezembro de 2016. Examinamos em que medida os novos medicamentos atendem a necessidade de saúde pública por meio de: checagem da inclusão em listas de medicamentos financiados pelo governo e/ou diretrizes clínicas; comparação de códigos da Classificação Anatômica Terapêutica Química (ATC, em inglês) e indicações de medicamentos com a lista de condições que mais contribuem para a carga de doença nacional; e avaliação de se os novos medicamentos tinham por objetivo tratar doenças negligenciadas. Foram aprovados 253 novos medicamentos. Antineoplásicos, imunossupressores, antidiabéticos e antivirais foram os mais frequentes. Trinta e três (14%) dos 236 medicamentos avaliados pela Câmara brasileira e 16 (8,2%) dos 195 avaliados pelo boletim francês Prescrire foram considerados inovadores. Trinta e seis medicamentos (14,2%) foram selecionados para cobertura no Sistema Único de Saúde (SUS), sete dos quais eram inovadores do ponto de vista terapêutico e nenhum dos quais tinha por objetivo tratar uma doença negligenciada. Em torno de 1/3 dos medicamentos aprovados tinha por objetivo o tratamento de doenças que figuram entre as principais contribuidoras da carga de doença no Brasil. Poucos medicamentos inovadores do ponto de vista terapêutico entraram no mercado brasileiro, dos quais apenas uma pequena proporção foi aprovada para ser coberta pelo SUS. Nossos resultados sugerem uma divergência entre necessidades de saúde pública, pesquisa e desenvolvimento (P&D) e procedimentos de licenciamento de medicamentos.

Resumen: El objetivo fue evaluar el nivel de innovación terapéutica de los nuevos medicamentos aprobados en Brasil durante 13 años y si cumplen con las necesidades sanitarias. Llevamos a cabo un análisis comparativo descriptivo acerca del valor terapéutico presente en las evaluaciones realizadas por la Cámara de Regulación del Mercado de Medicamentos (CMED) y la revista francesa Prescrire sobre los nuevos medicamentos autorizados en Brasil, desde el 1º de enero 2004 hasta el 31de diciembre de 2016. Su alcance, es decir, hasta qué punto los nuevos medicamentos cumplían con las necesidades de salud pública se comprobaron revisando las inclusiones en listas de medicamentos subvencionados por el gobierno y/o directrices clínicas; comparando los códigos de la Classificación Anatómicos Terapéuticos Químicos (ATC por sus siglas en inglés) y las indicaciones de los medicamentos respecto a la lista de enfermedades que contribuían a la mayor carga de morbilidad nacional; y asesorando si los nuevos medicamentos tenían como objetivo tratar enfermedades desatendidas. Se aprobaron 253 nuevos medicamentos. Los antineoplásicos, inmunosupresores, antidiabéticos y antivirales fueron los más frecuentes. Treinta y tres (14%), aparte de los 236 medicamentos evaluados por la Cámara Brasileña, y 16 (8,2%), aparte de los 195 evaluados por la revista francesa Prescrire, se consideraron innovadores. Treinta y seis medicamentos (14,2%) se seleccionaron para que tuvieran cobertura por el Sistema Único de Salud (SUS), siete de ellos eran terapéuticamente innovadores, y ninguno tenía como meta tratar enfermedades desatendidas. Alrededor de 1/3 de las medicinas aprobadas tenían como meta tratar problemas de salud entre las enfermedades con mayor carga de morbilidad en Brasil. Pocos medicamentos terapéuticamente innovadores accedieron al mercado brasileño y de éstos sólo una pequeña parte fueron aprobados para que fueran cubiertos por el SUS. Nuestros resultados sugieren una divergencia entre las necesidades públicas de salud, investigación & desarrollo (I&D) y los procedimientos para la autorización de medicamentos.

The impact of quality-of-life data in relative effectiveness assessments of new anti-cancer drugs in European countries.

PURPOSE: The aim of this study is to investigate the role of health-related quality-of-life (QoL) data in relative effectiveness assessments (REAs) of new anti-cancer drugs across European jurisdictions, during health technology assessment procedures. METHODS: Comparative analysis of guidelines and publicly available REAs in six European jurisdictions of anti-cancer drugs approved by EMA between 2011 and 2013. RESULTS: Fourteen anti-cancer drugs were included, adding up to 79 REAs. Whilst all guidelines state that QoL is a relevant endpoint to determine the relative effectiveness of new cancer drugs, QoL data were included in only 54% of the 79 reports and their impact on the recommendations was limited. CONCLUSIONS: Whilst national guidelines recognize the relevance of QoL to determine the relative effectiveness of new anti-cancer drugs, this is not well-reflected in current assessments. Developing and implementing into REAs specific evidence requirements for QoL data would improve the use of this patient-centred outcome in future reimbursement and pricing decisions.

Statins and Risk of Lower Limb Revision Surgery: The Influence of Differences in Study Design Using Electronic Health Records From the United Kingdom and Denmark.

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.

Can a Joint Assessment Provide Relevant Information for National/Local Relative Effectiveness Assessments? An In-Depth Comparison of Pazopanib Assessments.

BACKGROUND: In many European jurisdictions, relative effectiveness assessments (REAs) of pharmaceuticals are performed during the reimbursement decision-making process. International collaboration in the production of these assessments may prevent the duplication of information in various jurisdictions. A first pilot of a joint REA (pazopanib for the treatment of renal cell carcinoma) was published in 2011. OBJECTIVE: The objective was to investigate how well the methods used in the joint REA match the methods used in the national/local assessments on the same topic. METHODS: National/local assessments from European jurisdictions, available in English language, were identified through a literature search and an e-mail request to health technology assessment organizations. Data were abstracted from joint and national/local assessments using a structured data abstraction form. Results were compared for differences and similarities. RESULTS: In total, five national/local reports were included (Belgium, England/Wales, France, The Netherlands, and Scotland). The general methods (indication, main comparator, main end points, main trial) were similar. The details of the assessment (e.g., exact wording of indication, additional comparators, additional trials included, and method of indirect comparison), however, varied. Despite these differences, the joint REA included nearly all comparators, end points, trials, and methods of analysis that were used in national/local REA reports. CONCLUSIONS: This study has shown overlap in the methods national/local REA bodies in Europe have chosen for a pazopanib REA for renal cell carcinoma, except for the use and methods of indirect comparisons. Although some additional comparators and outcomes differed between national/local REAs, they can be captured in a comprehensive joint REA.

Occurrence and determinants of selective reporting of clinical drug trials: design of an inception cohort study.

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 3 months. Hence, a first draft of an article containing the results is expected before the end of October 2015.

Changes in mortality patterns following total hip or knee arthroplasty over the past two decades: a nationwide cohort study.

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.

From molecule to market access: drug regulatory science as an upcoming discipline.

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.

Patterns of risk of cancer in patients with metal-on-metal hip replacements versus other bearing surface types: a record linkage study between a prospective joint registry and general practice electronic health records in England.

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 (n = 11,540). 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.

Risk of gastrointestinal bleeding in patients undergoing total hip or knee replacement compared with matched controls: a nationwide cohort study.

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.

Timing of stroke in patients undergoing total hip replacement and matched controls: a nationwide cohort study.

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.

Timing of acute myocardial infarction in patients undergoing total hip or knee replacement: a nationwide cohort study.

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.

Knee arthroplasty and risk of hip fracture: a population-based, case-control study.

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.

Differences in the availability of medicines for chronic and acute conditions in the public and private sectors of developing countries.

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.

Use of organic nitrates and the risk of hip fracture: a population-based case-control study.

CONTEXT: Use of organic nitrates has been associated with increased bone mineral density. Moreover, a large Danish case-control study reported a decreased fracture risk. However, the association with duration of nitrate use, dose frequency, and impact of discontinuation has not been extensively studied. OBJECTIVE: Our objective was to evaluate the association between organic nitrates and hip fracture risk. METHODS: A case-control study was conducted using the Dutch PHARMO Record Linkage System (1991-2002, n = 6,763 hip fracture cases and 26,341 controls). Cases had their first admission for hip fracture, whereas controls had not sustained any fracture after enrollment. Current users of organic nitrates were patients who had received a prescription within 90 d before the index date. The analyses were adjusted for disease and drug history. RESULTS: Current use of nitrates was not associated with a decreased risk of hip fracture [adjusted odds ratio (OR) = 0.93; 95% confidence interval (CI) = 0.83-1.04]. Those who used as-needed medication only had a lower risk of hip fracture (adjusted OR = 0.83; 95% CI = 0.63-1.08) compared with users of maintenance medication only (adjusted OR = 1.17; 95% CI = 0.97-1.40). No association was found between duration of nitrate use and fracture risk. CONCLUSIONS: Our overall analyses showed that risk of a hip fracture was significantly lower among users of as-needed organic nitrates, when compared with users of maintenance medication. Our analyses of hip fracture risks with duration of use did not further support a beneficial effect of organic nitrates on hip fracture, although residual confounding may have masked beneficial effects.