Risk of connective tissue disease, morphoea and systemic vasculitis in patients with hidradenitis suppurativa.

BACKGROUND: Hidradenitis suppurativa (HS) has been associated with auto-inflammatory conditions, yet the risk of developing connective tissue disease (CTD), morphoea and systemic vasculitis has not been well-characterized. OBJECTIVES: We sought to evaluate the risk of developing CTD, morphoea and systemic vasculitis in patients with HS. METHODS: Using claims data, we identified patients with HS and used 2 : 1 risk-set sampling to identify patients without HS. Patients with existing CTD were excluded. Patient follow-up lasted until first occurrence of the following events: the occurrence of outcome (i.e. systemic lupus erythematosus, morphoea, systemic sclerosis, Sjogren's Syndrome and systemic vasculitis), death, disenrolment or end of data stream. Hazard ratios (HR) of developing CTD, morphoea and systemic vasculitis were computed after 1 : 1 propensity score (PS) matching. RESULTS: After 2 : 1 risk-set sampling, we identified 78 122 HS patients and 156 247 non-HS comparators. The mean follow-up was 540 days. After PS matching, HS patients had an increased risk of systemic lupus erythematosus HR = 1.63 (1.31-2.03) and morphoea HR = 2.02 (1.32-3.11), compared to non-HS patients. We did not observe an increased risk for systemic sclerosis HR = 0.90 (0.59-1.44), Sjogren's Syndrome HR = 0.91 (0.73-1.14) or systemic vasculitis HR = 0.87 (0.64-1.20). CONCLUSION: In this population-based study, we observed an increased risk of developing systemic lupus erythematous and morphoea subsequent to a first-recorded diagnosis of hidradenitis suppurativa.

Patients' perception about risks and benefits of antithrombotic treatment for the prevention of venous thromboembolism (VTE) after orthopedic surgery: a qualitative study.

BACKGROUND: The 9th edition of the American College of Chest Physicians' Antithrombotic Therapy and Prevention of Thrombosis guidelines emphasize the importance of considering the risk-benefit ratio of "patient-important" outcomes. However, little is known about patients' perception and understanding regarding the different outcomes of antithrombotic treatment after orthopedic surgery, and the factors that influence their decision to use these treatments. Using a series of semi-structured interviews, we explored patients' understanding and perception concerning the benefits and risks of antithrombotic treatment for the prevention of venous thromboembolism (VTE) after joint replacement surgery. METHODS: A series of semi-structured interviews were conducted with patients who had undergone knee or hip replacement surgery at a tertiary care hospital (Brigham and Women's Hospital, Boston, MA) in 2014. Discussions were recorded and transcribed. Two investigators independently coded and analyzed the data to identify important themes and concepts using the constant comparative method. RESULTS: Of 64 patients who were invited, 12 patients (19 %) completed the interviews. The majority of patients (92 %) were aware of the benefits of antithrombotic therapy for reducing the risk of blood clots, while less than half of them had a clear understanding of deep vein thrombosis and pulmonary embolism. While all patients were aware of risk of minor bleeding, only 6 patients (50 %) considered the risk of major bleeding as a possible side effect of antithrombotic treatment. Overall, patients perceived bleeding as a less important outcome than a thrombotic event. The lack of awareness about the risk of major bleeding, the assumption that a short-term exposure would not meaningfully affect bleeding risk, and the assumption that bleeding is a controllable event influenced their perception. Most patients (83 %) stated that their decision to use antithrombotic medications was mainly based on the trust in their physician's expertise. CONCLUSIONS: Patients perceived thrombotic events as more important outcomes than bleeding events. Patients' understanding of thrombotic and bleeding events varies and may play a key role in their preferences. The majority of patients stated that trust in their physician's expertise had a large influence on their decision to use antithrombotic medications.

Comparative mortality risks of antipsychotic medications in community-dwelling older adults.

BACKGROUND: All antipsychotic medications carry warnings of increased mortality for older adults, but little is known about comparative mortality risks between individual agents. AIMS: To estimate the comparative mortality risks of commonly prescribed antipsychotic agents in older people living in the community. METHOD: A retrospective, claims-based cohort study was conducted of people over 65 years old living in the community who had been newly prescribed risperidone, olanzapine, quetiapine, haloperidol, aripiprazole or ziprasidone (n = 136 393). Propensity score-adjusted Cox proportional hazards models assessed the 180-day mortality risk of each antipsychotic compared with risperidone. RESULTS: Risperidone, olanzapine and haloperidol showed a dose-response relation in mortality risk. After controlling for propensity score and dose, mortality risk was found to be increased for haloperidol (hazard ratio (HR) = 1.18, 95% CI 1.06-1.33) and decreased for quetiapine (HR = 0.81, 95% CI 0.73-0.89) and olanzapine (HR = 0.82, 95% CI 0.74-0.90). CONCLUSIONS: Significant variation in mortality risk across commonly prescribed antipsychotics suggests that antipsychotic selection and dosing may affect survival of older people living in the community.

Defining the epidemiology of bisphosphonate-associated osteonecrosis of the jaw: prior work and current challenges.

UNLABELLED: Bisphosphonate-related osteonecrosis of the jaw (BONJ) is an adverse effect of bisphosphonate use with a poorly described epidemiology in osteoporosis patients. We examined the literature and two new cohorts for BONJ. The literature suggests an incidence rate of 0.028 % to 4.3 %. Our cohort studies found an incidence of 0.02 % (95 % CI 0.004 %-0.11 %). INTRODUCTION: We examined the epidemiology of BONJ associated with osteoporosis dosing of bisphosphonates. METHODS: First, we systematically searched the literature about osteoporosis BONJ. Identified studies were abstracted by two authors. Second, we attempted to estimate the relative risk of BONJ among bisphosphonate users with osteoporosis. Two different large insurance databases, one from 2005-2007 and another from 2007-2010, combined with medical record review, were searched. The older dataset did not include the International Classification of Diagnoses (ICD) diagnosis code for osteonecrosis of the jaw (ONJ; ICD 733.45). Incidence rates and relative risks were estimated using Cox regression. RESULTS: The literature review produced nine studies of varying quality. The incidence rates for BONJ among osteoporosis patients varied from 0.028 % to 4.3 %. Two prior studies estimated the relative risk of ONJ related to bisphosphonates and found odds ratios of 7.2 and 9.2. Our attempts to estimate the incidence rate of BONJ encompassed 41,957 in the dataset from 2005-2007 and 466,645 in a separate dataset from 2007-2010. From the older dataset, we found 51 potential cases of BONJ using a broad definition of possible ONJ. One case was confirmed by a dentist for a prevalence of 0.02 % (95 % CI 0.004 %-0.11 %) among bisphosphonate users. From the newer dataset, we found 13 possible cases, but none could be confirmed. Most subjects with the ONJ diagnosis code appeared to have had an osteoporosis-related fracture and not ONJ. CONCLUSIONS: The literature suggests a broad range of possible values for the prevalence of BONJ; our estimate fell within the range from prior literature.

High-dimensional versus conventional propensity scores in a comparative effectiveness study of coxibs and reduced upper gastrointestinal complications.

PURPOSE: High-dimensional propensity score (hd-PS) adjustment has been proposed as a tool to improve control for confounding in pharmacoepidemiological studies using longitudinal claims databases. We investigated whether hd-PS matching improved confounding by indication in a study of Cox-2 inhibitors (coxibs) and traditional nonsteroidal anti-inflammatory drugs (tNSAIDs) and their association with the risk of upper gastrointestinal complications (UGIC). METHODS: In a cohort study of new users of coxibs and tNSAIDs we compared the effectiveness of these drugs to reduce UGIC using hd-PS matching and conventional propensity score (PS) matching in the German Pharmacoepidemiological Research Database. RESULTS: The unadjusted rate ratio (RR) of UGIC for coxib users versus tNSAID users was 1.21 [95 % confidence interval (CI) 0.91-1.61]. The conventional PS matched cohort based on 79 investigator-identified covariates resulted in a RR of 0.84 (0.56-1.26). The use of the hd-PS algorithm based on 900 empirical covariates further decreased the RR to 0.62 (0.43-0.91). CONCLUSIONS: A comparison of hd-PS matching versus conventional PS matching resulted in improved point estimates for studying an intended treatment effect of coxibs versus tNSAIDs when benchmarked against results from randomized controlled trials.

The relation between bisphosphonate use and non-union of fractures of the humerus in older adults.

SUMMARY: While nitrogen-containing bisphosphonates have been shown to reduce fracture risk in postmenopausal women and men, their safety in the period after a fracture is unclear. In fully adjusted multivariable regression models, bisphosphonate use in the post-fracture period was associated with an increased probability of non-union [odds ratio (OR) 2.37, 95% confidence interval (CI) 1.13-4.96]. Clinicians might consider waiting for several months before introduction of a bisphosphonate after a fracture. INTRODUCTION: While nitrogen-containing bisphosphonates have been shown to reduce fracture risk in postmenopausal women and men, their safety in the period after a fracture is unclear. We examined the risk of non-union associated with post-fracture bisphosphonate use among a group of older adults who had experienced a humerus fracture. METHODS: We conducted a nested case-control study among subjects who had experienced a humerus fracture. From this cohort, cases of non-union were defined as those with an orthopedic procedure related to non-union 91-365 days after the initial humerus fracture. Bisphosphonate exposure was assessed during the 365 days prior to the non-union among cases or the matched date for controls. Multivariable logistic regression models were examined to calculate the OR and 95% CI for the association of post-fracture bisphosphonate use with non-union. RESULTS: From the cohort of 19,731 patients with humerus fractures, 81 (0.4%) experienced a non-union. Among the 81 cases, 13 (16.0%) were exposed to bisphosphonates post-fracture, while 69 of the 810 controls (8.5%) were exposed in the post-fracture interval. In fully adjusted multivariable regression models, bisphosphonate use in the post-fracture period was associated with an increased odds of non-union (OR 2.37, 95% CI 1.13-4.96). Albeit limited by small sample sizes, the increased risk associated with bisphosphonate use persisted in the subgroup of patients without a history of osteoporosis or prior fractures (OR 1.91, 95% CI 0.75-4.83). CONCLUSIONS: In this study of older adults, non-union after a humerus fracture was rare. Bisphosphonate use after the fracture was associated with an approximate doubling of the risk of non-union.

Developments in post-marketing comparative effectiveness research.

Physicians and insurers need to weigh the effectiveness of new drugs against existing therapeutics in routine care to make decisions about treatment and formularies. Because Food and Drug Administration (FDA) approval of most new drugs requires demonstrating efficacy and safety against placebo, there is limited interest by manufacturers in conducting such head-to-head trials. Comparative effectiveness research seeks to provide head-to-head comparisons of treatment outcomes in routine care. Health-care utilization databases record drug use and selected health outcomes for large populations in a timely way and reflect routine care, and therefore may be the preferred data source for comparative effectiveness research. Confounding caused by selective prescribing based on indication, severity, and prognosis threatens the validity of non-randomized database studies that often have limited details on clinical information. Several recent developments may bring the field closer to acceptable validity, including approaches that exploit the concepts of proxy variables using high-dimensional propensity scores, within-patient variation of drug exposure using crossover designs, and between-provider variation in prescribing preference using instrumental variable (IV) analyses.

Improving therapeutic effectiveness and safety through big healthcare data.

Big healthcare data-electronically recorded longitudinal data generated during the provision and administration of healthcare for millions of patients-have become essential for understanding the effectiveness and safety of therapeutics. They are most effectively used in concert with experimental and laboratory research throughout the life cycle of a drug. Applications range from providing phenotype and health outcomes information in genome-wide association studies to postmarketing studies that assure prescribers of the safety of approved drugs (Figure ). [Figure: see text].

Considerations for the analysis of longitudinal electronic health records linked to claims data to study the effectiveness and safety of drugs.

Health insurance claims and electronic health records (EHR) databases have been considered the preferred data sources with which to study drug safety and effectiveness in routine care. Linking claims data to EHR allows researchers to leverage the complementary advantages of each data source to enhance study validity. We propose a framework to evaluate the need for supplementing claims data with EHR and vice versa to optimize outcome ascertainment, exposure assessment, and confounding adjustment.

Successful Comparison of US Food and Drug Administration Sentinel Analysis Tools to Traditional Approaches in Quantifying a Known Drug-Adverse Event Association.

The US Food and Drug Administration's Sentinel system has developed the capability to conduct active safety surveillance of marketed medical products in a large network of electronic healthcare databases. We assessed the extent to which the newly developed, semiautomated Sentinel Propensity Score Matching (PSM) tool could produce the same results as a customized protocol-driven assessment, which found an adjusted hazard ratio (HR) of 3.04 (95% confidence interval [CI], 2.81-3.27) comparing angioedema in patients initiating angiotensin-converting enzyme (ACE) inhibitors vs. beta-blockers. Using data from 13 Data Partners between 1 January 2008, and 30 September 2013, the PSM tool identified 2,211,215 eligible ACE inhibitor and 1,673,682 eligible beta-blocker initiators. The tool produced an HR of 3.14 (95% CI, 2.86-3.44). This comparison provides initial evidence that Sentinel analytic tools can produce findings similar to those produced by a highly customized protocol-driven assessment.

"Threshold-crossing": A Useful Way to Establish the Counterfactual in Clinical Trials?

A central question in the assessment of benefit/harm of new treatments is: how does the average outcome on the new treatment (the factual) compare to the average outcome had patients received no treatment or a different treatment known to be effective (the counterfactual)? Randomized controlled trials (RCTs) are the standard for comparing the factual with the counterfactual. Recent developments necessitate and enable a new way of determining the counterfactual for some new medicines. For select situations, we propose a new framework for evidence generation, which we call "threshold-crossing." This framework leverages the wealth of information that is becoming available from completed RCTs and from real world data sources. Relying on formalized procedures, information gleaned from these data is used to estimate the counterfactual, enabling efficacy assessment of new drugs. We propose future (research) activities to enable "threshold-crossing" for carefully selected products and indications in which RCTs are not feasible.

Real World Data in Adaptive Biomedical Innovation: A Framework for Generating Evidence Fit for Decision-Making.

Analyses of healthcare databases (claims, electronic health records [EHRs]) are useful supplements to clinical trials for generating evidence on the effectiveness, harm, use, and value of medical products in routine care. A constant stream of data from the routine operation of modern healthcare systems, which can be analyzed in rapid cycles, enables incremental evidence development to support accelerated and appropriate access to innovative medicines. Evidentiary needs by regulators, Health Technology Assessment, payers, clinicians, and patients after marketing authorization comprise (1) monitoring of medication performance in routine care, including the materialized effectiveness, harm, and value; (2) identifying new patient strata with added value or unacceptable harms; and (3) monitoring targeted utilization. Adaptive biomedical innovation (ABI) with rapid cycle database analytics is successfully enabled if evidence is meaningful, valid, expedited, and transparent. These principles will bring rigor and credibility to current efforts to increase research efficiency while upholding evidentiary standards required for effective decision-making in healthcare.

From adaptive licensing to adaptive pathways: delivering a flexible life-span approach to bring new drugs to patients.

The concept of adaptive licensing (AL) has met with considerable interest. Yet some remain skeptical about its feasibility. Others argue that the focus and name of AL should be broadened. Against this background of ongoing debate, we examine the environmental changes that will likely make adaptive pathways the preferred approach in the future. The key drivers include: growing patient demand for timely access to promising therapies, emerging science leading to fragmentation of treatment populations, rising payer influence on product accessibility, and pressure on pharma/investors to ensure sustainability of drug development. We also discuss a number of environmental changes that will enable an adaptive paradigm. A life-span approach to bringing innovation to patients is expected to help address the perceived access vs. evidence trade-off, help de-risk drug development, and lead to better outcomes for patients.

Ocular sequelae in premature infants.

OBJECTIVE: The authors report on the incidence of myopia and strabismus at 12 and 24 months postterm in a cohort of 190 premature infants with birth weights of less than 1251 g born in 1986 and 1987. METHODS: The neonatal and follow-up eye charts of a cohort of 190 premature infants were retrospectively reviewed. All 138 children who survived the neonatal period had at least one eye examination between day 28 and 42 of life that documented the presence and staging of retinopathy of prematurity (ROP) according to the International Classification of ROP. No infants received cryotherapy. Eye examinations conducted at 12 and 24 months postterm included assessment of vision, fundus, ocular motility, anterior segment abnormality, and refractive error. Eyes were refracted using cycloplegic retinoscopy. Strabismus was detected using the Hirschberg and cover tests. Eye reports were available for 80% (n = 110) at 12 months and 36% (n = 50) at 24 months. RESULTS: Fifty-three percent of the cohort exhibited ROP in the neonatal period; 12% of these progressed to stage 3 or 4 ROP. Myopia was observed in 16% (18/110) of the cohort at 12 months of age; 4.5% (5/110) measured more than 4.0 diopters of myopia. Children with birth weights of less than 751 g were 3.2 times more likely than those with birth weights between 751 and 1000 g and 10 times more likely than those with birth weights between 1001 and 1250 g to develop myopia in the first year of life. The likelihood of myopia at 12 months doubled with each increment in ROP stage. Of the 50 children reexamined at 24 months postterm, more than 80% demonstrated deteriorating vision. The incidence of myopia increased to 38% (19/50) overall, with 24% (12/50) of the cohort showing severe myopia. Astigmatism and anisometropia were highly correlated with severe myopia. Strabismus was seen with increasing frequency through the second year of life. All children with grade III or IV intraventricular hemorrhage in the neonatal period developed esotropia. CONCLUSION: This study emphasizes the significant roles of low birth weight, ROP, and intraventricular hemorrhage in the development of myopia and strabismus. Follow-up to 2 years of life is recommended given the demonstrated deterioration in our cohort.

Defects of the respiratory chain in oxyphil and chief cells of the normal parathyroid and in hyperfunction.

Immunohistochemical detection of complex HIII (ubiquinone- cytochrome-c-oxidoreductase) and complex IV (cytochrome-c-oxidase) of the respiratory chain was performed in parathyroids of 164 humans with normal renal function (group I) and in 55 patients with chronic renal insufficiency (group II) obtained at autopsy. In group I, 33 of the 164 cases showed defects of the respiratory chain (20%). Eighty-five percent of the defects occurred in advanced age (> 50 years). In group II, 39 of 55 cases (70%) had defects, and about 70% of the defects occurred after age 50. In both groups, more than 80% of the defects were localized in oxyphil cell nodules. However, not every oxyphil nodule was involved. In group I, selective defects of complex IV predominated and were found in 47 of 86 defects (55%). Combined defects of complexes III and IV were present in 25 of 86 defects (29%). In contrast, in group II combined defects predominated and were found in 45% (107 of 240 defects), whereas single defects of complex IV existed in 38% (93 of 240 defects). The frequency of selective defects of complex III was about 16% to 17% in both groups. In situ hybridization and PCR studies for the detection of the common deletion (4.977 base pairs) and of various point mutations of mitochondrial of (m)DNA revealed no consistent molecular genetic abnormalities. A point mutation in the tRNALeu(UUR) at nucleotide (nt) 3.260 was found in only one probe. The results show that defects of the respiratory chain occur already in normal parathyroids, most probably during cell aging, especially in oxyphil cells and at a higher rate in hyperfunction. The high predominance of respiratory chain defects in oxyphil cells and their random distribution favors mutations of mtDNA as a possible cause of oxyphilic cell transformation and of the respiratory chain defects. However, the mutations of mtDNA in the parathyroids are apparently different from those in other ageing tissues.

Anorexigens and pulmonary hypertension in the United States: results from the surveillance of North American pulmonary hypertension.

BACKGROUND: The use of appetite suppressants in Europe has been associated with the development of primary pulmonary hypertension (PPH). Recently, fenfluramine appetite suppressants became widely used in the United States but were withdrawn in September 1997 because of concerns over adverse effects. MATERIALS AND METHODS: We conducted a prospective surveillance study on patients diagnosed with pulmonary hypertension at 12 large referral centers in North America. Data collected on patients seen from September 1, 1996, to December 31, 1997, included the cause of the pulmonary hypertension and its severity. Patients with no identifiable cause of pulmonary hypertension were classed as PPH. A history of drug exposure also was taken with special attention on the use of antidepressants, anorexigens, and amphetamines. RESULTS: Five hundred seventy-nine patients were studied, 205 with PPH and 374 with pulmonary hypertension from other causes (secondary pulmonary hypertension [SPH]). The use of anorexigens was common in both groups. However, of the medications surveyed, only the fenfluramines had a significant preferential association with PPH as compared with SPH (adjusted odds ratio for use > 6 months, 7.5; 95% confidence interval, 1.7 to 32.4). The association was stronger with longer duration of use when compared to shorter duration of use and was more pronounced in recent users than in remote users. An unexpectedly high (11.4%) number of patients with SPH had used anorexigens. CONCLUSION: The magnitude of the association with PPH, the increase of association with increasing duration of use, and the specificity for fenfluramines are consistent with previous studies indicating that fenfluramines are causally related to PPH. The high prevalence of anorexigen use in patients with SPH also raises the possibility that these drugs precipitate pulmonary hypertension in patients with underlying conditions associated with SPH.

Use of comorbidity scores for control of confounding in studies using administrative databases.

BACKGROUND: Comorbidity scores are increasingly used to reduce potential confounding in epidemiological research. Our objective was to compare metrical and practical properties of published comorbidity scores for use in epidemiological research with administrative databases. METHODS: The literature was searched for studies of the validity of comorbidity scores as predictors of mortality and health service use, as measured by change in the area under the receiver operating characteristic (ROC) curve for dichotomous outcomes, and change in R(2) for continuous outcomes. RESULTS: Six scores were identified, including four versions of the Charlson Index (CI) which use either the three-digit International Classification of Diseases, Ninth Revision (ICD-9) or the full ICD-9-CM (clinical modification) code, and two versions of the Chronic Disease Score (CDS) which used outpatient pharmacy records. Depending on the population and exposure under study, predictive validities varied between c = 0.64 and c = 0.77 for in-hospital or 30-day mortality. This is only a slight improvement over age adjustment. In one study the simple measure 'number of diagnoses' outperformed the CI (c = 0.73 versus c = 0.65). Proprietary scores like Ambulatory Diagnosis Groups and Patient Management Categories do not necessarily perform better in predicting mortality. Comorbidity indices are susceptible to a variety of coding errors. CONCLUSIONS: Comorbidity scores, particularly the CDS or D'Hoore's CI based on three-digit ICD-9 codes, may be useful in exploratory data analysis. However, residual confounding by comorbidity is inevitable, given how these scores are derived. How much residual confounding usually remains is something that future studies of comorbidity scores should examine. In any given study, better control for confounding can be achieved by deriving study-specific weights, to aggregate comorbidities into groups with similar relative risks of the outcomes of interest.

The relative validity of vitamin intakes derived from a food frequency questionnaire compared to 24-hour recalls and biological measurements: results from the EPIC pilot study in Germany. European Prospective Investigation into Cancer and Nutrition.

BACKGROUND: For the European Prospective Investigation into Cancer and Nutrition (EPIC) study Germany, a self-administered food frequency questionnaire (FFQ) was developed and tested for its relative validity and reproducibility in 1991/1992. Study participants were 92 potential cohort members. This paper reports results regarding retinol, carotenoids, tocopherols and ascorbic acid. METHODS: Study participants were invited to the study centre in Heidelberg once a month over one year. At each visit, a 24 hour recall was obtained. The FFQ was filled in twice with a 6-month interval (FFQ1, FFQ2). In addition, a questionnaire on general consumption frequencies of 14 broad food groups was completed. This information was combined with estimates derived from FFQ2 and frequency-corrected food and nutrient intakes were calculated (FFQcorr). Blood specimens were taken in winter and summer 1992. RESULTS: The intraclass correlation of the FFQ ranged from 0.65 to 0.67 for retinol, tocopherols, carotenoids, and ascorbic acid. Intake of carotenoids by FFQcorr showed de-attenuated Pearson correlation coefficients with blood values in the order of 0.37, and with recall data of 0.44. Respective correlations for retinol were 0.21 and 0.29, for tocopherols 0.18 and 0.52, and for ascorbic acid 0.36 and 0.69. Errors of FFQcorr and 24-hour diet recalls were not correlated. CONCLUSIONS: In general, it was demonstrated that the FFQ was able to rank participants into biologically meaningful categories of intake or blood concentrations for carotenoids and ascorbic acid, but misclassification was higher for tocopherol and retinol.

Frequency and predictors of drug therapy interruptions after hospital discharge under physician drug budgets in Germany.

OBJECTIVE: We sought to study how frequently prescription drug therapy at hospital discharge was discontinued or changed by general practitioners under physician drug budgets in Germany and explore reasons and predictors for such discontinuations. METHODS: This cohort study was part of a larger project on clinical outcomes of acute hospital care in patients with 5 groups of medical diagnoses, including conditions of the heart, lung and brain, gastroduodenal ulcer disease and diabetes. Patients entered the study cohort at hospital admission and were followed throughout their stay until they had their first encounter with a primary care physician responsible for follow-up treatment after hospital discharge. Nurse practitioners and physicians assessed patient characteristics at admission and discharge. A 1-page questionnaire on continuity of care, including drug therapy, was provided to primary care physicians at the first patient encounter. The primary study endpoint was discontinuation of drug therapy by the primary care physician. Data were analyzed by multivariate logistic regression. RESULTS: A total of 3,267 patients in 22 primary care hospitals were eligible for the study. Standardized questionnaires on continuation of drug therapy were returned by 890 patients (27%); 846 patients (95%) used prescription drugs at discharge. Of those, drug therapy was interrupted in 122 (14%). Reasons for discontinuations included excessive costs of drugs in 66 patients (54%), excessive number of drugs prescribed (32, 26%) and differences in judgment on the clinical appropriateness of a drug (23, 19%). In a multivariate logistic regression, gastroduodenal ulcer disease was a significant predictor for discontinuation (OR = 3.1; 95% CI 1.5 - 6.5). Discontinuation tended to be more likely in older patients (69 - 76 years vs. < or = 58: OR = 2.0; 1.0 - 3.9) but slightly less likely in male patients (OR = 0.7; 0.4 - 1.1). CONCLUSION: Discontinuation of drug therapy after hospital discharge is common. The high costs of prescription drugs were the most common reason. Elderly patients seem to be particularly affected.

What is Germany's experience on reference based drug pricing and the etiology of adverse health outcomes or substitution?

Germany is frequently cited as an example of reference based pricing (RBP) in ongoing controversial discussions on the effect of RBP. There are thorough analyses of phase I and II RBP on Germany's drug market. However, any conclusions on the overall economic and public health impact of RBP, solely on the basis of aggregated data, must be suspect to substantial bias, since too many factors in a rapidly changing health care system remained uncontrolled. Parallel to the introduction of phase II RBP in 1992/1993, the second health care reform became active. The two major confounding factors were the introduction of fixed drug budgets and the many changes due to the unification of Germany that took place in the beginning of the 1990s. Published and unpublished aggregated data do not allow any conclusions on the etiology of adverse health events due to this change in drug reimbursement policy. Conclusions drawn from the German experience will be based on assumptions or speculations that are hard to prove. A health care system that identifies enough evidence and need to introduce RBP as a measure of cost control should make every effort to evaluate the effects in order to increase program compliance or, if indicated, make adaptations to the RBP policy. The introduction of RBP in British Columbia in 1995-1997 and its computerized administrative health databases covering a large proportion of the population should give rise to a thorough analysis of this policy.