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.

"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.

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.

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.

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].

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.

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.

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.

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.

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.

Drugs that inhibit gastric acid secretion may alter the course of inflammatory bowel disease.

BACKGROUND: Recent data suggest that acid suppressive medications may alter factors central to the pathophysiology of inflammatory bowel diseases (IBD), whether through shifts in the intestinal microbiome due to acid suppression or effects on immune function. AIM: To assess the relationship between the use of proton pump inhibitors (PPIs) or histamine2-receptor antagonists (H2Ra) and incidence of 'flares' (hospitalisation/surgery and change in medication). METHODS: We conducted a new user cohort study including individuals diagnosed with IBD in British Columbia using linked healthcare utilisation databases (available from July 1996 through April 2006). Propensity-score matched incidence rates during a 6-month follow-up period and rate ratios (RR) and 95% CI were calculated. RESULTS: Among 16 151 IBD patients, 1307 Crohn's disease (CD) and 996 ulcerative colitis (UC) patients experienced a new use of PPIs, whereas 741 CD and 738 UC used H2Ra. All IBD subgroups were matched separately to an equal number of unexposed IBD patients. H2Ra use in CD doubled the risk of hospitalisation/surgery (RR = 1.94; 95%CI 1.24-3.10) and numerically less so in UC patients (RR = 1.11) with widely overlapping CIs (0.61-2.03). Proton pump inhibitors use was associated with medication change in UC (RR = 1.39; 95%CI 1.20-1.62), but without meaningfully, increased risk of hospitalisation/surgery for UC or CD patients. Extending follow-up showed persistence, but attenuation, of all effects. CONCLUSIONS: Initiation of PPIs or H2Ra may be associated with short-term changes in the course of IBD. Although confounding by indication was adjusted using propensity score matching, residual confounding may persist and findings need to be interpreted cautiously.

Active safety monitoring of newly marketed medications in a distributed data network: application of a semi-automated monitoring system.

We developed a semi-automated active monitoring system that uses sequential matched-cohort analyses to assess drug safety across a distributed network of longitudinal electronic health-care data. In a retrospective analysis, we show that the system would have identified cerivastatin-induced rhabdomyolysis. In this study, we evaluated whether the system would generate alerts for three drug-outcome pairs: rosuvastatin and rhabdomyolysis (known null association), rosuvastatin and diabetes mellitus, and telithromycin and hepatotoxicity (two examples for which alerting would be questionable). Over >5 years of monitoring, rate differences (RDs) in comparisons of rosuvastatin with atorvastatin were -0.1 cases of rhabdomyolysis per 1,000 person-years (95% confidence interval (CI): -0.4, 0.1) and -2.2 diabetes cases per 1,000 person-years (95% CI: -6.0, 1.6). The RD for hepatotoxicity comparing telithromycin with azithromycin was 0.3 cases per 1,000 person-years (95% CI: -0.5, 1.0). In a setting in which false positivity is a major concern, the system did not generate alerts for the three drug-outcome pairs.

Differential risk of death in older residents in nursing homes prescribed specific antipsychotic drugs: population based cohort study.

OBJECTIVE: To assess risks of mortality associated with use of individual antipsychotic drugs in elderly residents in nursing homes. DESIGN: Population based cohort study with linked data from Medicaid, Medicare, the Minimum Data Set, the National Death Index, and a national assessment of nursing home quality. SETTING: Nursing homes in the United States. PARTICIPANTS: 75,445 new users of antipsychotic drugs (haloperidol, aripiprazole, olanzapine, quetiapine, risperidone, ziprasidone). All participants were aged ≥ 65, were eligible for Medicaid, and lived in a nursing home in 2001-5. MAIN OUTCOME MEASURES: Cox proportional hazards models were used to compare 180 day risks of all cause and cause specific mortality by individual drug, with propensity score adjustment to control for potential confounders. RESULTS: Compared with risperidone, users of haloperidol had an increased risk of mortality (hazard ratio 2.07, 95% confidence interval 1.89 to 2.26) and users of quetiapine a decreased risk (0.81, 0.75 to 0.88). The effects were strongest shortly after the start of treatment, remained after adjustment for dose, and were seen for all causes of death examined. No clinically meaningful differences were observed for the other drugs. There was no evidence that the effect measure modification in those with dementia or behavioural disturbances. There was a dose-response relation for all drugs except quetiapine. CONCLUSIONS: Though these findings cannot prove causality, and we cannot rule out the possibility of residual confounding, they provide more evidence of the risk of using these drugs in older patients, reinforcing the concept that they should not be used in the absence of clear need. The data suggest that the risk of mortality with these drugs is generally increased with higher doses and seems to be highest for haloperidol and least for quetiapine.

Assessing the comparative effectiveness of newly marketed medications: methodological challenges and implications for drug development.

Comparative-effectiveness research (CER) aims to produce actionable evidence regarding the effectiveness and safety of medical products and interventions as they are used outside of controlled research settings. Although CER evidence regarding medications is particularly needed shortly after market approval, key methodological challenges include (i) potential bias due to channeling of patients to the newly marketed medication because of various patient-, physician-, and system-related factors; (ii) rapid changes in the characteristics of the user population during the early phase of marketing; and (iii) lack of timely data and the often small number of users in the first few months of marketing. We propose a mix of approaches to generate comparative-effectiveness data in the early marketing period, including sequential cohort monitoring with secondary health-care data and propensity score (PS) balancing, as well as extended follow-up of phase III and phase IV trials, indirect comparisons of placebo-controlled trials, and modeling and simulation of virtual trials.

Refilling and switching of antiepileptic drugs and seizure-related events.

We sought to estimate the risk of seizure-related events associated with refilling prescriptions for antiepileptic drugs (AEDs) and to estimate the effect of switching between brand-name and generic drugs or between two generic versions of the same drug. We conducted a case-crossover study using health-care databases from British Columbia, Canada, among AED users who had an emergency room visit or hospitalization for seizure (index seizure-related event), defined using International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9) codes 345.xx (epilepsy and recurrent seizures) and 780.3x (convulsions), between 1997 and 2005. AED prescription refilling itself was associated with 2.3-fold elevated odds of seizure-related events when the refill occurred within 21 days before the index event (odds ratio (OR) 2.31; 95% confidence interval (CI) 1.56-3.44). The OR was 2.75 (95% CI 0.88-8.64) for refills that involved switching, yielding a refill-adjusted OR for switching of 1.19 (95% CI 0.35-3.99). Refilling the same AED prescription was associated with an elevated risk of seizure-related events whether or not the refill involved switching from a brand-name to a generic product.

Infliximab and other immunomodulating drugs in patients with inflammatory bowel disease and the risk of serious bacterial infections.

BACKGROUND: There remain concerns about the safety of infliximab therapy in patients with inflammatory bowel disease (IBD). AIM: To assess the association between the initiation of infliximab and other immunomodulating drugs and the risk of serious bacterial infection in the treatment of IBD. METHODS: We assembled a cohort study of patients with IBD, including Crohn's disease (CD) and ulcerative colitis (UC). All patients initiating an immunomodulating drug between January 2001 and April 2006 were identified in British Columbia from linked health care utilization databases. Exposure of interest was initiation of infliximab or corticosteroids compared with initiation of other immunosuppressive agents, including azathioprine, mercaptopurine (MP) and methotrexate (MTX). Outcome of interest was serious bacterial infections requiring hospitalization, including Clostridium difficile. RESULTS: Among 10 662 IBD patients, the incidence rate of bacteriaemia ranged from 3.8 per 1000 person-years (95% confidence interval 2.1-6.2) for other immunosuppressive agents to 7.4 (3.3-19.3) for infliximab with slightly higher rate for serious bacterial infections resulting in an adjusted relative risk 1.4 (0.47-4.24). Clostridium difficile infections occurred in 0/1000 (0-5.4) among 521 infliximab initiations and 14/1000 (10.6-18.2) for corticosteroids. Corticosteroid initiation tripled the risk of C. difficile infections (RR = 3.4; 1.9-6.1) compared with other immunosuppressant agents. This corticosteroid effect was neither dose-dependent nor duration-dependent. Bacteriaemia and other serious bacterial infections were not increased by corticosteroids or infliximab (5 events). CONCLUSIONS: In a population-based cohort of patients with IBD, we found no meaningful association between infliximab and serious bacterial infections, although some subgroups had few events. Corticosteroid initiation increased the risk for C. difficile infections in these patients.