Matthew W. Reynolds

A comparison of renal-related adverse drug reactions between rofecoxib and celecoxib, based on the World Health Organization/Uppsala Monitoring Centre safety database

BACKGROUND Two isoforms of cyclooxygenase (COX) have been identified, both of them inhibited by traditional nonsteroidal anti-inflammatory drugs (NSAIDs). Inhibition of COX-2 has been associated with the therapeutic effects of NSAIDs, whereas inhibition of COX-1 is believed to be the cause of the adverse gastrointestinal effects associated with NSAID therapy. When administered at therapeutic doses, new COX-2-specific inhibitors inhibit only the COX-2 isoform. OBJECTIVE This study sought to compare renal safety signals between the COX-2-specific inhibitors rofecoxib and celecoxib, based on spontaneous reports of adverse drug reactions (ADRs) in the World Health Organization/Uppsala Monitoring Centre (WHO/UMC) safety database through the end of the second quarter 2000. METHODS Disproportionality in the association between a particular drug and renal-related ADR was evaluated using a bayesian confidence propagation neural network method in which a statistical parameter, the information component (IC) value, was calculated for each drug-ADR combination. In this method, an IC value significantly greater than 0 implies that the association of a drug-ADR pair is stronger than background; the higher the IC value, the more the combination stands out from the background. The ratio of actual to expected numbers of ADRs was also used to assess disproportionality. RESULTS As with traditional NSAIDs, both COX-2-specific inhibitors were associated with renal-related ADRs. However, the adverse renal impact of rofecoxib was significantly greater than that of celecoxib. IC values were significantly different for the following comparisons: water retention (1.97 rofecoxib vs 1.18 celecoxib; P < 0.01); abnormal renal function (2.38 vs 0.70; P < 0.01); renal failure (2.22 vs 1.09; P < 0.01); cardiac failure (2.39 vs 0.48; P < 0.01); and hypertension (2.15 vs 1.33; P < 0.01). In an additional analysis, celecoxib was shown to have a similar renal safety profile to that of diclofenac and ibuprofen. CONCLUSIONS Based on spontaneous ADR reports in the WHO/UMC safety database at the end of the second quarter 2000, this analysis indicates that rofecoxib has significantly greater renal toxicity than celecoxib or traditional NSAIDs. This negative renal impact may have the potential to increase the risk for serious cardiac and/or cerebrovascular events.

A comparison of the safety and effectiveness of dabigatran and warfarin in non-valvular atrial fibrillation patients in a large healthcare system

Dabigatran is approved for stroke risk reduction in patients with nonvalvular atrial fibrillation (NVAF). Data from diverse clinical practice settings will help establish whether the risk:benefit ratio seen in clinical trials is comparable with routine clinical care. This study aimed to compare the safety and effectiveness of dabigatran and warfarin in clinical practice. We undertook a propensity score-matched (PSM) cohort study (N=12,793 per group; mean age 74) comparing treatment with dabigatran or warfarin in the US Department of Defense claims database, October 2009 to July 2013. Treatment-naïve patients with first prescription claim for dabigatran (either FDA-approved dose) or warfarin between October 2010 and July 2012 (index) and a diagnosis of NVAF during the 12 months before index date were included. Primary outcomes were stroke and major bleeding. Secondary outcomes included ischaemic and haemorrhagic stroke, major gastrointestinal (GI), urogenital or other bleeding, myocardial infarction (MI) and death. Time-to-event was investigated using Kaplan-Meier survival analyses. Outcomes comparisons were made utilising Cox-proportional hazards models of PSM groups. Dabigatran users experienced fewer strokes (adjusted hazard ratio [95 % confidence intervals] 0.73 [0.55-0.97]), major intracranial (0.49 [0.30-0.79]), urogenital (0.36 [0.18-0.74]) and other (0.38 [0.22-0.66]) bleeding, MI (0.65 [0.45-0.95]) and deaths (0.64 [0.55-0.74]) than the warfarin group. Major bleeding (0.87 [0.74-1.03]) and major GI bleeding (1.13 [0.94-1.37]) was similar between groups and major lower GI bleeding events were more frequent (1.30 [1.04-1.62]) with dabigatran. In conclusion, compared with warfarin, dabigatran treatment was associated with a lower risk of stroke and most outcomes measured, but increased incidence of major lower GI bleeding.

Quality of life and economic costs associated with postthrombotic syndrome.

PURPOSE Published evidence on quality-of-life (QOL) outcomes and health care costs in patients with postthrombotic syndrome (PTS), a common and difficult-to-diagnose complication of venous thromboembolism (VTE), is reviewed. SUMMARY Occurring in as many as 70% of patients with VTE, PTS remains a challenging and costly disorder, partly due to the lack of a standard diagnostic definition and varying classification systems. Searches of Medline and EMBASE identified 12 articles on humanistic and economic outcomes associated with PTS. The results of U.S. and international studies indicate that PTS is a key determinant of long-term QOL among patients with VTE. In one large study, 37% of patients with VTE developed PTS within two years of a diagnosis of deep venous thrombosis (DVT), and 4% developed severe PTS, with the occurrence of PTS linked to clinically relevant declines in measures of physical and mental health. Research indicates that the economic burden of PTS in the United States may be as high as

Clinical epidemiology and treatment patterns of patients with multicentric Castleman disease: results from two US treatment centres

200 million annually. Recent progress in efforts to develop standard PTS terminology may facilitate the dissemination of clear consensus guidelines to assist in timely PTS detection and optimal care. CONCLUSION Appropriate measures to decrease PTS-related burdens may include the prevention of DVT, clear diagnostic criteria for PTS, and an education campaign aimed at increased standardization in the management of DVT. Gaps in the current understanding of the risk factors, diagnostic criteria, preventive strategies, and even treatment modalities for PTS hamper the ability of clinicians to employ measures that could reduce the occurrence of this disorder and the associated morbidity.

A safety review of topical bovine thrombin-induced generation of antibodies to bovine proteins

Multicentric Castleman disease (MCD) is a rare lymphoproliferative disease with little known about its epidemiology or treatment modalities. Clinical and demographic data of MCD patients identified between 2000 and 2009 were collected from medical records at two United States (US) MCD referral centres. ZIP codes identified patient residences; prevalence and incidence were estimated based on catchment areas. Patient clinical, demographic, and biochemical characteristics, drug therapies and medical utilization were descriptively reported. MCD patients (n = 59) were 61% male, mean age of 53 years (median = 55 years) and 68% Caucasian. Of those with known human immunodeficiency virus (HIV) status (n = 41), 85% (n = 35) were negative, 15% (n = 6) were positive. Most frequent physician‐reported symptoms (n = 33) were fatigue (49%, n = 16), fever (39%, n = 13), and night sweats (30%, n = 10). The estimated US 10‐year prevalence was 2·4 per million. During first year of follow‐up after study entry, the top two systemic therapies (n = 27) were monotherapies: prednisone (33%, n = 9) and rituximab (19%, n = 5). After a follow‐up of 2 years, 92% of patients were alive. This study provides new information on MCD population demographics, treatment patterns, and medical utilization; a minimal US period prevalence rate is proposed. Study replication is needed to improve external validity.

A systematic review of validated methods for identifying anaphylaxis, including anaphylactic shock and angioneurotic edema, using administrative and claims data

BACKGROUND Topical bovine thrombin has been used to accelerate attainment of hemostasis in the surgical setting for >60 years, and its immunogenicity has been widely reported. Although the development of antibodies is inherent in the introduction of any non-self-therapeutic protein such as bovine-sourced thrombin, there are questions about the relationship between the presence of antibodies to constituents of the therapeutic protein preparation and the occurrence of clinically relevant adverse events (AEs). OBJECTIVE This review examines the proposed mechanisms for the immunogenicity of topical bovine thrombin preparations and summarizes available evidence from randomized clinical trials, observational studies, and case reports to explore possible relationships between the reported immunogenicity of topical bovine thrombin and the occurrence of AEs. METHODS A search of MEDLINE (1966-August 2008) for studies published in English was conducted using the Medical Subject Heading terms surgery, antibodies, and hemorrhage, as well as equivalent key words for bovine, adverse events, and thrombin. For inclusion in the review, studies had to report clinical or laboratory safety data for patients exposed to topical bovine thrombin during surgery. RESULTS The evidence suggests that patients with repeated perioperative exposure to topical bovine thrombin have a 3- to 10-fold greater risk for development of antibodies to topical bovine thrombin than do patients with no history of surgery-related exposure to this agent. Early case reports associated the development of anti-bovine protein antibodies with bleeding and/or thrombotic complications. However, in one prospective, randomized controlled trial comparing topical bovine thrombin with topical recombinant human thrombin, 99.5% of patients in each treatment arm developed postoperative AEs. In an-other, 54% and 55% of patients in the respective treatment arms developed postoperative AEs. In a prospective, randomized controlled trial that compared topical bovine thrombin and plasma-derived human thrombin, 95.5% of patients in each treatment arm developed postoperative AEs. CONCLUSIONS Repeated perioperative exposure to topical bovine thrombin may increase both the prevalence and titers of antibodies to >or=1 protein contained in nonhomogeneous topical bovine thrombin preparations. However, the evidence reviewed does not support a definitive association between preoperative or postoperative generation of anti-bovine protein antibodies and an increased risk of AEs in surgical patients treated with topical bovine thrombin.

Topical bovine thrombin: a 21‐year review of topical bovine thrombin spontaneous case safety reports submitted to FDA's Adverse Event Reporting System

The Food and Drug Administrations Mini‐Sentinel pilot program initially aims to conduct active surveillance to refine safety signals that emerge for marketed medical products. A key facet of this surveillance is to develop and understand the validity of algorithms for identifying health outcomes of interest from administrative and claims data. This article summarizes the process and findings of the algorithm review of anaphylaxis.

A systematic review of validated methods for identifying erythema multiforme major/minor/not otherwise specified, Stevens–Johnson Syndrome, or toxic epidermal necrolysis using administrative and claims data

To review topical bovine thrombin spontaneous adverse event (AE) reports that were forwarded to the US Food and Drug Administrations (FDA) Adverse Event Reporting System (AERS) between January 1986 and December 2006.

Over-the-counter ibuprofen and risk of gastrointestinal bleeding complications: a systematic literature review

The Food and Drug Administrations (FDA) Mini‐Sentinel pilot program aims to conduct active surveillance to refine safety signals that emerge for marketed medical products. A key facet of this surveillance is to develop and understand the validity of algorithms for identifying health outcomes of interest (HOIs) from administrative and claims data. This paper summarizes the process and findings of the algorithm review of erythema multiforme and related conditions.

A systematic review of validated methods for identifying pulmonary fibrosis and interstitial lung disease using administrative and claims data.

Abstract Background: Exposure to over-the-counter (OTC) ibuprofen and other OTC non-steroidal anti-inflammatory drugs (NSAIDs) is substantial. Although the literature on gastrointestinal (GI) safety of NSAID therapy is extensive, the risk profiles of OTC and prescription dosing are seldom separated, and few studies provide risks specific to OTC ibuprofen. Objective: To conduct a literature review to evaluate the risk of GI bleeding events related to OTC ibuprofen use. Methods: Published clinical trials, observational studies, and meta-analyses of OTC ibuprofen use, defined as up to 1200 mg/day or stated as ‘over the counter,’ reporting endpoints of incidence rates and proportions of GI bleeding events (e.g., GI bleeding-related hospitalizations and deaths) were identified via MEDLINE through 2010. Data from these studies were summarized. Results: Twenty studies (nine observational, ten clinical trials, one meta-analysis) reporting incidence rates and proportions of a GI bleeding-related event associated with OTC or OTC-specific doses of ibuprofen were included. The frequency of a GI-related hospitalization was <0.2% for patients on OTC-comparable doses. Incidence rates among those using OTC-comparable doses ranged from 0 to 3.19 per 1000 patient-years. The incidence of a GI bleeding-related event increased with age and the use of concomitant medications, and there was a general, though not always statistically significant, ibuprofen dose–response relationship. The relative risk of any GI bleeding-related event ranged from 1.1 to 2.4 for users of OTC-specific doses of ibuprofen compared to non-users. Conclusions: Studies reported low incidence of GI bleeding events with use of OTC ibuprofen. Few published studies that specifically investigated OTC ibuprofen use were identified. Varying methodologies and definitions of exposure and outcomes prevented direct comparison of many results. Only studies that used the methods herein described were identified. Further research evaluating the risk of GI bleeding events in patients taking OTC-specific ibuprofen use may be useful.