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Background: Pharmacovigilance data-mining algorithms (DMAs) are known to generate significant numbers of false-positive signals of disproportionate reporting (SDRs), using various standards to define the terms 'true positive' and 'false positive'.Objective: To construct a highly inclusive reference event database of reported adverse events for a limited set of drugs, and to utilize that database to evaluate three DMAs for their overall yield of scientifically supported adverse drug effects, with an emphasis on ascertaining false-positive rates as defined by matching to the database, and to assess the overlap among SDRs detected by various DMAs.Methods: A sample of 35 drugs approved by the US FDA between 2000 and 2004 was selected, including three drugs added to cover therapeutic categories not included in the original sample. We compiled a reference event database of adverse event information for these drugs from historical and current US prescribing information, from peer-reviewed literature covering 1999 through March 2006, from regulatory actions announced by the FDA and from adverse event listings in the British National Formulary. Every adverse event mentioned in these sources was entered into the database, even those with minimal evidence for causality. To provide some selectivity regarding causality, each entry was assigned a level of evidence based on the source of the information, using rules developed by the authors. Using the FDA adverse event reporting system data for 2002 through 2005, SDRs were identified for each drug using three DMAs: an urn-model based algorithm, the Gamma Poisson Shrinker (GPS) and proportional reporting ratio (PRR), using previously published signalling thresholds. The absolute number and fraction of SDRs matching the reference event database at each level of evidence was determined for each report source and the data-mining method. Overlap of the SDR lists among the various methods and report sources was tabulated as well.Results: The GPS algorithm had the lowest overall yield of SDRs (763), with the highest fraction of events matching the reference event database (89 SDRs, 11.7%), excluding events described in the prescribing information at the time of drug approval. The urn model yielded more SDRs (1562), with a non-significantly lower fraction matching (175 SDRs, 11.2%). PRR detected still more SDRs (3616), but with a lower fraction matching (296 SDRs, 8.2%). In terms of overlap of SDRs among algorithms, PRR uniquely detected the highest number of SDRs (2231, with 144, or 6.5%, matching), followed by the urn model (212, with 26, or 12.3%, matching) and then GPS (0 SDRs uniquely detected).Conclusions: The three DMAs studied offer significantly different tradeoffs between the number of SDRs detected and the degree to which those SDRs are supported by external evidence. Those differences may reflect choices of detection thresholds as well as features of the algorithms themselves. For all three algorithms, there is a substantial fraction of SDRs for which no external supporting evidence can be found, even when a highly inclusive search for such evidence is conducted. [ABSTRACT FROM AUTHOR]

The Jarvik 2000 bridge to transplant investigational device exemption study was a multicentered, prospective study of 150 UNOS status I patients implanted with the Jarvik 2000 between 2005 and 2012. During the study period, there were numerous modifications of the system that included converting from pin to cone bearings. Results were analyzed for three cohorts: total (n = 150), pin (n = 128), and cone (n = 22). Baseline demographics included age (52 ± 13), gender (79% male), size (BSA 1.98), and etiology (37% idiopathic dilated cardiomyopathy; 43% Ischemic). Seventy percent of patients were either INTERMACS 1 or 2. The primary endpoint-defined as successful transplantation or listing at 180 days (prespecified at 65%; 95% lower CI: 57%)-was successfully achieved for the total cohort (67.3%; 95% CI: 59.5%-74.3%; p = 0.006). In subgroup analysis of the more contemporary, cone-bearing group, the primary endpoint was met in 91% (95% CI: 72%-97.5%; p = 0.001). Compared with pin patients, cone-bearing patients had less hemolysis as well as decreased end-organ dysfunction. Functional and quality of life scores improved after implantation independent type of bearing. In conclusion, despite a particularly sick patient population, the Jarvik 2000 was shown to be effective in supporting the advanced HF patient., (Copyright © ASAIO 2022.)

Importance: Current guidelines recommend ticagrelor as the preferred P2Y12 platelet inhibitor for patients with acute coronary syndrome (ACS), primarily based on a single large randomized clinical trial. The benefits and risks associated with ticagrelor vs clopidogrel in routine practice merits attention., Objective: To determine the association of ticagrelor vs clopidogrel with ischemic and hemorrhagic events in patients undergoing percutaneous coronary intervention (PCI) for ACS in clinical practice., Design, Setting, and Participants: A retrospective cohort study of patients with ACS who underwent PCI and received ticagrelor or clopidogrel was conducted using 2 United States electronic health record-based databases and 1 nationwide South Korean database from November 2011 to March 2019. Patients were matched using a large-scale propensity score algorithm, and the date of final follow-up was March 2019., Exposures: Ticagrelor vs clopidogrel., Main Outcomes and Measures: The primary end point was net adverse clinical events (NACE) at 12 months, composed of ischemic events (recurrent myocardial infarction, revascularization, or ischemic stroke) and hemorrhagic events (hemorrhagic stroke or gastrointestinal bleeding). Secondary outcomes included NACE or mortality, all-cause mortality, ischemic events, hemorrhagic events, individual components of the primary outcome, and dyspnea at 12 months. The database-level hazard ratios (HRs) were pooled to calculate summary HRs by random-effects meta-analysis., Results: After propensity score matching among 31 290 propensity-matched pairs (median age group, 60-64 years; 29.3% women), 95.5% of patients took aspirin together with ticagrelor or clopidogrel. The 1-year risk of NACE was not significantly different between ticagrelor and clopidogrel (15.1% [3484/23 116 person-years] vs 14.6% [3290/22 587 person-years]; summary HR, 1.05 [95% CI, 1.00-1.10]; P = .06). There was also no significant difference in the risk of all-cause mortality (2.0% for ticagrelor vs 2.1% for clopidogrel; summary HR, 0.97 [95% CI, 0.81-1.16]; P = .74) or ischemic events (13.5% for ticagrelor vs 13.4% for clopidogrel; summary HR, 1.03 [95% CI, 0.98-1.08]; P = .32). The risks of hemorrhagic events (2.1% for ticagrelor vs 1.6% for clopidogrel; summary HR, 1.35 [95% CI, 1.13-1.61]; P = .001) and dyspnea (27.3% for ticagrelor vs 22.6% for clopidogrel; summary HR, 1.21 [95% CI, 1.17-1.26]; P < .001) were significantly higher in the ticagrelor group., Conclusions and Relevance: Among patients with ACS who underwent PCI in routine clinical practice, ticagrelor, compared with clopidogrel, was not associated with significant difference in the risk of NACE at 12 months. Because the possibility of unmeasured confounders cannot be excluded, further research is needed to determine whether ticagrelor is more effective than clopidogrel in this setting.

Background: The use of mechanism of injury as a predictor of injury outcome presents practical challenges because this variable may be missing or inaccurate in many databases. The purpose of this study was to determine the importance of mechanism of injury as a predictor of mortality among injured children., Methods: The records of children (<15-y-old) sustaining a blunt injury were obtained from the National Trauma Data Bank. Models predicting injury mortality were developed using mechanism of injury and injury coding using either abbreviated injury scale post-dot values (low-dimensional injury coding) or injury International Classification of Diseases, Ninth Revision codes and their two-way interactions (high-dimensional injury coding). Model performance with and without inclusion of mechanism of injury was compared for both coding schemes, and the relative importance of mechanism of injury as a variable in each model type was evaluated., Results: Among 62,569 records, a mortality rate of 0.9% was observed. Inclusion of mechanism of injury improved model performance when using low-dimensional injury coding but was associated with no improvement when using high-dimensional injury coding. Mechanism of injury contributed to 28% of model variance when using low-dimensional injury coding and <1% when high-dimensional injury coding was used., Conclusions: Although mechanism of injury may be an important predictor of injury mortality among children sustaining blunt trauma, its importance as a predictor of mortality depends on the approach used for injury coding. Mechanism of injury is not an essential predictor of outcome after injury when coding schemes are used that better characterize injuries sustained after blunt pediatric trauma., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Purpose: To compare the results of drug safety data mining with three different algorithms, when adverse events are identified using MedDRA Preferred Terms (PT) vs. High Level Terms (HLT) vs. Standardised MedDRA Queries (SMQ)., Methods: For a representative set of 26 drugs, data from the FDA Adverse Event Reporting System (AERS) database from 2001 through 2005 was mined for signals of disproportionate reporting (SDRs) using three different data mining algorithms (DMAs): the Gamma Poisson Shrinker (GPS), the urn-model algorithm (URN), and the proportional reporting rate (PRR) algorithm. Results were evaluated using a previously described Reference Event Database (RED) which contains documented drug-event associations for the 26 drugs. Analysis emphasized the percentage of SDRs in the "unlabeled supported" category, corresponding to those adverse events that were not described in the U.S. prescribing information for the drug at the time of its approval, but which were supported by some published evidence for an association with the drug., Results: Based on a logistic regression analysis, the percentage of unlabeled supported SDRs was smallest at the PT level, intermediate at the HLT level, and largest at the SMQ level, for all three algorithms. The GPS and URN methods detected comparable percentages of unlabeled supported SDRs while the PRR method detected a smaller percentage, at all three MedDRA levels. No evidence of a method/level interaction was seen., Conclusions: Use of HLT and SMQ groupings can improve the percentage of unlabeled supported SDRs in data mining results. The trade-off for this gain is the medically less-specific language of HLTs and SMQs compared to PTs, and the need for the added step in data mining of examining the component PTs of each HLT or SMQ that results in a signal of disproportionate reporting.

Background: In September 2004, rofecoxib was voluntarily withdrawn from the worldwide market. Our objective was to determine whether and when analysis of published and unpublished placebo-controlled trials could have revealed cardiovascular risk associated with rofecoxib before its withdrawal as an example to inform future postmarket pharmaceutical safety surveillance efforts., Methods: We conducted a cumulative subject-level pooled analysis of data from all randomized, placebo-controlled trials of rofecoxib conducted by the manufacturer before September 2004. Our main outcome measurement was incidence of any investigator-reported death from any cause or cardiovascular thromboembolic (CVT) adverse event., Results: We identified 30 randomized, placebo-controlled trials of rofecoxib that enrolled a combined 20 152 subjects. Trial duration ranged from 4 weeks to 4 years; enrollment ranged from 17 to 2586 subjects prescribed either rofecoxib or placebo; and rofecoxib dose ranged from 12.5 mg to 50 mg. As of December 2000, 21 of these trials had been completed (70%), and the risk of a CVT adverse event or death was greater among subjects assigned to the rofecoxib group (rate ratio [RR], 2.18; 95% confidence interval [CI], 0.93-5.81) (P = .07), raising concerns from a safety standpoint. Subsequently collected data through June 2001 showed that rofecoxib was associated with a 35% increased risk of a CVT adverse event or death (RR, 1.35; 95% CI, 1.00-1.96) (P = .05). Analyzing data available as of April 2002, we found a 39% increased risk (RR, 1.39; 95% CI, 1.07-1.80) (P = .02), and using data available as of September 2004, we found a 43% increased risk (RR,1.43; 95% CI, 1.16-1.76) (P < .001)., Conclusion: Cumulative pooled analysis of all randomized, placebo-controlled trials demonstrates a trend toward increased cardiovascular risk associated with rofecoxib compared with placebo as early as December 2000, the comparison reaching a P value of .05 by June 2001, nearly 3(1/2) years before the manufacturer's voluntary market withdrawal.

Introduction: A population-based analysis has suggested that the publication of the RALES (Randomized Aldactone Evaluation Study) in late 1999 was associated with both the wider use of spironolactone to treat heart failure and a corresponding increase in hyperkalaemia-associated morbidity and mortality in patients also being treated with ACE inhibitors., Objectives: To gain further insight into the reporting of spironolactone-associated hyperkalaemia in an independent dataset by analysing the spontaneous reporting experience in relation to the publication of RALES, and to determine whether the implementation of a commonly used data mining algorithm (DMA) might have directed the attention of safety reviewers to the spironolactone/hyperkalaemia association in advance of epidemiological findings., Methods: We calculated the reporting rate of spironolactone-associated hyperkalaemia per 1,000 reports per year from 1970 through to the end of 2005 by identifying relevant cases in the US FDA Adverse Event Reporting System. We did this for reports of spironolactone-associated hyperkalaemia (where spironolactone was listed as a suspect drug) and according to whether the reports listed an ACE inhibitor as a co-suspect or concomitant medication. A further statistical analysis of the overall reporting of spironolactone (suspect drug)-associated hyperkalaemia was also performed. We also performed 3-dimensional (3-D; drug-drug-event) disproportionality analyses using a DMA known as the multi-item gamma-Poisson shrinker, which allows the calculation and display of a 3-D disproportionality metric known as the 'interaction signal score' (INTSS). This metric is a measure of the strength of a higher order reporting relationship of a triplet (i.e. drug-drug-event) association above and beyond what would be expected from the largest disproportionalities associated with the individual 2-way associations., Results: Visual inspection of a graph of the reporting frequency of spironolactone (suspect drug)-associated hyperkalaemia per 1,000 reports was highly suggestive of a change point. The t-test on the arcsine-transformed data showed a significant difference in reporting of spironolactone-hyperkalaemia combination through 1999 compared with 2000 onwards (p < 0.001). When examining the reporting time trends according to the presence or absence of an ACE inhibitor, the change point seemed to be mostly attributable to an increase in the number of spironolactone (suspect drug)-associated hyperkalaemia reports with ACE inhibitors listed as a co-suspect drug. No obvious change points in INTSSs for spironolactone-ACE inhibitor-hyperkalaemia reports were observed., Discussion: Although we could not pinpoint the relative contribution of many possible artifacts in the reporting process, as well as increased drug exposure, increased adverse event incidence and/or a change in patient monitoring practices, to our findings, we observed a notable change in reporting frequency of spironolactone-associated hyperkalaemia in temporal proximity to the publication of RALES. Evidence of this was provided by a trend analysis depicted in a simple graph that was supported by statistical analysis. The observed trend was in large part due to increased reporting of spironolactone-associated hyperkalaemia with reported co-medication with ACE inhibitors., Conclusion: These findings are consistent with those originally reported in an epidemiological analysis. In this retrospective exercise, a simple graph was more illuminating than more complex data mining analyses.