Self-controlled assessment of thromboembolic event (TEE) risk following intravenous immune globulin (IGIV) in the U.S. (2006-2012).

Since 2013, the U.S. Food and Drug administration (FDA) has required that intravenous immune globulin (IGIV) products carry a boxed warning concerning the risk of thromboembolic events (TEEs). This study assessed the incidence of TEEs attributable to IGIV in a large population-based cohort. A self-controlled risk interval design was used to quantify the transient increase in TEE risk during the risk interval (days 0-2 and 0-13 following IGIV for arterial and venous TEEs, respectively) relative to a later control interval (days 14-27 following IGIV). Potential IGIV-exposed TEE cases from 2006 to 2012 were identified from the FDA-sponsored Sentinel Distributed Database and confirmed through medical record review. Inpatient IGIV exposures were not included in the venous TEE analysis due to concerns about time-varying confounding. 19,069 new users of IGIV who received 93,555 treatment episodes were included. Charts were retrieved for 62% and 70% of potential venous and arterial cases, respectively. There was a transient increase in the risk of arterial TEEs during days 0-2 following IGIV treatment (RR = 4.69; 95% CI 1.87, 11.90; absolute increase in risk = 8.86 events per 10,000 patients, 95% CI 3.25, 14.6), but no significant increase in venous TEE risk during days 0-13 following outpatient IGIV treatments (RR = 1.07, 95% CI 0.34, 3.48). Our results suggest there is a small increase in the absolute risk of arterial TEEs following IGIV. However, lower-than-expected chart retrieval rates and the possibility of time-varying confounding mean that our results should be interpreted cautiously. Continued pharmacovigilance efforts are warranted.

Intravenous immune globulin and thromboembolic adverse events in patients with hematologic malignancy.

In patients with hypogammaglobulinemia secondary to chronic lymphocytic leukemia (CLL) or multiple myeloma (MM), intravenous immune globulin (IVIg) may be administered to reduce the risk of infection. Since 2013, IVIg products have carried a boxed safety warning about the risk of thromboembolic events (TEEs), with TEEs reported in 0.5% to 15% of patients treated with IVIg. In this retrospective cohort study of older patients with CLL or MM identified from the Surveillance, Epidemiology, and End Results-Medicare Linked Database, we assessed rates of clinically serious TEEs in 2724 new users of IVIg and a propensity-matched comparison group of 8035 nonusers. For the primary end point, arterial TEE, we observed a transient increased risk of TEE during the day of an IVIg infusion and the day afterward (hazard ration = 3.40; 95% confidence interval [CI]: 1.25, 9.25); this risk declined over the remainder of the 30-day treatment cycle. When considered in terms of absolute risk averaged over a 1-year treatment period, the increase in risk attributable to IVIg was estimated to be 0.7% (95% CI: -0.2%, 2.0%) compared with a baseline risk of 1.8% for the arterial TEE end point. A statistically nonsignificant risk increase of 0.3% (95% CI: -0.4%, 1.5%) compared with a baseline risk of 1.1% was observed for the venous TEE end point. Further research is needed to establish the generalizability of these results to patients receiving higher doses of IVIg for other indications.

Chart validation of inpatient ICD-9-CM administrative diagnosis codes for acute myocardial infarction (AMI) among intravenous immune globulin (IGIV) users in the Sentinel Distributed Database.

BACKGROUND: The Sentinel Distributed Database (SDD) is a large database of patient-level administrative health care records, primarily derived from insurance claims and electronic health records, and is sponsored by the US Food and Drug Administration for medical product safety evaluations. Acute myocardial infarction (AMI) is a common study endpoint for drug safety studies that rely on health records from the SDD and other administrative databases. PURPOSE: In this chart validation study, we report on the positive predictive value (PPV) of inpatient International Classification of Diseases, Ninth Revision, Clinical Modification AMI administrative diagnosis codes (410.x1 and 410.x0) in the SDD. METHODS: As part of an assessment of thromboembolic adverse event risk following treatment with intravenous immune globulin, charts were obtained for 103 potential post-intravenous immune globulin AMI cases. Charts were abstracted by trained nurses and physician-adjudicated based on prespecified diagnostic criteria. RESULTS: Acute myocardial infarction status could be determined for 89 potential cases. The PPVs for the inpatient AMI diagnoses recorded in the SDD were 75% overall (95% CI, 65-84%), 93% (95% CI, 78-99%) for principal-position diagnoses, 88% (95% CI, 72-97%) for secondary diagnoses, and 38% (95% CI, 20-59%) for position-unspecified diagnoses (eg, diagnoses originating from separate physician claims associated with an inpatient stay). Of the confirmed AMI cases, demand ischemia was the suspected etiology more often for those coded in secondary or unspecified positions (72% and 40%, respectively) than for principal-position AMI diagnoses (21%). CONCLUSIONS: The PPVs for principal and secondary AMI diagnoses were high and similar to estimates from prior chart validation studies. Position-unspecified diagnosis codes were less likely to represent true AMI cases.

Intravenous immune globulin and thromboembolic adverse events: A systematic review and meta-analysis of RCTs.

Prior case reports and observational studies indicate that intravenous immune globulin (IVIg) products may cause thromboembolic events (TEEs), leading the FDA to require a boxed warning in 2013. The effect of IVIg treatment on the risk of serious TEEs (acute myocardial infarction, ischemic stroke, or venous thromboembolism) was assessed using adverse event data reported in randomized controlled trials (RCTs) of IVIg. RCTs of IVIg in adult patients from 1995 to 2015 were identified from Pubmed, Embase, ClinicalTrials.Gov, and two large prior reviews of IVIg's therapeutic applications. Trials at high risk of detection or reporting bias for serious adverse events were excluded. 31 RCTs with a total of 4,129 participants (2,318 IVIg-treated, 1,811 control) were eligible for quantitative synthesis. No evidence was found of increased TEE risk among IVIg-treated patients compared with control patients (odds ratio = 1.10, 95% CI: 0.44, 2.88; risk difference = 0.0%, 95% CI: -0.7%, 0.7%, I(2) = 0%). No significant increase in risk was found when arterial and venous TEEs were analyzed as separate endpoints. Trial publications provided little specific information concerning the methods used to ascertain potential adverse events. Care should be taken in extrapolating the results to patients with higher baseline risks of TEE. Am. J. Hematol. 91:594-605, 2016. © 2016 Wiley Periodicals, Inc.

Pediatric registries at the Food and Drug Administration: design aspects that increase their likelihood of success.

PURPOSE: To determine aspects of the design of pediatric registries that contribute to the success of registries conducted as a postmarketing study following approval of drugs or biological products by the US Food and Drug Administration. METHODS: Pediatric registries for drugs and biological products were identified by searching the US Food and Drug Administration Postmarketing Requirements and Commitments database. Based on the recruitment of patients, the meeting of predetermined deadlines, and the submission of data, we classified studies as successful, unsuccessful, or unevaluable. Design aspects of successful and unsuccessful registries were examined for commonalities. RESULTS: Thirty-eight studies were identified, and ten registries met the criteria for successful. Four (40%) successful registries utilized a registry established prior to product approval, and six (60%) were disease-based. Among unsuccessful registries, none were disease-based or utilized a pre-existing registry. CONCLUSIONS: Characteristics identified as more common to successful registries included utilizing a disease-based registry and a registry established prior to product approval. Future studies might examine a larger sample of registries to see if these aspects consistently result in successful studies. Published 2015. This article is a U.S. Government work and is in the public domain in the USA.

Adverse Events Following Measles, Mumps, and Rubella Vaccine in Adults Reported to the Vaccine Adverse Event Reporting System (VAERS), 2003-2013.

BACKGROUND: Limited data exist on the safety of the measles, mumps, and rubella (MMR) vaccine in adults. We reviewed reports of adverse events (AEs) to the Vaccine Adverse Event Reporting System (VAERS) to assess safety in this previously understudied group. METHODS: VAERS is the national spontaneous vaccine safety surveillance system coadministered by the Centers for Disease Control and Prevention and the US Food and Drug Administration. We searched the VAERS database for US reports of adults aged ≥19 years who received the MMR vaccine from 1 January 2003 to 31 July 2013. We clinically reviewed reports and available medical records for serious AEs, pregnancy reports, and reports for selected prespecified outcomes. RESULTS: During this period, VAERS received 3175 US reports after MMR vaccine in adults. Of these, 168 (5%) were classified as serious, including 7 reports of death. Females accounted for 77% of reports. The most common signs and symptoms for all reports were pyrexia (19%), rash (17%), pain (13%), and arthralgia (13%). We did not detect any new safety findings in empirical Bayesian data mining. We identified 131 reports of MMR vaccine administered to a pregnant woman; the majority of these vaccinations were in the first trimester and in 83 (62%), no AE was reported. CONCLUSIONS: In our review of VAERS data, we did not detect any new or unexpected safety concerns for MMR vaccination in adults. We identified reports of pregnant women exposed to MMR, which is a group in whom the vaccine is contraindicated, suggesting the need for continued provider education on vaccine recommendations and screening.

Characteristics Associated With U.S. Outpatient Opioid Analgesic Prescribing and Gabapentinoid Co-Prescribing.

INTRODUCTION: A considerable burden of prescription and illicit opioid-related mortality and morbidity in the U.S. is attributable to potentially unnecessary or excessive opioid prescribing, and co-prescribing gabapentinoids may increase risk of harm. Data are needed regarding physician and patient characteristics associated with opioid analgesic and opioid analgesic-gabapentinoid co-prescriptions to elucidate targets for reducing preventable harm. METHODS: Multiple logistic regression was utilized to examine patient and physician predictors of opioid analgesic prescriptions and opioid analgesic-gabapentinoid co-prescriptions in adult noncancer patients using the National Ambulatory Medical Care Survey 2015 public use data set. Potential predictors were selected based on literature review, clinical relevance, and random forest machine learning algorithms. RESULTS: Among the 11.8% (95% CI=9.8%, 13.9%) of medical encounters with an opioid prescription, 16.2% (95% CI=12.6%, 19.8%) had a gabapentinoid co-prescription. Among all gabapentinoid encounters, 40.7% (95% CI=32.6%, 48.7%) had an opioid co-prescription. Predictors of opioid prescription included arthritis (OR=1.87, 95% CI=1.30, 2.69). Predictors of new opioid prescription included physician status as an independent contractor (OR=3.67, 95% CI=1.38, 9.81) or part owner of the practice (OR=3.34, 95% CI=1.74, 6.42). Predictors of opioid-gabapentinoid co-prescription included patient age (peaking at age 55-64 years; OR=35.67, 95% CI=4.32, 294.43). CONCLUSIONS: Predictors of opioid analgesic prescriptions with and without gabapentinoid co-prescriptions were identified. These predictors can help inform and reinforce (e.g., educational) interventions seeking to reduce preventable harm, help identify populations for elucidating opioid-gabapentinoid risk-benefit profiles, and provide a baseline for evaluating subsequent public health measures.

Opioid Stewardship in Urology: Quality Improvement Summit 2018.

INTRODUCTION: We summarize the 2018 AUA (American Urological Association) Quality Improvement Summit, Opioid Stewardship in Urology, highlighting appropriate urological opioid use as well as reviewing programs that have been successful in reducing opioid prescribing. The AUA brought together nearly 100 attendees from across the United States, including clinicians who specialize in urology and other specialties, as well as researchers, government officials and others. METHODS: The 2018 AUA Quality Improvement Summit was a 1-day meeting held at AUA headquarters in Linthicum, Maryland. Talks and panels highlighted opioid stewardship programs and emphasized research on the nature and management of postoperative pain. RESULTS: The impact of the opioid epidemic is profound and the contribution of postoperative prescribing is noteworthy (eg 6% of opioid naïve patients demonstrate new persistent use habits after surgery and up to 70% of opioid pills prescribed after surgery go unused). Speakers raised awareness of these facts and detailed opportunities to improve, including prudent prescribing, opioid reclamation, use of nonopioid alternatives, and outreach and education. CONCLUSIONS: The 2018 AUA Quality Improvement Summit provided a platform for urologists to discuss the opioid epidemic and to learn strategies for combatting this issue from multidisciplinary experts. Physician led opioid stewardship and research, facilitated by this Summit, may enhance the quality and safety of medical care and improve the lives of patients, their families and their communities.

Chart validation of inpatient International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) administrative diagnosis codes for venous thromboembolism (VTE) among intravenous immune globulin (IGIV) users in the Sentinel Distributed Database.

The Sentinel Distributed Database (SDD) is a database of patient administrative healthcare records, derived from insurance claims and electronic health records, sponsored by the US Food and Drug Administration for evaluation of medical product outcomes. There is limited information on the validity of diagnosis codes for acute venous thromboembolism (VTE) in the SDD and administrative healthcare data more generally.In this chart validation study, we report on the positive predictive value (PPV) of inpatient administrative diagnosis codes for acute VTE-pulmonary embolism (PE) or lower-extremity or site-unspecified deep vein thrombosis (DVT)-within the SDD. As part of an assessment of thromboembolic adverse event risk following treatment with intravenous immune globulin (IGIV), charts were obtained for 75 potential VTE cases, abstracted, and physician-adjudicated.VTE status was determined for 62 potential cases. PPVs for lower-extremity DVT and/or PE were 90% (95% CI: 73-98%) for principal-position diagnoses, 80% (95% CI: 28-99%) for secondary diagnoses, and 26% (95% CI: 11-46%) for position-unspecified diagnoses (originating from physician claims associated with an inpatient stay). Average symptom onset was 1.5 days prior to hospital admission (range: 19 days prior to 4 days after admission).PPVs for principal and secondary VTE discharge diagnoses were similar to prior study estimates. Position-unspecified diagnoses were less likely to represent true acute VTE cases.

Cognitive testing to evaluate revisions to the Vaccine Adverse Event Reporting System (VAERS) reporting form.

INTRODUCTION: The Vaccine Adverse Event Reporting System (VAERS) is the spontaneous (passive) reporting system CDC and FDA use to monitor vaccine safety. We used cognitive testing to evaluate proposed revisions to the current VAERS form. METHODS: We conducted in-person cognitive interviews with 22 volunteers to evaluate proposed revisions in a prototype VAERS 2.0 form (new VAERS form). We analyzed data using thematic analysis. RESULTS: Repeating themes included preferences for: brevity, simplicity and clarity; features to minimize time requirements and facilitate ease of completion; logical ordering of questions by topic and importance; and visual cues like color-coded highlighting. Interviews identified instances of discordance between the intended meaning questions (from the perspective of CDC and FDA) and interpretation by volunteers. CONCLUSIONS: Cognitive testing yielded useful information to guide further revisions of the VAERS form. Cognitive testing can be an effective tool for public health programs interested in developing surveys and reporting forms.

Chart validation of inpatient ICD-9-CM administrative diagnosis codes for ischemic stroke among IGIV users in the Sentinel Distributed Database.

The Sentinel Distributed Database (SDD) is a large database of patient-level medical and prescription records, primarily derived from insurance claims and electronic health records, and is sponsored by the U.S. Food and Drug Administration for drug safety assessments. In this chart validation study, we report on the positive predictive value (PPV) of inpatient ICD-9-CM acute ischemic stroke (AIS) administrative diagnosis codes (433.x1, 434.xx, and 436) in the SDD.As part of an assessment of the risk of thromboembolic adverse events following treatment with intravenous immune globulin (IGIV), charts were obtained for 131 potential post-IGIV AIS cases. Charts were abstracted by trained nurses and then adjudicated by stroke experts using pre-specified diagnostic criteria.Case status could be determined for 128 potential AIS cases, of which 34 were confirmed. The PPVs for the inpatient AIS diagnoses recorded in the SDD were 27% overall [95% confidence interval (95% CI): 19-35], 60% (95% CI: 32-84) for principal-position diagnoses, 42% (95% CI: 28-57) for secondary diagnoses, and 6% (95% CI: 2-15) for position-unspecified diagnoses (which in the SDD generally originate from separate physician claims associated with an inpatient stay).Position-unspecified diagnoses were unlikely to represent true AIS cases. PPVs for principal and secondary inpatient diagnosis codes were higher, but still meaningfully lower than estimates from prior chart validation studies. The low PPVs may be specific to the IGIV user study population. Additional research is needed to assess the validity of AIS administrative diagnosis codes in other study populations within the SDD.

Adverse Events After MMR or MMRV Vaccine in Infants Under Nine Months Old.

BACKGROUND: In the United States, measles is resurging, with more than 700 confirmed cases since January 2014. During measles outbreaks, vaccination as early as at 6 months of age is sometimes recommended for infants who are at risk for exposure. METHODS: We searched the Vaccine Adverse Event Reporting System for reports of measles, mumps and rubella vaccine combined or measles, mumps, rubella and varicella vaccine combined vaccination in children less than 9 months of age. We performed a clinical assessment of each report and summarized the frequency, range, onset time and severity of adverse events. RESULTS: After excluding 346 reports because they were duplicates or because they contained insufficient information about the child's age or vaccine(s), we retained 204 reports in the analysis, including 35 (17%) that were serious. Among the 169 nonserious reports, more than half (88; 52%) described a vaccination error without any adverse event per se. Other nonserious reports described fever, injection reactions and gastrointestinal symptoms. Serious adverse events included developmental disorders, fever and fussiness. There were 44 reports of fever, but only 4 cases began 5-12 days after immunization, the peak risk window. The vast majority of fever reports listed concomitant vaccines, such as diphtheria and tetanus toxoids, acellular or whole-cell pertussis vaccine. CONCLUSIONS: This review did not identify any major safety concerns. These findings may facilitate discussions about the risks and benefits of vaccinating infants who are potentially exposed to this life-threatening disease.

Motor palsies of cranial nerves (excluding VII) after vaccination: reports to the US Vaccine Adverse Event Reporting System.

We reviewed cranial nerve palsies, other than VII, that have been reported to the US Vaccine Adverse Event Reporting System (VAERS). We examined patterns for differences in vaccine types, seriousness, age, and clinical characteristics. We identified 68 reports of cranial nerve palsies, most commonly involving the oculomotor (III), trochlear (IV), and abducens (VI) nerves. Isolated cranial nerve palsies, as well as palsies occurring as part of a broader clinical entity, were reported. Forty reports (59%) were classified as serious, suggesting that a cranial nerve palsy may sometimes be the harbinger of a broader and more ominous clinical entity, such as a stroke or encephalomyelitis. There was no conspicuous clustering of live vs. inactivated vaccines. The patient age range spanned the spectrum from infants to the elderly. Independent data may help to clarify whether, when, and to what extent the rates of cranial nerve palsies following particular vaccines may exceed background levels.