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Risk of emergent bradycardia associated with initiation of immediate- or slow-release metoprolol.

ABSTRACT: To estimate and compare the risk of emergent bradycardia associated with starting immediate-release (IR) and slow-release (SR) formulations of metoprolol.Retrospective analysis of administrative claims data.State of California Medicaid program (Medi-Cal) claims database.A total of 31,574 adults beginning metoprolol between May 1, 2004, and November 1, 2009, without a pharmacy claim for a ? blocker within the previous 6 months of metoprolol initiation; patients with a primary or secondary diagnosis of symptomatic bradycardia, pacemaker, or implantable cardioverter-defibrillator placement before metoprolol initiation were excluded.The study outcome was the time to first occurrence of emergent bradycardia, measured at an emergency department visit or hospitalization due to diagnosis of symptomatic bradycardia, after metoprolol initiation. We calculated the incidence and compared the risk of emergent bradycardia by using a proportional hazards model that included the metoprolol formulation with adjustment for total daily metoprolol dose and the use of other drugs as time-varying covariates, as well as demographics and comorbidities. Among 31,574 patients starting metoprolol, 18,516 (58.6%) used the IR formulation. The incidence of emergent bradycardia was 19.1/1000 person-years overall but was nearly twice as common in patients using the IR versus the SR formulation (24.1/1000 person-yrs in the IR group versus 12.9/1000 person-yrs in the SR group, unadjusted hazard ratio [HR] 1.81, 95% confidence interval [CI] 1.28-2.56). Adjustment for other drugs also associated with symptomatic bradycardia (cytochrome P450 2D6 inhibitors, class I or III antiarrhythmics, and atrioventricular node-blocking agents), metoprolol dose, and other participant characteristics somewhat attenuated the association (adjusted HR 1.48, 95% CI 1.03-2.13).The risk of emergent bradycardia associated with metoprolol initiation was higher with the IR formulation than the SR formulation, although the absolute risk was low.

SUBMITTER: Shin J

PROVIDER: S-EPMC3797244 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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Risk of emergent bradycardia associated with initiation of immediate- or slow-release metoprolol.

Shin Jaekyu J Gonzales Marco M Pletcher Mark J MJ

Pharmacotherapy 20130627 12

<h4>Objectives</h4>To estimate and compare the risk of emergent bradycardia associated with starting immediate-release (IR) and slow-release (SR) formulations of metoprolol.<h4>Design</h4>Retrospective analysis of administrative claims data.<h4>Data source</h4>State of California Medicaid program (Medi-Cal) claims database.<h4>Patients</h4>A total of 31,574 adults beginning metoprolol between May 1, 2004, and November 1, 2009, without a pharmacy claim for a β blocker within the previous 6 months ...[more]

PMID: 23813768

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Project description:BACKGROUND:Cardiopulmonary resuscitation (CPR) is initiated in hospitalized children with bradycardia and poor perfusion. However, their rate of progression to pulseless cardiac arrest despite CPR and the differences in survival compared with initially pulseless arrest are unknown. We examined the prevalence and predictors of survival of children who progress from bradycardia to pulseless in-hospital cardiac arrest despite CPR. METHODS:Pediatric patients >30 days and <18 years of age who received CPR at hospitals participating in Get With The Guidelines-Resuscitation during 2000 to 2016 were included. Each CPR event was classified as bradycardia with pulse, bradycardia with subsequent pulselessness, and initial pulseless cardiac arrest. We assessed risk-adjusted rates of survival to hospital discharge using multilevel Poisson regression models. RESULTS:Overall, 5592 pediatric patients were treated with CPR, of whom 2799 (50.1%) received CPR for bradycardia with poor perfusion and 2793 (49.9%) for initial pulseless cardiac arrest. Among those with bradycardia, 869 (31.0%, or 15.5% of cohort) became pulseless after a median of 3 minutes of CPR (interquartile range, 1-9 minutes). Rates of survival to discharge were 70.0% (1351 of 1930) for bradycardia with pulse, 30.1% (262 of 869) for bradycardia progressing to pulselessness, and 37.5% (1046 of 2793) for initial pulseless cardiac arrest (P for difference across groups <0.001). Children who became pulseless despite CPR for bradycardia had a 19% lower likelihood (risk ratio, 0.81 [95% CI, 0.70, 0.93]; P=0.004) of surviving to hospital discharge than those who were initially pulseless. Among children who progressed to pulselessness despite CPR for bradycardia, a longer interval between CPR and pulselessness was a predictor of lower survival (reference, <2 minutes; for 2-5 minutes, risk ratio, 0.54 [95% CI, 0.41-0.70]; for >5 minutes, risk ratio, 0.41 [95% CI, 0.32-0.53]). CONCLUSIONS:Among hospitalized children in whom CPR is initiated, half have bradycardia with poor perfusion at the initiation of chest compressions, and nearly one-third of these progress to pulseless in-hospital cardiac arrest despite CPR. Survival was significantly lower for children who progress to pulselessness despite CPR compared with those who were initially pulseless. These findings suggest that pediatric patients who lose their pulse despite resuscitation attempts are at particularly high risk and require a renewed focus on postresuscitation care.

Project description:Importance:The United States spends more money on medications than any other country. Most extended-release drugs have not consistently shown therapeutic or adherence superiority, and switching these medications to less expensive, generic, immediate-release formulations may offer an opportunity to reduce health care spending. Objective:To evaluate Medicare Part D and Medicaid spending on extended-release drug formulations and the potential savings associated with switching to generic immediate-release formulations. Design, Setting, and Participants:This cross-sectional study used the 2012 to 2017 Medicare Part D Drug Event and Medicaid Spending and Utilization data sets to analyze 20 extended-release drugs with 37 Medicare formulations and 36 Medicaid formulations. Only cardiovascular, diabetes, neurologic, and psychiatric extended-release drugs saving at most 1 additional daily dose compared with their immediate-release counterparts were included. Extended-release drugs with therapeutic superiority were excluded. Analyses were conducted from January to December 2019. Main Outcomes and Measures:Estimated Medicare Part D and Medicaid savings from switching extended-release to immediate-release drug formulations between 2012 and 2017. Results:Of the 6252 drugs screened for eligibility from the 2017 Medicaid Drug Utilization database and the 2017 Medicare Part D database, 67 drugs with extended-release formulations that were identified in the Medicare data set (20 distinct drugs with 37 formulations [19 brand, 18 generic]) were included in the analysis. In 2017, Medicare Part D spent $2.2 billion and Medicaid spent $952 million (a combined $3.1 billion) on 20 extended-release drugs. Between 2012 and 2017, Medicare Part D and Medicaid spent $12 billion and $5.9 billion, respectively, on extended-release formulations. Switching from brand-name to generic extended-release formulations was estimated to be associated with a $247 million reduction in Medicare spending and $299 million reduction in Medicaid spending in 2017, whereas switching all brand-name and generic extended-release formulations to immediate-release formulations in both Medicare and Medicaid was estimated to reduce spending by $2.6 billion ($1.8 billion for Medicare and $836 million for Medicaid) in 2017. During the study period, the estimated spending reduction associated with switching all patients receiving extended-release formulations (brand name extended-release and generic extended-release) to generic immediate-release formulations was $13.7 billion ($8.5 billion from Medicare and $5.2 billion from Medicaid). Conclusions and Relevance:The findings suggest that switching from extended-release drug formulations to therapeutically equivalent immediate-release formulations when available represents a potential option to reduce Medicare and Medicaid spending.

Project description:Herpes simplex virus 1 (HSV-1) transcription is tightly regulated in a temporal cascade, utilizing cellular RNA polymerase. We previously observed that infection with HSV-1 mutants lacking immediate early (IE) genes α0, α4, and α22 exhibited high levels of aberrant transcription across the viral genome at just 1.5 hpi. The strongest effect occurred in the absence of full-length ICP4 which is both an essential transcriptional activator and repressor. The goal of the current study was to define the mechanism of ICP4-mediated early transcriptional repression on the viral genome. Using PRO-Cap, PRO-Seq, GRO-Seq, and Nanopore direct RNA sequencing to analyze viral transcription, we found that initiation was elevated at viral promoters of all temporal classes in the absence of ICP4. Despite higher levels of initiation, transcription of non-IE genes was stalled within gene bodies and did not lead to production of mature mRNA. Thus, ICP4-independent mechanisms limit expression of viral genes that initiate prematurely. GRO-seq data also indicated rapid release from promoter proximal pausing, and rapid progression along HSV IE gene bodies, with termination as an important rate-limiting regulatory step. These findings highlight multiple mechanisms that HSV-1 employs to regulate early transcription and shows that ICP4's repressive role is to restrict initiation, thereby ensuring correct progression of the temporal cascade. IMPORTANCE Infection with herpes simplex virus 1 (HSV-1) leads to lifelong infection due to the virus's remarkable ability to control transcription of its own genome, resulting in two transcriptional programs: lytic (highly active) and latent (restricted). The lytic program requires immediate early (IE) proteins to first repress transcription of late viral genes, which then undergo sequential de-repression, leading to a specific sequence of gene expression. Here, we show that the IE ICP4 functions to regulate the cascade by limiting RNA polymerase initiation at immediate early times. However, late viral genes that initiate too early in the absence of ICP4 do not yield mRNA as transcription stalls within gene bodies. It follows that other regulatory steps intercede to prevent elongation of genes at the incorrect time, demonstrating the precise control HSV-1 exerts over its own transcription.

Project description:ImportanceTransmucosal immediate-release fentanyls (TIRFs), indicated solely for breakthrough cancer pain in opioid-tolerant patients, are subject to a US Food and Drug Administration (FDA) Risk Evaluation and Mitigation Strategy (REMS) to prevent them from being prescribed inappropriately.ObjectivesTo evaluate knowledge assessments of pharmacists, prescribers, and patients regarding appropriate TIRF use; to describe sponsor assessments, based on claims data, of whether the REMS program was meeting its goals; and to characterize how the FDA responded to REMS assessments.Design, setting, and participantsQualitative analysis of 4877 pages of FDA documents obtained through a Freedom of Information Act request, including 6 annual REMS assessment reports (2012-2017), FDA evaluations of these reports, and FDA-sponsor correspondence about safety issues.ExposureA REMS program to reduce the risk of adverse outcomes, including misuse, abuse, addiction, and overdose, arising from use of TIRFs.Main outcomes and measures(1) Knowledge assessments of pharmacists, prescribers, and patients; (2) survey and claims-based prescribing assessments; (3) FDA and TIRF sponsor communications; (4) modifications to the REMS program; and (5) disenrollment of noncompliant prescribers.ResultsTwelve months after initiation of the program, 24 of 302 pharmacists (7.9%), 35 of 302 prescribers (11.6%), and 5 of 192 patients (2.6%) incorrectly reported that TIRFs can be prescribed to opioid-nontolerant patients, with similar levels of misunderstanding maintained in the subsequent reports. At 60 months, product-specific analyses of claims data indicated that between 34.6% and 55.4% of patients prescribed TIRFs were opioid-nontolerant. In the 48-month survey, 106 of 310 prescribers (34.2%) reported prescribing TIRFs for opioid-tolerant patients with chronic, noncancer pain; at 60 months, 54 of 302 prescribers (18.4%) and 148 of 310 patients (47.7%) erroneously reported that TIRFs were FDA-approved for such use. Over the 60-month period examined, there were few substantive changes made to the REMS to address evidence of high rates of off-label TIRF use, and, although the REMS program had a noncompliance plan, there was no report of prescribers being disenrolled for inappropriate prescribing.Conclusions and relevanceIn this review of FDA documents pertaining to the TIRF REMS, surveys of pharmacists, prescribers, and patients reflected generally high levels of knowledge regarding proper TIRF prescribing, yet some survey items as well as claims-based analyses indicated substantial rates of inappropriate TIRF use. Despite these findings, the FDA did not require substantive changes to the program.

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Risk of emergent bradycardia associated with initiation of immediate- or slow-release metoprolol.

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Risk of emergent bradycardia associated with initiation of immediate- or slow-release metoprolol.

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