Annals of Pharmacotherapy

Atrial fibrillation (AF) increases the risk of stroke and direct oral anticoagulants (DOACs) are first-line agents for prevention. Gaps in the literature cause reluctance in prescribing DOACs for patients with renal dysfunction and/or extremes in body weight.

To evaluate the impact body weight and renal function have on major and clinically relevant nonmajor (CRNM) bleeding events and ischemic strokes in AF patients receiving a DOAC.

This retrospective cohort study included adults with nonvalvular atrial fibrillation (NVAF) or atrial flutter (AFL) receiving a DOAC ≥12 months. The primary outcome was a composite of major and CRNM bleeding events. Secondary outcomes included ischemic stroke and risk factors for bleeding events.

Of the 233 patients analyzed, 25 patients experienced a bleeding event. Patients who bled weighed 10 kg less (P = 0.043) than those who did not and had a higher HASBLED score (P = 0.003). Multivariate logistic regression identified weight (P = 0.048), serum creatinine (SCr; P = 0.027), and HASBLED score (P = 0.024) as the significant predictors for experiencing a bleed. Three patients experienced a stroke.

This study demonstrates an association between higher baseline SCr, elevated HASBLED score, and lower weight, with an increased risk of bleeding in patients with NVAF or AFL receiving a DOAC. These findings add to prescribing considerations when initiating DOACs. Closer monitoring is advised for patients with significant renal dysfunction and/or low body weight, even with renal dose adjustments.

Oseltamivir is frequently administered to critically ill patients with presumed influenza. It may modulate Na⁺, K⁺, and Ca²⁺ channels to produce bradycardia.

To evaluate the association between oseltamivir and bradycardia in critically ill patients and assess parameters associated with bradycardia.

This was a retrospective audit of 203 critically ill adults with presumed influenza receiving at least 2 doses of oseltamivir. The primary outcome was the occurrence of bradycardia, defined as a heart rate (HR) ≤59 beats per minute (BPM) while receiving oseltamivir or a decrease of ≥20 BPM compared with the lowest HR before initiating oseltamivir.

A total of 88 (43.4%) patients manifested bradycardia, 59 with HR ≤59 BPM, 19 with HR decrease of ≥20 BPM, and 10 with both. The time from first dose to bradycardia was 51.4 ± 43 hours. In all, 48 (54.6%) patients received therapies for bradycardia, including increased inotropic/vasopressor dose, electrolyte replacement, electrocardiogram, discontinuation of other medications, cardiology consult, discontinuation of oseltamivir, and pacer placement. There were no significant differences between groups with bradycardia versus without in terms of demographics, laboratory values, hospital characteristics, or oseltamivir dosing. Multivariate logistic regression showed that bradycardia was associated with baseline HR, age, past medical history of neurological issues, and positive influenza status. Between hours 6 through 126, significant differences existed between groups in actual and lowest HR.

Oseltamivir was associated with clinically relevant bradycardia in critically ill patients. Clinicians should closely monitor HR in critically ill patients receiving oseltamivir.

Glycemic control within goal blood glucose (BG) ranges is essential to minimize hospital complications for patients with type 2 diabetes mellitus (T2DM). Optimal treatment in the non–intensive care unit (ICU) setting includes a basal insulin containing regimen. Dipeptidyl peptidase-IV (DPP-IV) inhibitors have minimal hypoglycemia incidence and may be an appropriate bolus insulin replacement in the inpatient setting.

To determine the effect of basal insulin plus DPP-IV inhibitor compared with basal plus bolus insulin in hospitalized patients with T2DM.

This multicenter cohort study included adult patients with T2DM admitted to the non-ICU setting and prescribed either basal insulin plus DPP-IV inhibitor or basal plus bolus insulin. Propensity-score matching was performed for age, sex, Charlson Comorbidity Index, first BG reading during hospitalization, and hemoglobin A_1C (A1C). The primary outcome was the difference in mean daily BG during hospitalization. Secondary outcomes included hospital length of stay (LOS), total daily dose (TDD) of insulin, hypoglycemic events, and mean daily BG in patients with an A1C >8%.

A total of 105 patients were included in each group. Mean daily BG during hospitalization was lower in the basal insulin plus DPP-IV inhibitor group (199.3 ± 52.5 vs 213.6 ± 45.8 mg/dL; P = 0.04). There was a significant difference in hospital LOS (5 [interquartile range = 3-8] vs 6 [4-11] days; P = 0.02) and short-acting insulin TDD (11.6 ± 9.1 vs 20.5 ± 21.2 units; P < 0.001). No differences were observed in basal insulin TDD and hypoglycemia. There was no difference in mean daily BG in the subgroup analysis of patients with a A1C >8%.

A significant difference in mean daily BG and hospital LOS was found with a basal insulin plus DPP-IV inhibitor regimen. Use of a DPP-IV inhibitor to replace bolus insulin in hospitalized patients with T2DM should be considered.

In a recent human reliability analysis (HRA) of simulated pediatric resuscitations, ineffective retrieval of preparation and administration instructions from online injectable medicines guidelines was a key factor contributing to medication administration errors (MAEs).

The aim of the present study was to use a specific HRA to understand where intravenous medicines guidelines are vulnerable to misinterpretation, focusing on deviations from expected practice (discrepancies) that contributed to large-magnitude and/or clinically significant MAEs.

Video recordings from the original study were reanalyzed to identify discrepancies in the steps required to find and extract information from the NHS Injectable Medicines Guide (IMG) website. These data were combined with MAE data from the same original study.

In total, 44 discrepancies during use of the IMG were observed across 180 medication administrations. Of these discrepancies, 21 (48%) were associated with an MAE, 16 of which (36% of 44 discrepancies) made a major contribution to that error. There were more discrepancies (31 in total, 70%) during the steps required to access the correct drug webpage than there were in the steps required to read this information (13 in total, 30%). Discrepancies when using injectable medicines guidelines made a major contribution to 6 (27%) of 22 clinically significant and 4 (15%) of 27 large-magnitude MAEs.

Discrepancies during the use of an online injectable medicines guideline were often associated with subsequent MAEs, including those with potentially significant consequences. This highlights the need to test the usability of guidelines before clinical use.

Studies have shown that intravenous methadone intraoperatively can reduce opioid usage postoperatively.

This study’s purpose was to evaluate the effect of intravenous methadone on postoperative opioid use.

A prospective, single-center observational study was conducted to evaluate patients who received intravenous methadone intraoperatively. A control group was identified by matching procedure, gender, and age in a 1:3 ratio of methadone to control. Exclusion criteria included patients less than 18 years old or on methadone maintenance therapy. The primary outcome was morphine milligram equivalents (MME) administered 24h postoperatively. Secondary outcomes included MME administered 48h and 72h postoperatively, discharge prescription MME, daily mean postoperative pain scores, and length of hospital stay. A subgroup analysis was performed comparing opioid-naïve patients.

A total of 240 patients were included in the analysis. At 24h, postoperative MME was increased in the methadone group (142.6 vs 84.5; P = 0.0026). Postoperative MME was also increased in the methadone group at 48h and 72h. Daily pain scores were similar between both groups at all time intervals. Discharge prescription MME was reduced in the methadone group compared with controls, but not statistically significant. A subgroup analysis of opioid-naïve patients showed a significant reduction in MME at 48h (P = 0.0240) and daily pain scores at 24h (P = 0.0366) in the methadone group.

Intravenous methadone intraoperatively did not show a significant reduction in postoperative opioid use and discharge prescription MMEs when comparing all patients; however, benefit was seen when examining opioid-naïve patients.

An impaired sleep-wake cycle may be one factor that affects the development of delirium in critically ill patients. Several small studies suggest that exogenous melatonin or ramelteon may decrease the incidence and/or duration of delirium.

To compare the effect of prophylactic administration of melatonin, ramelteon, or no melatonin receptor agonist on the development of delirium in the intensive care unit (ICU).

This was a single-center, retrospective, observational cohort study of nondelirious patients in the ICU who received melatonin, ramelteon, or no melatonin receptor agonist. The primary end point was the incidence of delirium. Secondary end points included assessments of daily level of sedation and daily utilization of antipsychotic, sedative, and opioid agents.

No difference was observed in the incidence of delirium among the melatonin, ramelteon, and placebo cohorts (18.7% vs 14.3% vs 13.8%; P = 0.77). A difference was observed in the rate of agitation and sedation among the 3 groups, with the greatest observed in the melatonin cohort. Additionally, there was a difference in the use of propofol, dexmedetomidine, and opioids. Overall, there was no difference in clinical outcomes, including duration of mechanical ventilation and ICU or hospital length of stay.

Therapy with melatonin, ramelteon, and no melatonin receptor agonist resulted in similar rates of delirium in a mixed ICU population. Despite significant differences in agitation, sedation, and medication utilization, there was no differences in the clinical outcomes evaluated.

False penicillin allergies lead to increased antimicrobial resistance, adverse effects, and health care costs by promoting the use of broad-spectrum antibiotics. The Infectious Diseases Society of America recommends the implementation of allergy testing.

The primary objective of this research was to estimate the number of pharmacist full-time equivalents (FTEs) required for an intervention aimed at determining penicillin allergy in hospitalized patients. Acceptance of pharmacists’ suggestions on antibiotic therapy are described.

A quasi-experimental study was conducted in a 712-bed university hospital involving hospitalized patients with a suspected penicillin allergy and an infection treatable with penicillin. The time required for the intervention, which included a questionnaire, penicillin allergy testing (skin-prick test, intradermal injection, and oral provocation test), and recommendations on antibiotic therapy were measured to calculate the number of pharmacist FTEs.

A total of 55 patients were included. Scarification allergy testing was performed on 37, intradermal allergy test on 33, and oral provocation test on 26 patients. The intervention ruled out penicillin allergy in 26 patients, with no serious adverse effects. The intervention was associated with a median weekly pharmacist FTE of 0.15 (interquartile range = 0.12-0.25). The acceptance of pharmacists’ suggestions was high and led to 9 patients being switched to an antibiotic with a narrower spectrum of activity.

This study describes penicillin allergy testing and the number of median weekly hospital pharmacist FTEs required, which was approximately 0.15. These data may aid in the implementation of this safe intervention that promotes narrower-spectrum antibiotherapy.

To evaluate evidence for high-dose daptomycin (doses ≥ 8 mg/kg/d).

A PubMed/MEDLINE literature search was performed (January 2000 to December 2020) using the search terms daptomycin, high dose, and dosing. Review article references and society guidelines were reviewed.

Clinical trials, observational studies, retrospective studies, meta-analyses, and systematic reviews reporting on high-dose daptomycin were included.

Experimentally, daptomycin outperforms other antimicrobials for high inoculum and biofilm-associated infections. Clinically, high-dose daptomycin is supported as salvage and first-line therapy for endocarditis and bacteremia, primarily when caused by methicillin-resistant Staphylococcus aureus (when vancomycin minimum inhibitory concentration is >1 mg/L) and Enterococcus. High-dose daptomycin appears effective for osteomyelitis and central nervous system infections, although comparative studies are lacking. High dosing in renal replacement therapy requires considering clearance modality to achieve exposures like normal renal function. Weight-based dosing in obesity draws concern for elevated exposures, although high doses have not been evaluated kinetically in obesity. Some data show benefits of high doses in overweight populations. Burn patients clear daptomycin more rapidly, and high doses may only achieve drug exposures similar to standard doses (6 mg/kg).

This review analyzes the efficacy and safety of high-dose daptomycin in serious gram-positive infections. Discussion of specific infectious etiologies and patient populations should encourage clinicians to evaluate their daptomycin dosing standards.

The efficacy of high-dose daptomycin and limited safety concerns encourage clinicians to consider high-dose daptomycin more liberally in severe gram-positive infections.

To evaluate the evidence for common therapeutic controversies in the medical management of valvular heart disease (VHD).

A literature search of PubMed (inception to December 2020) was performed using the terms angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) and aortic stenosis (AS); and adrenergic β-antagonists and aortic valve regurgitation (AR) or mitral stenosis (MS).

Randomized controlled trials (RCTs) and meta-analyses conducted in humans and published in English that reported ≥1 clinical outcome were included.

Nine articles were included: 3 RCTs and 1 meta-analysis for ACE inhibitors/ARBs in AS, 1 RCT for β-blockers in AR, and 4 RCTs for β-blockers in MS. Evidence suggests that ACE inhibitors/ARBs do not increase the risk of adverse outcomes in patients with AS but may delay valve replacement. β-Blockers do not appear to worsen outcomes in patients with chronic AR and may improve left-ventricular function in patients with a reduced ejection fraction. β-Blockers do not improve and may actually worsen exercise tolerance in patients with MS in sinus rhythm.

ACE inhibitors/ARBs and β-blockers can likely be safely used in patients with AS or AR, respectively, who have a compelling indication. There is insufficient evidence to recommend routine use of β-blockers in patients with MS without atrial fibrillation.

Common beliefs about the medical treatment of VHD are not supported by high-quality data. There remains a need for larger-scale RCTs in the medical management of VHD.

To explore mechanistic benefits of glucose-lowering agents that extend beyond glycemic control with the potential to mitigate coronavirus disease 2019 (COVID-19) complications.

The following PubMed literature search terms were used from July 2020 to January 2, 2021: diabetes, COVID-19, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), glucose-lowering agents, and pharmacology.

English-language studies reporting on the association between diabetes, COVID-19 adverse outcomes, and the potential roles of glucose-lowering agents were reviewed.

Selected glucose-lowering agents have benefits beyond glycemic control, with the potential to reduce the risks of severe complications during SARS-CoV-2 infection. Key benefits include anti-inflammatory, anticoagulant, immune modulating, and enzyme/receptor effects.

This review summarizes the current knowledge of glucose-lowering agents and their potential roles in COVID-19 outcomes. Considering beneficial mechanisms on COVID-19 outcomes that extend beyond glycemic control as well as safety profiles, current data suggest that dipeptidyl peptidase-IV (DPP-IV) inhibitors and metformin may have the most promise and warrant further investigation.

Certain glucose-lowering agents may offer additional benefits beyond glucose control—namely, by modulating the mechanisms contributing to adverse outcomes related to COVID-19 in patients with diabetes. DPP-IV inhibitors and metformin appear to have the most promise. However, current published literature on diabetes medications and COVID-19 should be interpreted with caution. Most published studies are retrospective and consist of convenience samples, and some lack adequate analytical approaches with confounding biases. Ongoing trials aim to evaluate the effects of glucose-lowering agents in reducing the severity of COVID-19 outcomes.

To review the efficacy and safety of cabotegravir (CAB) with rilpivirine (RPV) in the treatment of HIV-1 infection.

A literature search was performed using PubMed and Google Scholar (2010 to January 2021) with the search terms cabotegravir and rilpivirine. Other resources included abstracts presented at recent conferences and the manufacturer’s website and prescribing information.

All English-language articles of studies assessing the efficacy and safety of CAB with RPV were included.

The combination of CAB, a new integrase strand transfer inhibitor, and RPV, an established nonnucleoside reverse transcriptase inhibitor, is the first long-acting dual therapy approved for the treatment of HIV-1 infection in adults who have achieved viral suppression on a standard antiretroviral therapy (ART). This regimen demonstrated comparable maintenance of viral suppression evaluated up to 160 weeks, with low rates of virological failure. CAB and RPV are available as suspension given intramuscularly in 2 separate injections every 4 weeks. Common adverse effects include injection site reactions, pyrexia, fatigue, and headache. CAB and RPV are also available as tablets given orally for bridging therapy.

This long-acting dual therapy represents an attractive option with a high barrier to resistance for adults who have achieved viral suppression on standard ART and who prefer monthly injections over daily oral therapy.

CAB-RPV is the first complete long-acting injectable that provides a convenient way to maintain viral suppression with no negative effects on renal and bone health and few drug interactions.

To review the pharmacology, efficacy, and safety of antibody-drug conjugate fam-trastuzumab deruxtecan-nxki in the treatment of advanced, unresectable, or metastatic breast cancer.

Relevant information was identified through a MEDLINE/PubMed (January 2015 to December 2020) literature search. The new drug application, prescribing information, clinical practice guideline, and abstracts from scientific meetings were also reviewed.

The literature search was limited to human studies published in the English language. All studies evaluating the pharmacology, efficacy, or safety of fam-trastuzumab deruxtecan-nxki for breast cancer were included.

Fam-trastuzumab deruxtecan-nxki is composed of an anti–human epidermal growth factor receptor 2 (HER2) antibody and topoisomerase I inhibitor (DXd), which causes DNA damage and apoptotic cell death. Major phase I and phase II clinical trials established the efficacy and safety of fam-trastuzumab deruxtecan-nxki for treatment of HER2-positive advanced, unresectable, or metastatic breast cancers that are refractory or intolerant to standard treatment. In these trials, the response rate was 60.9% (95% CI = 53.4-68.0) Common adverse effects included fatigue, nausea, vomiting, decreased appetite, constipation, diarrhea, alopecia, neutropenia, anemia, and thrombocytopenia. Serious adverse effects included interstitial lung disease or pneumonia, febrile neutropenia, left ventricular dysfunction, and embryo-fetal toxicity.

Fam-trastuzumab deruxtecan-nxki is an option for HER2-positive breast cancer following 2 previous lines of HER2-targeted therapy.

Fam-trastuzumab deruxtecan-nxki is an effective treatment for HER2-positive breast cancer in the metastatic setting, but randomized controlled trials are needed.