SUPPORT-AF II: Supporting Use of Anticoagulants Through Provider Profiling of Oral Anticoagulant Therapy for Atrial Fibrillation: A Cluster-Randomized Study of Electronic Profiling and Messaging Combined With Academic Detailing for Providers Making Decisions About Anticoagulation in Patients With Atrial Fibrillation.

BACKGROUND: Previous provider-directed electronic messaging interventions have not by themselves improved anticoagulation use in patients with atrial fibrillation. Direct engagement with providers using academic detailing coupled with electronic messaging may overcome the limitations of the prior interventions. METHODS AND RESULTS: We randomized outpatient providers affiliated with our health system in a 2.5:1 ratio to our electronic profiling/messaging combined with academic detailing intervention. In the intervention, we emailed providers monthly reports of their anticoagulation percentage relative to peers for atrial fibrillation patients with elevated stroke risk (CHA2DS2-VASc ≥2). We also sent electronic medical record-based messages shortly before an appointment with an anticoagulation-eligible but untreated atrial fibrillation patient. Providers had the option to send responses with explanations for prescribing decisions. We also offered to meet with intervention providers using an academic detailing approach developed based on knowledge gaps discussed in provider focus groups. To assess feasibility, we tracked provider review of our messages. To assess effectiveness, we measured the change in anticoagulation for patients of intervention providers relative to controls. We identified 85 intervention and 34 control providers taking care of 3591 and 1908 patients, respectively; 33 intervention providers participated in academic detailing. More than 80% of intervention providers read our emails, and 98% of the time a provider reviewed our in-basket messages. Replies to messages identified patient refusal as the most common reason for patients not being on anticoagulation (11.2%). For the group of patients not on anticoagulation at baseline assigned to an intervention versus control provider, the adjusted percent increase in the use of anticoagulation over 6 months was 5.2% versus 7.4%, respectively (P=0.21). CONCLUSIONS: Our electronic messaging and academic detailing intervention was feasible but did not increase anticoagulation use. Patient-directed interventions or provider interventions targeting patients declining anticoagulation may be necessary to raise the rate of anticoagulation. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT03583008.

A Review of Deflazacort for Patients With Duchenne Muscular Dystrophy.

Objective: The objective of this article is to review the pharmacology, pharmacokinetics, efficacy, safety, dosage and administration, and formulary considerations of deflazacort. Data Sources: A search of MEDLINE and EMBASE (1946 to December 31, 2019) was conducted using the terms deflazacort and Duchenne muscular dystrophy (DMD). Results were limited to clinical trials, humans, and English. Additional sources and data were obtained from the references of included articles and prescribing information. Study Selection and Data Extraction: All articles published after July 2014 related to pharmacology, pharmacokinetics, efficacy, or safety of the therapy in human subjects were included. Data Synthesis: Deflazacort 0.9 mg/kg/d is a once-daily oral corticosteroid and is the first drug of its class to be Food and Drug Administration (FDA) approved for DMD. Studies with deflazacort show improved functional outcomes, delayed onset of cardiomyopathy, reduction in scoliosis surgery, and improved survival, but these improvements are supported by relatively weak evidence. Relevance to Patient Care and Clinical Practice: This review presents data from studies published after the most recent DMD 2016 treatment guidelines and offers prescribing considerations, including pharmacology, pharmacokinetics, adverse effects, formulary considerations, and areas of uncertainty. Conclusions: Deflazacort presents an additional, FDA-approved corticosteroid option for patients that offers improved quality of life for DMD patients. However, there is weak evidence to support these benefits; a full risk-benefit analysis considering adverse events, efficacy, cost, and previous trials of steroid therapy is necessary when selecting therapy. Further research will help clarify deflazacort's optimal dose, duration of treatment, and impact on quality of life.

Reducing Hospitalizations and Emergency Department Visits in Patients With Venous Thromboembolism Using a Multicomponent Care Transition Intervention.

Preventing utilization of hospital and emergency department after diagnosis of venous thromboembolism is a complex problem. The objective of this study is to assess the impact of a care transition intervention on hospitalizations and emergency department visits after venous thromboembolism. We randomized adults diagnosed with a new episode of venous thromboembolism to usual care or a multicomponent intervention that included a home pharmacist visit in the week after randomization (typically occurring at time of discharge), illustrated medication instructions distributed during home visit, and a follow-up phone call with an anticoagulation expert scheduled for 8 to 30 days from time of randomization. Through physician chart review of the 90 days following randomization, we measured the incidence rate of hospital and emergency department visits for each group and their ratio. We also determined which visits were related to recurrent venous thromboembolism, bleeding, or anticoagulation and which where preventable. We enrolled 77 intervention and 85 control patients. The incidence rate was 4.50 versus 6.01 visits per 1000 patient days in the intervention versus control group (incidence rate ratio = 0.71; 95% confidence interval = 0.40-1.27). Most visits in the control group were not related to venous thromboembolism or bleeding (21%) and of those that were, most were not preventable (25%). The adjusted incidence rate ratio for the intervention was 1.05 (95% confidence interval = 0.57-1.91). Our patients had a significant number of hospital and emergency department visits after diagnosis. Most visits were not related to recurrent venous thromboembolism or bleeding and of those that were, most were not preventable. Our multicomponent intervention did not decrease hospitalizations and emergency department visits.

Nintedanib for Idiopathic Pulmonary Fibrosis.

OBJECTIVE: To review the pharmacology, safety, and efficacy of nintedanib for the treatment of idiopathic pulmonary fibrosis (IPF). METHODS: A literature search was conducted via PubMed using the MeSH term "idiopathic pulmonary fibrosis" combined with the key word "nintedanib." Additional online searches using Google Scholar, Micromedex, and PubMed were performed to obtain prescribing and cost information. RESULTS: One phase II and 2 replicate phase III clinical trials that examined the safety and efficacy of nintedanib for IPF were identified. In patients with IPF, nintedanib was more effective than placebo in slowing the annual rate of decline in forced vital capacity (FVC). Improvements in mortality, quality of life, and risk of acute exacerbations have not been consistently demonstrated in clinical trials. Diarrhea was the most common adverse effect associated with nintedanib use. Outside of these clinical trials, there are limited data evaluating nintedanib for the treatment of IPF. CONCLUSIONS: Nintedanib is a safe and effective treatment option for patients with IPF. Nintedanib slows IPF disease progression by reducing the rate of decline in FVC. Reductions in mortality and acute exacerbations may be present in certain subgroups of patients, but these outcomes require further research. Future studies on nintedanib are needed to explore its use in more advanced stages of IPF, its long-term safety and efficacy, its value in combination with pirfenidone or other therapies for IPF, and its cost-effectiveness in clinical practice.

Idarucizumab for Reversal of Dabigatran-Associated Anticoagulation.

OBJECTIVE: To review clinical data on idarucizumab for the reversal of dabigatran-associated anticoagulation. DATA SOURCES: Articles for this review were identified via PubMed using the MeSH term dabigatran combined with the keyword idarucizumab Additional online searches via PubMed and Google Scholar were conducted for both prescribing and cost information. STUDY SELECTION AND DATA EXTRACTION: English-language clinical trials published between 1946 and May 2016 were included for review. Bibliographies of selected articles were also manually reviewed for relevant publications that focused on reversal strategies for dabigatran-associated anticoagulation. DATA SYNTHESIS: The safety and tolerability of idarucizumab has been evaluated in 3 phase I clinical trials. The use of idarucizumab for reversing dabigatran-associated anticoagulation is also being evaluated in the phase III RE-VERSE AD study. Interim results of the RE-VERSE AD study have been published. CONCLUSIONS: Idarucizumab rapidly neutralizes the anticoagulant effect of dabigatran in healthy volunteers, in patients with life-threatening bleeding, and in patients requiring urgent surgery that cannot be delayed. These observations are largely based on laboratory assessments rather than clinical outcomes. Idarucizumab is well tolerated, and it does not appear to induce procoagulant or immunogenic adverse effects.

The Impact of Liver and Renal Dysfunction on the Pharmacokinetics and Pharmacodynamics of Sedative and Analgesic Drugs in Critically Ill Adult Patients.

The use of sedative and analgesic drug therapy is often necessary for the care of critically ill patients. Renal and hepatic dysfunction, which occurs frequently in this patient population, can significantly alter drugs' pharmacokinetic and pharmacodynamics properties. By anticipating how these medications may be affected by liver or kidney dysfunction, health care practitioners may be able to provide tailored dosing regimens that ensure optimal comfort while minimizing the risk of adverse events.

Nutrition as medical therapy.

Recent data support the use of nutritional agents for use as targeted medical therapy. This article reviews some of the pharmacologic roles that parenteral nutritional ingredients (selenium, lipid emulsion, insulin, and levocarnitine) can play in the setting of critical illness.

Pirfenidone: a novel agent for the treatment of idiopathic pulmonary fibrosis.

OBJECTIVE: To evaluate the published clinical literature on the role of pirfenidone for the treatment of idiopathic pulmonary fibrosis (IPF). DATA SOURCES: A systematic literature search was performed using the key words pirfenidone or Esbriet, alone and in combination, with IPF or idiopathic pulmonary fibrosis (expanded using MESH terminology). MEDLINE (1948-September 2012) was the primary database used for search purposes. In addition, all available articles and abstracts referenced by the articles identified via literature search were included. STUDY SELECTION AND DATA EXTRACTION: The search was limited to English-language publications. All available clinical trials of pirfenidone pertinent to its pharmacology, pharmacokinetics, efficacy, and safety were included. DATA SYNTHESIS: Pirfenidone is the first agent specifically developed for the treatment of IPF. It has been approved for use in Europe and Japan, but not in the US. Although Phase 3 trials have shown pirfenidone to improve certain clinical (6-minute walk test) and functional (change in forced vital capacity) outcomes in patients with IPF, an independent benefit on either mortality or acute exacerbation rates has yet to be demonstrated. Until more definitive supportive data are available, international guidelines have recommended against using pirfenidone to treat most patients with IPF. CONCLUSIONS: Although pirfenidone appears to be an effective treatment for IPF, additional clinical trials are needed to better delineate its risk-benefit profile.

Introduction to drug pharmacokinetics in the critically ill patient.

Despite regular use of drugs for critically ill patients, overall data are limited regarding the impact of critical illness on pharmacokinetics (PK). Designing safe and effective drug regimens for patients with critical illness requires an understanding of PK. This article reviews general principles of PK, including absorption, distribution, metabolism, and elimination, and how critical illness can influence these parameters. In the area of drug absorption, we discuss the impact of vasopressor use, delayed gastric emptying and feeding tubes, and nutrient interactions. On the topic of drug distribution, we review fluid resuscitation, alterations in plasma protein binding, and tissue perfusion. With drug metabolism, we discuss hepatic enzyme activity, protein binding, and hepatic blood flow. Finally, we review drug elimination in the critically ill patient and discuss the impact of augmented renal clearance and acute kidney injury on drug therapies. In each section, we highlight select literature reviewing the PK impact of these conditions on a drug PK profile and, where appropriate, provide general suggestions for clinicians on how to modify drug regimens to manage PK challenges.

Evaluation of the impact of a tele-ICU pharmacist on the management of sedation in critically ill mechanically ventilated patients.

BACKGROUND: An organized and uniform approach to managing sedation in critically ill patients has been associated with improved outcomes, but the most effective means of optimizing sedative medication use in clinical practice has not been fully determined. Pharmacist interventions directed at improving sedation guideline compliance have been shown to reduce the duration of mechanical ventilation. OBJECTIVE: To determine the impact that pharmacy staffing configurations that include a tele-ICU pharmacist have on compliance with an intensive care unit (ICU) sedation guideline in critically ill mechanically ventilated patients requiring continuous-infusion sedative medications. METHODS: Compliance with an established ICU sedation guideline, the performance of daily sedative interruptions, and the number of sedative medication-related interventions were evaluated before and after expansion of the ICU pharmacist staffing model to include comprehensive off-hours pharmacist coverage supported with established tele-ICU resources. In both groups, sedation was managed by the primary ICU team. In the intervention group, a pharmacist working in the tele-ICU center performed electronic record audits and made sedative medication recommendations to the primary team. RESULTS: The addition of third shift tele-ICU pharmacist support was associated with a significant increase in the percentage of patients who received a daily sedative interruption (45% vs 54%; p < 0.0001). This occurred in the context of significant increases in the total number of ICU pharmacist interventions (36 vs 49.4 per 100 patient days, p < 0.0001), the number of therapeutic interventions (20.4 vs 26.1 per 100 patient days, p < 0.001), and the number of sedative-related interventions (0.9 vs 4.4 per 100 patient days, p < 0.0001). CONCLUSIONS: Tele-ICU resources can be utilized to increase compliance with an established ICU sedation guideline and extend the benefits that daytime ICU clinical pharmacy services provide. Increased ICU pharmacist availability may have additional benefits not measured in this study.

Incidence of propofol-related infusion syndrome in critically ill adults: a prospective, multicenter study.

INTRODUCTION: While propofol is associated with an infusion syndrome (PRIS) that may cause death, the incidence of PRIS is unknown. Determining the incidence of PRIS and the frequency of PRIS-related clinical manifestations are key steps prior to the completion of any controlled studies investigating PRIS. This prospective, multicenter study sought to determine the incidence of PRIS and PRIS-related clinical manifestations in a large cohort of critically ill adults prescribed propofol. METHODS: Critically ill adults from 11 academic medical centers administered an infusion of propofol for [>or=] 24 hours were monitored at baseline and then on a daily basis until propofol was discontinued for the presence of 11 different PRIS-associated clinical manifestations and risk factors derived from 83 published case reports of PRIS. RESULTS: Among 1017 patients [medical (35%), neurosurgical (25%)], PRIS (defined as metabolic acidosis plus cardiac dysfunction and [>or=] 1 of: rhabdomyolysis, hypertriglyceridemia or renal failure occurring after the start of propofol therapy) developed in 11 (1.1%) patients an average of 3 (1-6) [median (range)] days after the start of propofol. While most (91%) of the patients who developed PRIS were receiving a vasopressor (80% initiated after the start of propofol therapy), few received a propofol dose >83 mcg/kg/min (18%) or died (18%). Compared to the 1006 patients who did not develop PRIS, the APACHE II score (25 +/- 6 vs 20 +/- 7, P = 0.01) was greater in patients with PRIS but both the duration of propofol use (P = 0.43) and ICU length of stay (P = 0.82) were similar. CONCLUSIONS: Despite using a conservative definition for PRIS, and only considering new-onset PRIS clinical manifestations, the incidence of PRIS slightly exceeds 1%. Future controlled studies focusing on evaluating whether propofol manifests the derangements of critical illness more frequently than other sedatives will need to be large. These studies should also investigate the mechanism(s) and risk factors for PRIS.

Propylene glycol-induced lactic acidosis in a patient receiving continuous infusion pentobarbital.

OBJECTIVE: To report a case of probable propylene glycol (PG) toxicity in a patient receiving continuous infusion of pentobarbital for refractory status epilepticus. CASE SUMMARY: A 59-year-old woman with a declining mental status was admitted to the intensive care unit for management of status epilepticus. After failing to achieve the therapeutic endpoint of electroencephalogram burst suppression with a continuous infusion of propofol, the sedative regimen was changed to continuous infusion of pentobarbital. The patient received a loading dose of 450 mg (5 mg/kg), and the maintenance infusion was titrated to a dose of 10 mg/kg/h to achieve burst suppression. Twelve hours after the pentobarbital infusion was started, the patient developed an anion gap metabolic acidosis, elevated serum lactate level, hyperosmolality, and increased osmolal gap. The pentobarbital infusion was discontinued, and the patient's acidosis and hyperosmolality resolved. DISCUSSION: Pentobarbital contains 40% v/v of PG, which was thought to be a potential source of the patient's metabolic derangements. Reports of toxicity with drugs containing PG, particularly intravenous lorazepam, have been well described in the literature. What we describe, however, is one of few reports involving intravenous pentobarbital. The Naranjo probability scale supports a probable drug-related adverse event in our patient. CONCLUSIONS: PG toxicity is a potential complication associated with intravenous pentobarbital. Practitioners should be aware of the PG content of pentobarbital and should be familiar with the signs and symptoms associated with PG toxicity.

The effects of liver and renal dysfunction on the pharmacokinetics of sedatives and analgesics in the critically ill patient.

In critically ill patients, the duration of effect and dose-response relationship of sedative and analgesic drugs can be significantly affected by the presence of renal or hepatic dysfunction. Alterations in pharmacokinetics and pharmacodynamics vary according to the degree of organ impairment and presence of comorbid illnesses. This article reviews the principals that govern the absorption, distribution, metabolism, and elimination of sedatives and analgesics during renal and hepatic impairment. By anticipating changes in pharmacokinetics, and by routinely assessing the clinical response to therapy, unintended adverse consequences of sedative and analgesic drug therapy may be avoided.

Antifactor Xa levels in four patients with burn injuries who received enoxaparin to prevent venous thromboembolism.

Four patients with severe burn injuries received enoxaparin 40 mg twice/day subcutaneously for the prophylaxis of venous thromboembolism (VTE). Peak antifactor Xa levels were measured 4 hours after administration of a dose, and trough antifactor Xa levels were measured 30 minutes before the next scheduled dose. Ultrasonography was performed once/week to assess the presence of VTE. Any occurrence of major bleeding was documented in the patients' charts. All patients had trough antifactor Xa levels below 0.1 U/ml. Enoxaparin dosages were subsequently adjusted to achieve trough antifactor Xa levels of 0.1-0.2 U/ml. This required dosages higher than those typically recommended for VTE prophylaxis (40 mg every 24 hrs or 30 mg every 12 hrs). One patient needed more than 60 mg every 12 hours. No patient had a venous thromboembolic event or major bleeding. The low antifactor Xa levels that were observed suggest that a reduced dose-response relationship may exist between subcutaneously administered enoxaparin and antifactor Xa activity in patients with severe burn injuries. Prospective studies should be performed to further investigate this relationship.