Resmetirom: The First Food and Drug Administration-Approved Medication for Nonalcoholic Steatohepatitis (NASH).

OBJECTIVE: To review the literature leading to the Food and Drug Administration (FDA) approval of the first medication, resmetirom, for the treatment of nonalcoholic steatohepatitis (NASH), including the pharmacology, pharmacokinetics, clinical studies, dosing, and adverse effects. Relevant data will be used to discuss how resmetirom impacts clinical practice. DATA SOURCES: A literature search was conducted using MEDLINE from database inception to May 12, 2024. Keywords included non-alcoholic steatohepatitis, nonalcoholic fatty liver disease, and resmetirom. Study selection, data extraction and all English-language studies involving the use of resmetirom for nonalcoholic fatty liver disease (NAFLD)/NASH were included. DATA SYNTHESIS: Resmetirom, a thyroid hormone receptor agonist, is administered at daily doses of either 80 mg or 100 mg. The drug was shown to provide NASH resolution as assessed by the NAFLD activity score, 80 mg-24.2%, 100 mg-25.9% compared to 14.2% with the placebo group (P < 0.001). Resmetirom, improved liver fibrosis, 80 mg-25.9%, 100 mg-29.9% compared to 9.7% with the placebo group (P < 0.001). Resmetirom's ability to improve fibrosis in patients with F2-F3 fibrosis offers valuable benefit for patients at risk of progressing to cirrhosis. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: Resmetirom expands the medication options available to treat patients with NASH which can be given alongside other medications to optimize metabolic factors such as glucagon-like peptide-1 and hydroxymethylglutaryl-coenzyme A reductase inhibitors. Resmetirom was well tolerated in studies. CONCLUSION: Resmetirom serves as an attractive option in patients diagnosed with NASH with evidence of advanced fibrosis (F2-F3) in combination with exercise, diet, and other multimodal therapies targeting metabolic risk factors.

Betrixaban: A Novel Oral Anticoagulant With a New Niche.

Objective: To evaluate the efficacy, safety, and clinical implication of betrixaban for prophylaxis of venous thromboembolism (VTE) in patients with acute medical illness. Data Sources: A search for clinical trials was performed from January 2006 to January 2017 in English language using Clinicaltrials.gov and PubMed/MEDLINE. The following search terms were used: betrixaban, pharmacokinetics, pharmacology, and drug safety. Study Selection: The following limits were used to access the clinical trials: controlled clinical trial, randomized clinical trial, clinical trial, clinical trial phase II, and clinical trial phase III. The search was narrowed to include only humans. Data Extraction: The search criteria resulted in 6 clinical trials assessing the safety and efficacy of betrixaban. Additionally, references from publications assessing the safety and efficacy of betrixaban in atrial fibrillation, treatment and prevention of VTE, and extended duration VTE prophylaxis were assessed. Data Synthesis: Prior to 2017, no anticoagulant therapy had been approved for extended VTE prophylaxis in acutely ill medical patients. Betrixaban is the first direct oral anticoagulant approved for VTE prophylaxis in adult, acutely ill patients at risk for thromboembolisms. Based on the APEX trial, betrixaban 80 mg administered daily for 35 to 42 days was compared to enoxaparin administered daily for 6 to 14 days. In 7441 patients, fewer VTEs were seen in the betrixaban compared to enoxaparin with no significant difference in adverse reactions. Conclusion: Based on clinical trials, betrixaban appears to be safe and effective in preventing VTE in acutely ill patients who are at risk of developing VTE.

A New Mechanism of Action in Heart Failure: Angiotensin-Receptor Neprilysin Inhibition.

Objective: To evaluate the efficacy, safety, and clinical significance of sacubitril/valsartan (Entresto) in patients with heart failure with a reduced ejection fraction (HFrEF). Data Sources: An extensive search was conducted on Ovid MEDLINE using keywords and medical subject headings LCZ696, sacubitril/valsartan, angiotensin-receptor neprilysin inhibitor, and Entresto. Study Selection and Data Extraction: The search was conducted to retrieve clinical trials comparing sacubitril/valsartan to current guideline-directed therapy for HF. Articles using the limits of clinical trials "all" (phase I to IV), in English, and published within the past 5 years were reviewed. Supplemental sources included the Entresto package insert via the manufacturer's website. Primary end points included all-cause mortality and time to first hospitalization. Safety end points included incidence and severity of angioedema, cough, hyperkalemia, increased serum creatinine, and hypotension. Data Synthesis: This review critiques both clinical and statistical significance of the "Prospective Comparison of ARNi with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure" or PARADIGM-HF and other phase II to III clinical trials. Sacubitril/valsartan showed a 20% reduction in cardiovascular death and first hospitalization from HF compared with enalapril. Despite an overall reduction in adverse events, sacubitril/valsartan had increased occurrences of hypotension and nonserious angioedema. Conclusion: Sacubitril/valsartan is a viable option for newly diagnosed New York Heart Association (NYHA) class II to III and is an alternative to patients who are currently being treated with the maximum doses of current gold standard treatment. Clinicians initiating sacubitril/valsartan must monitor patients closely for signs, symptoms, and history of hypotension and angioedema.

Preventing medication errors in transitions of care: A patient case approach.

OBJECTIVE: To discuss common causes of medication errors occurring upon transitions of care and review key interventions that should be implemented to ensure effective communication and accurate completion of medication reconciliation. DATA SOURCES: MEDLINE (1946 to November 2014) using MeSH terms medication errors, medication reconciliation, and nursing homes in addition to conventional text words, including transitions of care and medication safety; Agency for Healthcare Research and Quality Patient Safety Network using search terms transitions of care, medication errors, and medication reconciliation; and relevant websites of national organizations pertaining to transitions of care and medication reconciliation. STUDY SELECTION: Limited to English-language journals with no limitation set on the year of publication for clinical trials, meta-analyses, and reviews. DATA EXTRACTION: At the authors' discretion, preference was given to references focusing on pharmacists' role in transitions of care and medication reconciliation. RESULTS: Most medication errors stem from a lack of effective communication between health care providers during transitions of care. Part of successful communication and correct patient hand-off is completing accurate medication reconciliation. A patient case highlights a life-threatening medication error that occurred during a transition of care due to ineffective communication between a pharmacist and nurse while transferring medication information. CONCLUSION: To provide patients with accurate medication information, pharmacists should perform medication reconciliation upon transitions of care using The Joint Commission's five-step process. Pharmacists can conduct numerous interventions to prevent medication errors during transitions of care and ensure patient safety. Pharmacists are integral to evaluating the appropriateness of medication use, ensuring information is updated in the health record, and verbally communicating accurate information to other health professionals.

Emerging therapies for the treatment of nonalcoholic steatohepatitis: A systematic review.

To describe the mechanism, efficacy, and safety of novel agents that have reached phase 3 clinical trials for the treatment of biopsy-proven nonalcoholic steatohepatitis (NASH). A literature search was conducted using the PRISMA guidelines of MEDLINE databases (1990 to October 2020) with the following MeSH terms: NASH, nonalcoholic liver disease, fatty liver, liver diseases, steatohepatitis, liver fibrosis; combined with obeticholic acid, FXR agonist, cenicriviroc, CCR5 receptor antagonist, elafibranor, PPAR, selonsertib, ASK-1 inhibitor, resmetirom, THR-ß receptor, arachidyl amido cholanoic acid (Aramchol™), and SCD-1 modulator. Results were verified via clinicaltrials.gov, Google Scholar, and Google. Articles were included if the medications of interest had ongoing or completed phase 3 trials in biopsy-proven NASH with outcomes directly related to NASH resolution. Eleven studies were identified involving obeticholic acid (OCA), elafibranor, cenicriviroc, Aramchol, and resmetirom. Two agents have reported data from phase 3 trials: OCA and elafibranor. OCA demonstrated safety and efficacy in NASH with a primary end point of improvement or NASH resolution; a new drug approval has been submitted. Elafibranor failed to show efficacy in NASH in the preliminary report from the RESOLVE-IT trial; however, the study is being extended to reassess outcomes. The remaining agents demonstrated positive results in phase 2b studies and have initiated phase 3 trials. With projections for increased prevalence of patients with NASH and the current lack of treatment options, novel agents with targeted mechanisms could potentially change the treatment landscape. The manufacturer of OCA is first to submit a new drug application for the treatment of NASH. These novel agents may fill a pharmacotherapy gap in patients with NASH and possibly prevent progression to advanced liver disease.

Vitamin C, Thiamine, and Steroids in the Sepsis Conquest: Replete to Defeat.

PURPOSE: Sepsis and septic shock are significant health issues in the United States. Novel treatment options focusing on mitigating the dysregulated host response while reducing the need for vasopressor support are needed. This review discusses ascorbic acid, thiamine, and steroids as monotherapy and in combination for the treatment of sepsis and septic shock. SUMMARY: The results of clinical studies using ascorbic acid, thiamine, and steroids as monotherapy or in combination are reviewed. High doses of IV ascorbic acid improved organ failure evidenced by changes in SOFA scores, declining CRP and PCT levels, and reduced vasopressor use. Thiamine initiation improved lactate levels in thiamine deficient patients in one study and demonstrated quicker lactate clearance and lower 28-day mortality in another study. Steroid studies demonstrated greatest benefit when initiating hydrocortisone and fludrocortisone early in septic shock. Combination therapy with ascorbic acid, thiamine and steroids reduced hospital mortality and vasopressor use in sepsis and septic shock in a small single-center study. CONCLUSION: Initial studies in patients with sepsis and septic shock demonstrated beneficial effects of ascorbic acid, thiamine, and steroids as monotherapy or in combination without safety concerns. However, the efficacy and safety of these therapies warrant further validation in larger clinical studies.

Efinaconazole and Tavaborole.

PURPOSE: The purpose of this article is to review the safety, efficacy, and role of efinaconazole and tavaborole in the treatment of onychomycosis. SUMMARY: Onychomycosis is a fungal infection of the nail caused by dermatophytes, yeasts, and nondermatophyte fungi. Distal and lateral subungual onychomycosis (DLSO) accounts for the majority of the cases. These infections cause structural damage to the nail which makes treatment difficult. Both oral and topical agents exist for the treatment of onychomycosis. Oral medications have generally been more effective, yet adverse effects and drug interactions limit their use in some patients. Food and Drug Administration (FDA)-approved agents in the United States for oral therapies include terbinafine, itraconazole, and griseofulvin. The only topical product available up to recently was ciclopirox. CONCLUSION: This article will review efinaconazole and tavaborole, 2 new topical antifungal agents released in 2014.

Vedolizumab: A New Opponent in the Battle Against Crohn's Disease and Ulcerative Colitis.

Inflammatory bowel diseases (IBDs) are chronic inflammatory disorders affecting the gastrointestinal (GI) tract that encompass Crohn's disease (CD) and ulcerative colitis (UC). In these disease states, epithelial damage of the intestinal mucosa is evident due to increased lymphocyte trafficking to the area, which affects the normal intestinal barrier function. Currently available pharmacotherapy can be limited in terms of efficacy and associated toxicities. Newer agents have emerged, including the monoclonal antibody natalizumab, which antagonizes integrin, an important component within the inflammation cascade. Natalizumab works by modulating both the GI and brain biologic responses and as a result there is risk of the opportunistic infection known as progressive multifocal leukoencephalopathy (PML), putting patients at risk for severe disability and death. Vedolizumab, another integrin inhibitor, is selective for modulating the gut biologic response but not the brain, consequently decreasing the risk for PML. To generate information regarding the role of vedolizumab in the treatment of IBD, a literature search was conducted, yielding 7 phase I to III clinical trials. This article serves as a summary of efficacy, safety, and other relevant information from clinical studies to explore the role of vedolizumab in the treatment of CD and UC.

Establishing Edoxaban's Role in Anticoagulation.

PURPOSE: This article serves as a review of the current literature regarding the role of edoxaban for the prevention of stroke in patients with nonvalvular atrial fibrillation (AF) and the treatment of venous thromboembolism (VTE). SUMMARY: Until recent years, oral treatment options for both treatment and prevention of VTE and stroke were limited to warfarin. Dabigatran was the first new oral anticoagulant approved in over 50 years followed by rivaroxaban and apixaban. These new oral anticoagulants offer many benefits over warfarin. Edoxaban is the newest member among the oral anticoagulants and exerts its action by direct inhibition of factor Xa. It may offer some advantages in that it is the second Food and Drug Administration-approved once-daily anticoagulant available and does not interact with the cytochrome P450 (CYP450) system. However, there are concerns in patients with AF and preserved renal function (>95 mL/min), as these cohorts experienced a higher incidence of stroke in trials. CONCLUSION: Based on the 3 clinical trials, edoxaban appears to be a safe and effective factor Xa inhibitor in patients with a creatinine clearance of <95 mL/min. It will serve as an alternative anticoagulant for those with a preference for once-daily dosing and/or taking medications that interact with the CYP450 system.

Emerging therapies for the management of chronic hyperkalemia in the ambulatory care setting.

PURPOSE: Emerging treatment options for the management of chronic hyperkalemia in the outpatient setting are reviewed. SUMMARY: Current treatment options for the management of hyperkalemia are limited and often accompanied by serious adverse effects. Two investigational drugs for the treatment of hyperkalemia are being evaluated in Phase III trials: sodium zirconium cyclosilicate and patiromer. Both of these drugs are administered orally and act by enhancing potassium's removal, predominantly through the gastrointestinal tract. The safety and efficacy of sodium zirconium cyclosilicate and patiromer were evaluated in Phase II and III trials. Both agents were studied in patients with chronic mild-to-severe hyperkalemia, chronic kidney disease (CKD), or heart failure as well as those taking a renin-angiotensin system (RAS) inhibitor, an aldosterone antagonist, or both therapies. These clinical trials found that sodium zirconium cyclosilicate and patiromer normalized serum potassium levels quickly and maintained normalized serum potassium levels over several weeks. Both medications caused a rapid decrease in serum potassium, with two studies examining efficacy endpoints for 12 weeks or longer. The overall frequency of adverse effects in these clinical trials was low, with gastrointestinal adverse events being the most commonly observed. CONCLUSION: Options for the management of hyperkalemia, particularly chronic hyperkalemia in the outpatient setting, are limited. Both sodium zirconium cyclosilicate and patiromer are emerging therapies that may provide long-term management of hyperkalemia, particularly in patients with underlying heart failure or CKD as well as those taking an RAS inhibitor, an aldosterone antagonist, or both.

Probable linezolid-induced thrombocytopenia in a patient with vancomycin-resistant enterococci.

PURPOSE: A probable case of linezolid-induced thrombocytopenia is reported. SUMMARY: A 74-year-old Caucasian male with renal dysfunction was diagnosed with diverticulosis. Patient was prescribed linezolid 600 mg orally twice daily for vancomycin-resistant enterococci abdominal infection that developed secondary to colon resection. Upon initiation of linezolid, platelet count dropped from 248 000 cells/mm(3) on day 1 to 97 000 cells/mm(3) on day 5 of treatment. Linezolid was discontinued and platelet counts improved to pretreatment levels. Application of the Naranjo probability scale indicated a probable association of linezolid therapy and thrombocytopenia. Clinicians should be aware that linezolid has this hematologic side effect and that patients with renal dysfunction are at increased risk. Monitoring platelet count more than once weekly should be advisable in these patients. CONCLUSION: A 74-year-old Caucasian male with renal dysfunction developed a probable case of linezolid-induced thrombocytopenia after receiving the drug for 5 days for treatment of vancomycin-resistant enterococci abdominal infection.