Cardiac Myosin Inhibitors: Expanding the Horizon for Hypertrophic Cardiomyopathy Management.

OBJECTIVE: To review the current literature on the efficacy and safety of cardiac myosin inhibitors (CMIs) for the treatment of hypertrophic cardiomyopathy (HCM). DATA SOURCES: A literature search was conducted on PubMed from origin to April 2023, using the search terms "MYK-461," "mavacamten," "CK-3773274," and "aficamten." Studies were limited to English-based literature, human subjects, and clinical trials resulting in the inclusion of 13 articles. ClinicalTrials.gov was also used with the same search terms for ongoing and completed trials. STUDY SELECTION AND DATA EXTRACTION: Only phase II and III studies were included in this review except for pharmacokinetic studies that were used to describe drug properties. DATA SYNTHESIS: CMIs enable cardiac muscle relaxation by decreasing the number of myosin heads that can bind to actin and form cross-bridges. Mavacamten, the first Food and Drug Administration (FDA)-approved drug in this class, has been shown to improve hemodynamic, functional, and quality of life measures in HCM with obstruction. In addition, aficamten is likely to become the next FDA-approved CMI with promising phase II data and an ongoing phase III trial expected to release results in the next year. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE IN COMPARISON WITH EXISTING DRUGS: CMIs provide a novel option for obstructive hypertrophic cardiomyopathy, particularly in those not suitable for septal reduction therapy. Utilization of these agents requires knowledge of drug interactions, dose titration schemes, and monitoring parameters for safety and efficacy. CONCLUSIONS: CMIs represent a new class of disease-specific drugs for treatment of HCM. Cost-effectiveness studies are needed to delineate the role of these agents in patient therapy.

Amifampridine for the Management of Lambert-Eaton Myasthenic Syndrome: A New Take on an Old Drug.

Objective: The purpose of this article is to review the literature for both 3,4-diaminopyridine (3,4-DAP) and amifampridine for the treatment of Lambert-Eaton myasthenic syndrome (LEMS). Amifampridine (Firdapse) is the salt form of 3,4-DAP and was approved by the Food and Drug Administration for the treatment of LEMS. Data Sources: PubMed, TRIP database, and EMBASE searches were conducted without a back date (current to June 2019) utilizing the following search terms: amifampridine, 3,4-diaminopyridine, and Lambert-Eaton myasthenic syndrome. Completed trials were also reviewed at clinicaltrials.gov. Study Selection and Data Extraction: Criteria for article inclusion consisted of human subjects, age ≥18 years, phase II or III clinical trials, and English language for both drugs. Observational and pharmacokinetic studies for amifampridine were also included. Data Synthesis: Prior to the approval of amifampridine, 3,4-DAP was first-line for the management of LEMS symptoms. Two phase III trials have evaluated amifampridine to confirm efficacy, both showing superiority over placebo in the management of LEMS symptoms, with minimal adverse effects. A significant improvement in both quantitative myasthenia gravis scores and Subjective Global Impression scores was established at days 4 and 14. Relevance to Patient Care and Clinical Practice: With an improved stability profile and decreased dose variability, amifampridine will likely assume the role of first-line management of LEMS. Conclusions: Amifampridine has been shown to improve symptoms of LEMS and is generally well tolerated.

Biologics for the treatment of dyslipidemias: a look beyond conventional therapy.

OBJECTIVE: To evaluate the monoclonal antibodies to proprotein convertase subtilisin/kexin type 9 (PCSK9) in the management of dyslipidemias. DATA SOURCES: MEDLINE/PubMed, NHS Evidence, TRIP database and EMBASE searches were conducted using the terms proprotein convertase subtilisin/kexin type 9, PCSK9, and monoclonal antibody. No date limits were utilized; search results were current to September 2013. STUDY SELECTION AND DATA EXTRACTION: Articles were limited to phase 2 or 3 clinical trials of monoclonal antibodies to PCSK9 assessing surrogate markers of clinical end points. DATA SYNTHESIS: AMG145 and REGN727/SAR236553 are human monoclonal antibodies to PCSK9, a serine protease responsible for low-density lipoprotein cholesterol (LDL-C) regulation. PCSK9 binds to LDL receptors targeting them for intracellular degradation. AMG145 and REGN727/SAR236553 blocks the interaction between PCSK9 and the LDL receptor, increasing LDL receptor availability and allowing the removal of LDL-C from the circulation. These therapies have been evaluated as monotherapy and in combination with statins and ezetimibe in phase 2 trials and have demonstrated significant and dose-related reductions in LDL-C. LDL-C reductions were as high as 72% with REGN727/SAR236553 and 66% with AMG145. These agents were generally well tolerated; nasopharyngitis and injection site reactions were the most common reactions with both agents. Gastrointestinal disturbances and infections were also common with REGN727/SAR236553. CONCLUSIONS: These agents may eventually play a role as add-on therapy in those with dyslipidemias because of their significant effect on LDL-C. Further explorations in large phase 3 clinical trials are warranted to evaluate the effect of these therapies on cardiovascular clinical outcomes and long-term safety.

Lecanemab: A Second in Class Therapy for the Management of Early Alzheimer's Disease.

The Food and Drug Administration granted traditional approval of lecanemab for the treatment of Alzheimer's disease (AD). Lecanemab is a humanized anti-amyloid monoclonal antibody directed towards Aß protofibrils. Lecanemab is the only drug that targets Aß soluble protofibrils and has shown statistical differences in mild AD or mild cognitive impairment. In its landmark phase III trial, lecanemab was shown to slow the progression of clinical decline, and a reduction in amyloid protein accumulation. The difference in mean CDR-SOB score improvement between the treatment and placebo groups was -0.45, of which the clinical significance could be argued. Amyloid burden was also considerably reduced as well, but the true clinical consequence of this reduction remains to be seen. This beneficial impact on daily living is offset by rare but serious side effects including amyloid-related imaging abnormalities (ARIA) causing cerebral edema (ARIA-E) or cerebral microhemorrhages or hemosiderin deposits (ARIA-H). Benefits of therapy must be considered against the risk of cerebral microhemorrhages and edema. Affordability must also be taken into consideration. The current estimated yearly cost for twice monthly lecanemab infusion is $26,500. In addition to the significant cost challenges, the frequent infusions may pose concerns related to access. Additional agents within this class are in the pipelines with possibly increased efficacy or decreased adverse events.

Alpha2 Agonist Use in Critically Ill Adults: A Focus on Sedation and Withdrawal Prevention.

The management of sedation in critically ill adults poses a unique challenge to clinicians. Dexmedetomidine, an α2 agonist, has a unique mechanism and favorable pharmacokinetics, making it an attractive intravenous option for sedation and delirium in the intensive care unit. However, patients may be at risk for withdrawal with prolonged use, adding to the complexity of sedation and agitation management in this patient population. Enteral α2 agents have the benefit of cost savings and ease of administration, thus playing a role in the ability to decrease intravenous sedative use and prevent dexmedetomidine withdrawal. Clonidine and guanfacine are the two most common enteral α2 agents utilized for this purpose, however, there is a paucity of evidence regarding the comparative benefit between the two agents. The decision to use one vs the other agent should be determined based on their differing pharmacology, pharmacokinetics, and side effect profile. The most effective dosing strategy for these agents is also unknown. Ultimately, more robust literature is required to determine enteral α2 agonists place in therapy. This narrative review evaluates the currently available literature on the use of α2 agonists in critically ill adults with an emphasis on sedation, delirium, and withdrawal.

Lean into Clinical Pharmacy: An Experience in Implementing Key Performance Indicators and Gemba Walks into Clinical Pharmacy Services.

Purpose: The Lean methodology was applied to clinical metrics by a critical care pharmacy team. The experiences associated with the development and implementation of clinical metrics and their impact on daily workflow are described. Summary: The Lean methodology has been introduced into the healthcare system as a means of process improvement, which can eliminate waste through appropriate medication utilization. At OhioHealth Riverside Methodist Hospital, the department of pharmacy was tasked with the development of clinical metrics after a health system wide Gemba walk was initiated. The pharmacy department's critical care team developed a strategy identifying and evaluating clinical metrics pertaining to their everyday workflow. Each clinical metric was evaluated in accordance with a pre-defined goal. Metrics requiring heavy documentation and those in which the pharmacist does not have autonomous authority to manage were often challenging to implement and were less successful. Throughout this process, the lessons learned focused on generating ideas that were easily documented, evidence-based, and department specific. The critical care team discovered that the outcome of the most successful metrics highlighted clinical pharmacist value and data generated could be used to support funding for additional resources. Conclusion: The critical care pharmacy team developed a streamlined process to implement clinical metrics as means of identifying areas for improvement using the Lean methodology.

Review of the Target-Specific Oral Anticoagulants in Development for the Treatment and Prevention of Venous Thromboembolism.

Anticoagulation therapy is often indicated for the treatment and prevention of venous thromboembolism (VTE). Despite advances in anticoagulant management with parenteral anticoagulants and vitamin K antagonists, limitations to their use still exists, leading to investigation of alternative anticoagulants such as factor Xa inhibitors and direct thrombin inhibitors. To date, 3 target-specific oral anticoagulants (TSOACs) are Food and Drug Administration approved; several other agents are currently in development to optimize VTE management and minimize bleeding risks. The objective of this systematic review article is to provide clinicians an overview of the clinical evidence on the investigational TSOACs for the treatment and prevention of VTE. Of the agents in development, edoxaban holds the most promise due to robust data supporting its clinical benefit with a similar bleeding risk to currently approved agents. Clinicians should understand the TSOACs under investigation, since differences in pharmacokinetics and pharmacodynamics may influence clinical decision making and agent selection for management of VTE. Currently, no direct comparisons between TSOACs have been conducted. Agents under investigation have yet to overcome the major limitations of the currently existing TSOACs. Further studies are necessary to clarify which TSOAC agent is best for management of VTE in clinical practice.