Effect of L-Methylfolate Supplementation on Sleep for Patients with Reduced Methylenetetrahydrofolate Reductase Activity.

INTRODUCTION: Clinicians have limited options outside controlled substances to address sleep disturbance, which left untreated can negatively affect patient outcomes in cardiovascular health, mental health, immunologic function, and more. For some, genetic factors may influence sleep disturbances. L-methylfolate, the active form of folate, plays a critical role in regulation of monoamine neurotransmitters known to have significant impact on sleep regulation: dopamine, serotonin, norepinephrine. Single nucleotide polymorphisms of the enzyme methylene-tetrahydrofolate-reductase are common and can impact monoamine production. The goal of this study was to evaluate effects of L-methylfolate supplementation on sleep in a cohort with reduced methylene tetrahydrofolate reductase (MTHFR) activity. METHODS: A retrospective cohort of patients being treated with L-methylfolate in a concierge medical clinic setting was studied. Patients presenting with sleep complaints were evaluated using the Patient-Reported Outcomes Measurement Information System at baseline. Patients with known MTHFR polymorphisms at either C667T and/or A1298C were recommended 5 mg of L-methylfolate daily and were reevaluated at 2 wks, at 4 wks, and at 8 wks of supplementation. Statistical comparisons were made utilizing ANOVA and T-test comparisons. RESULTS: Ten were included in the final cohort: six male and four female, average age 43 ± 16 years. Beginning at wk 2, average sleep disturbance improved significantly by -6.94 points (p = 0.005) and by 8 wks, all patients had improvement with a -14.34 change in disturbance from baseline (p = 0.001). CONCLUSION: Improvement in sleep disturbance was seen in both low and intermediate function phenotypes. L-methylfolate may be useful for improving sleep in patients with MTHFR polymorphism.

Assessing the Impact of Comprehensive Medication Management on Achievement of the Quadruple Aim.

Nonoptimized medication regimens cost patients and payors in the United States more than $528 billion in additional health care expenses each year. Comprehensive medication management is a patient-centered approach to medication optimization delivered by a clinical pharmacist working with the patient, physicians, and other members of the health care team. Comprehensive medication management ensures medications are assessed for appropriateness, effectiveness, and safety given the patient's clinical status, comorbidities, and other medications, as well as the patient's ability to take the medications as intended and adhere to the regimen. This article reviews the growing body of literature demonstrating the value of comprehensive medication management in achieving the quadruple aim of health care: better care, reduced health care costs, an improved patient experience, and provider well-being.

Dual Antiplatelet Therapy for Long-term Secondary Prevention of Atherosclerotic Cardiovascular Events.

PURPOSE: Dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 inhibitor is currently recommended to prevent further ischemic events after percutaneous coronary intervention and acute coronary syndrome (ACS). Guidelines currently recommend a minimum of 6 months after elective drug-eluting stent placement and at least 12 months of DAPT after ACS; however, the benefits of prolonged treatment are unclear. The purpose of this review was to conduct a detailed examination of the data refuting or supporting the use of DAPT beyond 1 year in patients with ACS and in patients receiving percutaneous coronary intervention with stenting. METHODS: A search of PubMed was performed to identify articles published in the last 20 years that addressed the role of DAPT beyond 12 months' duration. FINDINGS: A number of studies have shown ischemic benefits associated with prolonging DAPT beyond 12 months, but this finding is dependent on the patient population studied and the quality of the study design. Many studies also show that longer duration therapy has been associated with increased bleeding risk. In patients with previous myocardial infarction completing at least 1 year of DAPT, continuing DAPT with a reduced dose of ticagrelor 60 mg BID is a regimen to be considered for these patients; in general ACS patients, a reduced dose of 60 mg BID of ticagrelor after the first year of DAPT should be considered; and in the post-percutaneous coronary intervention patients, DAPT beyond 1 year should be considered after careful evaluation of the patient's thrombotic and bleeding risks. IMPLICATIONS: The duration of DAPT, and the choice of P2Y12 inhibitor, should be tailored to the individual patient. To optimize patient outcomes, the benefits and risks associated with prolonging DAPT need to be evaluated, considering comorbidities and the presence of bleeding and ischemic risk factors. Despite some limitations, risk scores, such as the DAPT score, are available to help guide decisions for the best approach for each patient.

The Fall Risk with Alpha blockers Given InitiaL dose or Elderly status (FRAGILE) Study.

Background: α-1 adrenergic antagonists are commonly prescribed, but there is question regarding their safety in patients at increased fall risk. Objective: The purpose of the FRAGILE study was to determine the risk for developing adverse drug events (ADEs) in veterans prescribed α-1 blockers. Methods: A single-center, retrospective, observational cohort analysis was conducted of veterans newly initiated on α-1 antagonists. Veterans were categorized into at-risk (patients who met at least 1 of 2 criteria: age 65 or older or high initial dose of α blockade) or control (veterans without either risk factor) groups. The primary outcome was the composite all-cause ADEs, including hospitalizations or emergency department (ED) visits. Secondary outcomes included number of fall-related ADEs and medication discontinuation rates with follow-up for 12 months. Results: A total of 300 veterans were evaluated. There was no significant difference in the composite outcome of all-cause ED visits between at-risk (n = 169) versus control (n = 131) groups (0.81 vs 1.17, P = 0.09) or all-cause hospitalizations (0.28 vs 0.39, P = 0.25). Seventy-three veterans in the at-risk group experienced an all-cause ADE versus 64 in the control group (P = 0.36). No significant differences in secondary outcomes were found. Fall-related side effects occurred in 8% of the total cohort. Conclusion and Relevance: Rates of all-cause or fall-related ADEs were not significantly different. An 8% discontinuation rate resulting from fall-related ADEs and high rates of coadministered medications that could increase fall risk. Pharmacists can play a key role in optimizing α-1 blocker administration.

An Underappreciated and Prolonged Drug Interaction Leads to Ineffective Anticoagulation.

A poorly understood significant drug-drug interaction compounded by ineffective communication among providers at times of care transition most likely contributed to multiple thromboembolic events in an 81-year-old patient. Increased awareness of drug interactions with direct oral anticoagulants (DOACs), as well as improved communication among inpatient and outpatient providers at the time of discharge is essential in maximizing efficacy and safety outcomes in patients requiring chronic anticoagulation. When rifampin is coadministered with apixaban, a reduction in apixaban exposure results in decreased efficacy and increased risk for thromboembolic events. The delayed effect of rifampin deinduction should be considered with regard to potential drug interactions even after its discontinuation. Equally as important, patients with multiple comorbidities and polypharmacy are at significant risk from adverse drug events during the transition from hospital to home. All efforts to improve continuity of care at times of transition, including medication reconciliation, prompt delivery of discharge summaries to outpatient providers, effective communication among providers, and patient education are components of a best practices model that has the potential to lower costs, improve medication adherence, decrease adverse drug events, and reduce hospital readmissions.

A New Option for Reversing the Anticoagulant Effect of Factor Xa Inhibitors: Andexanet Alfa (ANDEXXA).

The use of direct oral anticoagulants over traditional warfarin has increased in the United States over the past 10 years because of advantages such as ease of use, predictable pharmacokinetic response, and safety. In 2015, the U.S. Food and Drug Administration approved idarucizumab (Praxbind) for the reversal of the direct thrombin inhibitor dabigatran, but no reversal agent has been available for oral factor Xa (FXa) inhibitors until recently. Andexanet alfa was approved in May 2018, under the brand name ANDEXXA, for the reversal of 2 of FXa inhibitors, apixaban and rivaroxaban, when life-threatening or uncontrolled bleeding occurs. This accelerated approval was based on change in anti-FXa activity from baseline that indicated a reversal of the anticoagulant effect. Any expanded Food and Drug Administration indication will be contingent on results demonstrating improved hemostasis and efficacy for reversing other FXa inhibitors.

Contemporary Management of Direct Oral Anticoagulants During Cardioversion and Ablation for Nonvalvular Atrial Fibrillation.

As overall prevalence of atrial fibrillation (AF) continues to rise, the number of patients who undergo ablation, or electrical/chemical cardioversion, to restore normal sinus rhythm continues to increase as well. As direct oral anticoagulants (DOACs) have continued to be incorporated into clinical practice for long-term anticoagulation for AF, experience with how best to manage use of DOACs during electrophysiologic procedures is evolving. This review is intended to provide health care providers with a summary of current evidence regarding the use of DOACs during cardioversion and catheter ablation and provide key considerations for their use during such electrophysiologic procedures. PubMed and MEDLINE were searched from inception through June 2018 for studies in humans comparing DOACs alone or against vitamin K antagonists (VKAs) in adult patients (> 18 yrs) who underwent cardioversion or AF catheter ablation using the following key words: "rivaroxaban," "dabigatran," "apixaban," "edoxaban," "non-vitamin K antagonists," "direct or new oral anticoagulants," "warfarin," "vitamin K antagonists," "cardioversion," "ablation of atrial fibrillation," "uninterrupted," and "catheter ablation." Four retrospective studies and three prospective trials comparing DOACs with VKA in patients undergoing cardioversion and three prospective studies in patients undergoing catheter ablation for AF were identified. Observational data and meta-analyses were also critically reviewed. Prospective trials to date suggest similar efficacy and safety with using DOACs in the setting of cardioversion and AF ablation compared to traditional therapy with VKA, with or without bridging. Injectable anticoagulant overlap can be avoided in patients receiving DOACs in the setting of cardioversion for AF. Minimal interruption in anticoagulation may be only necessary for AF ablation in those with highest bleeding risk, such as in renal dysfunction and where drug-drug interactions may increase risk for anticoagulant accumulation. Periprocedural advantages of DOACs include convenience, rapid and predictable onset of effect, improved patient satisfaction, and potential for reduced costs.

Periprocedural Management of Direct Oral Anticoagulants Surrounding Cardioversion and Invasive Electrophysiological Procedures.

As direct oral anticoagulants (DOACs) have demonstrated favorable efficacy and safety outcomes compared with vitamin K antagonists for the treatment and prevention of venous thromboembolism and the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation, their role in the management of anticoagulation during electrophysiological procedures continues to evolve. At present, guidelines are limited regarding specific recommendations for the use of DOACs in these clinical settings. Here, we review available data regarding the risks and benefits associated with various periprocedural anticoagulation management approaches when patients receiving DOACs undergo electrophysiologic procedures including cardioversion, ablation, and device implantation. This discussion is intended to provide clinicians with an overview of available evidence and best practices to minimize the risk of both thromboembolic and bleeding events in the periprocedural setting.

Evaluation of bleeding in patients receiving direct oral anticoagulants.

Direct oral anticoagulants (DOACs) are recognized by evidence-based treatment guidelines as the first-line option for the treatment of venous thromboembolism and prevention of stroke and systemic embolism in nonvalvular atrial fibrillation. As use of these anticoagulants has become favored over the past several years, reported bleeding-related adverse drug events with these agents has increased. In randomized clinical trials, all DOACs have a reduced risk for intracranial hemorrhage, while major and other bleeding results have varied among the agents compared to vitamin K antagonists. We have reviewed the bleeding incidence and severity from randomized and real-world data in patients receiving DOACs in an effort to provide the clinician with a critical review of bleeding and offer practical considerations for avoiding adverse events with these anticoagulants.

Edoxaban: How Does the Newest Agent Fit into the DOAC Landscape?

Edoxaban is the most recently approved factor Xa inhibitor within the class of direct oral anticoagulants (DOACs). Like other DOACs, edoxaban was approved by the US Food and Drug Administration for treatment of venous thromboembolism and prevention of stroke in patients with nonvalvular atrial fibrillation. Similar to other DOACs, edoxaban has fewer drug-drug interactions than warfarin and does not require routine laboratory monitoring. Unlike other DOACs, edoxaban has yet to be approved for secondary or postoperative venous thromboembolism thromboprophylaxis. Currently no antidote for edoxaban is available. To optimally prescribe agents in the DOAC class, it is critical that providers 1) understand how the agents compare; and 2) identify specific settings in which one agent may be preferred over another.

Reversal Agents for Direct Oral Anticoagulants: Understanding New and Upcoming Options.

Direct oral anticoagulants (DOACs), originally developed as an alternative for vitamin K antagonists, are shifting the landscape of antithrombotic therapy. DOACs such as dabigatran, rivaroxaban, apixaban, and edoxaban offer enhancements in safety, convenience, and efficacy compared with warfarin. However, as choices for oral anticoagulation therapy have increased, so has the need for effectual antidotes before urgent surgical procedures and for the reversal of serious adverse events caused by DOACs. To date, one antidote has been FDA approved in the United States for the reversal of dabigatran, and two antidotes are undergoing phase 2and 3clinical trials. This review will summarize currently available and developing data for DOAC antidotes: idarucizumab, exanet alfa, and ciraparantag.

Student Pharmacists' Perceptions of a Composite Examination in Their First Professional Year.

OBJECTIVE: To assess first-year (P1) pharmacy students' studying behaviors and perceptions after implementation of a new computerized "composite examination" (CE) testing procedure. METHODS: Student surveys were conducted to assess studying behavior and perceptions about the CE before and after its implementation. RESULTS: Surveys were completed by 149 P1 students (92% response rate). Significant changes between survey results before and after the CE included an increase in students' concerns about the limited number of questions per course on each examination and decreased concerns about the time allotted and the inability to write on the CEs. Significant changes in study habits included a decrease in cramming (studying shortly before the test) and an increase in priority studying (spending more time on one course than another). CONCLUSION: The CE positively changed assessment practice at the college. It helped overcome logistic challenges in computerized testing and drove positive changes in study habits.

Management of Venous Thromboembolism: Recent Advances in Oral Anticoagulation Therapy.

OBJECTIVE: To review clinical data on direct oral anticoagulants (DOACs) used in the acute treatment of venous thromboembolism (VTE) as well as practical considerations when using these products. DATA SOURCES: Searches of PubMed and Google Scholar for VTE, deep vein thrombosis, pulmonary embolism, and relevant drug international nonproprietary names were conducted. Additional online searches were conducted for prescribing information. STUDY SELECTION AND DATA EXTRACTION: Relevant articles on dabigatran, rivaroxaban, apixaban, and edoxaban for the management of VTE compared with oral vitamin K antagonists (VKAs; published between 1966 and December 2015) were reviewed and summarized, together with information on dosing, pharmacokinetics/pharmacodynamics, and drug-drug interactions. DATA SYNTHESIS: The DOACs have the potential to circumvent many of the disadvantages of VKAs. At a minimum, they greatly increase the available therapeutic options, thus providing a greater opportunity for clinicians to select a management option that best fits the needs of individual patients. Despite the significant advance that DOACs represent, they are not without risk and require careful consideration of a number of clinical issues to optimize safety and efficacy. CONCLUSIONS: The emergence of DOACs for the management of thromboembolic disorders represents a paradigm shift from oral VKAs. The DOACs provide similar efficacy and improved safety in selected patients as compared with VKAs. Clinicians treating VTE need to be familiar with the intricacies involved in using these agents, including the appropriate dose selection for the relevant indication, avoidance of drug-drug and drug-disease interactions, and consideration of dose adjustments in specific clinical situations, such as organ dysfunction.

Heparin Versus Bivalirudin Monotherapy in the Setting of Primary Percutaneous Coronary Intervention for Patients With ST-Segment Elevation Myocardial Infarction.

OBJECTIVE: To evaluate direct comparisons of bivalirudin versus unfractionated heparin (UFH) as anticoagulants during ST-segment elevation myocardial infarction (STEMI) in patients undergoing primary percutaneous coronary intervention (PPCI). DATA SOURCES: Relevant information was identified through a search of MEDLINE (1966-September 2015), International Pharmaceutical Abstracts (1960-September 2015), and Cochrane Databases (publications archived until September 2015) using the terms bivalirudin, unfractionated heparin, ST-segment elevation myocardial infarction, and primary percutaneous coronary intervention. STUDY SELECTION AND DATA EXTRACTION: English-language randomized controlled trials and meta-analyses were eligible for inclusion for data review of STEMI where PPCI was performed. DATA SYNTHESIS: Either bivalirudin or UFH is recommended in the setting of STEMI where PPCI is to be performed. Bivalirudin is touted for its predictable pharmacokinetics, effects on thrombin-mediated platelet inhibition, and favorable outcomes with regard to adverse bleeding profiles, whereas UFH, the gold standard anticoagulant during PPCI, remains a viable treatment strategy. Only recently have direct comparisons of UFH and bivalirudin during PPCI become available. The evidence available is complicated by variances in use of glycoprotein IIb/IIIa inhibitors (GPIs), P2Y12 inhibitors, access sites, and anticoagulant dosing strategies. We provide a review of contemporary trials and advancements in this area. CONCLUSIONS: When compared to UFH with limited use of GPI, available evidence demonstrates that bivalirudin reduces bleeding at the expense of increasing risk for acute stent thrombosis. Further randomized studies are needed to determine the potential benefits of a post-PCI infusion of bivalirudin to reduce the risk for acute stent thrombosis, long-term follow-up beyond 30 days, and mortality.

Clinical efficacy and safety of cilostazol: a critical review of the literature.

Cilostazol is a unique antiplatelet agent that has been commercially available for over two decades. As a phosphodiesterase III inhibitor, it reversibly inhibits platelet aggregation yet also possesses vasodilatory and antiproliferative properties. It has been widely studied in a variety of disease states, including peripheral arterial disease, cerebrovascular disease, and coronary artery disease with percutaneous coronary intervention. Overall, cilostazol appears to be a promising agent in the management of these disease states with a bleeding profile comparable to placebo; even when combined with other antiplatelet agents, cilostazol does not appear to increase the rate of bleeding. Despite the possible benefit of cilostazol, its use is limited by tolerability as some patients often report drug discontinuation due to headache, diarrhea, dizziness, or increased heart rate. To date, it has been predominantly studied in the Asian population, making it difficult to extrapolate these results to a more diverse patient population. This paper discusses the evolving role of cilostazol in the treatment of vascular diseases.