• 17 Nov 2021 11:53 AM | Anonymous

    Program Number:   2021-10-02
    Approved Dates:    December 1, 2021-June 1, 2022
    Approved Contact Hours:  One Hour(s) (1) CE(s) per session

    Pharmacist Continuing Education: 2021 Rheumatoid Arthritis Guideline Update and Therapy Review Authors: Annie Ungerman, PharmD, BCPS, University Health - Kansas City, MO and Mary Beth Seipel, PharmD, BCACP, University Health - Kansas City, MO

     

    Learning Objectives:

    1. Describe physical exam and laboratory findings that are common in those diagnosed with rheumatoid arthritis.
    2. Recognize initial treatment strategies for rheumatoid arthritis.
    3. Interpret levels of disease activity of the different instruments available to measure.
    4. Identify different therapies available used in treating rheumatoid arthritis and important monitoring parameters.
    5. Distinguish how special populations require alterations in treatment plans.

    What is Rheumatoid Arthritis?

    Rheumatoid arthritis (RA) is an autoimmune disorder with unknown etiology that is commonly characterized by chronic inflammation, severe pain, joint stiffness, fatigue, and limited mobility.1,2 RA usually leads to destruction of joints due to erosion of cartilage and bone, which may cause joint deformities. Onset can occur at any time, but incidence increases with age. Women are more likely to be diagnosed than men are (by two-to-three times). Other characteristics that are more common in those developing rheumatoid arthritis are women who have never given birth, cigarette smoking, and obesity.1,2 Early evaluation, diagnosis, and management are imperative in achieving adequate control of disease and prevention of further progression.3  

    Early evaluation for suspected RA1

    Diagnosis of RA often relies on a detailed past medical history, thorough physical examination, pertinent laboratory tests, and radiographic evidence consistent with joint damage. Radiographs of the hands, wrists, and feet are frequently used as a baseline for monitoring disease activity or progression.

    Pertinent information to collect and examine may include, but is not limited to the following: 

    • Distribution of swollen or tender joints
    • Location & severity of joint pain/swelling
    • Duration of morning stiffness
    • Range of motion for affected joints
    • Length of symptoms

    The following laboratory tests should be considered and may support a diagnosis of RA if positive and/or elevated:

    • Rheumatoid factor (RF)
      • Abnormal level: >14 IU/mL
    • Anti-citrullinated peptide antibodies (ACPA) 
      • Abnormal level: >20 EU/mL
    • Erythrocyte sedimentation rate (ESR) 
      • Abnormal level: >20 mm/hr
    • Serum C-reactive protein (CRP)
      • Mild inflammation: 1-5 mg/dL
      • Severe inflammation: >5-10 mg/dL
      • Serious processes/bacterial infection: >10 mg/dL

    Diagnosis of RA4

    Based on the 2010 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) Classification criteria for RA (as described below), classification of “definite RA” is outlined as:

    • Presence of synovitis (swelling) in ≥ 1 joint
    • Lack of an alternative diagnosis that better explains the synovitis
    • Score of ≥6/10 (based on the criteria presented in Table 1 below)

    Management of RA3

    Pharmacological treatment of RA involves the following:

    • Conventional synthetic disease-modifying antirheumatic drugs (csDMARDs)
    • Biologic disease-modifying antirheumatic drugs (bDMARDs)
    • Targeted synthetic disease-modifying antirheumatic drugs (tsDMARDs)
    • Glucocorticoids

    A treat-to-target approach is recommended for individuals who have not been previously treated with or have experienced an inadequate response to bDMARDs or tsDMARDs. This approach involves frequent monitoring of disease activity levels through the use of validated instruments. Modifications to an individual’s treatment are implemented based on response to prescribed therapy, which is determined by a reduction in disease activity. The overall goal of pharmacological treatment is to achieve a predefined target of low disease activity or remission. It is recommended to reevaluate treatment decisions within a minimum of 3 months based on efficacy and tolerability of prescribed DMARDs.3

    Instruments to measure RA disease activity are recommended by the ACR for use to further define levels of disease activity (low, moderate, high) based on a variety of factors, including patient-reported symptoms, provider assessments, laboratory values, and/or imaging modalities.5 Table 2 shares details regarding thresholds of disease activity based on the tool used. The DAS28, CDAI, and SDAI all require a 28 count of specific joints, stating if they are tender and/or swollen joints. They vary in whether they incorporate an inflammatory marker or patient/provider rating of global health. Both the RAPID-3 and PAS II have similar questions on patient reported ability in being able to carry out 10 different tasks, a pain assessment, and/or a personal assessment.6-10


    Moderate-to-high disease activity:

    In patients that have moderate-to-high disease activity and are DMARD naive, methotrexate is strongly recommended over hydroxychloroquine or sulfasalazine and bDMARDs or tsDMARD monotherapy. In this same patient population, methotrexate is conditionally recommended over leflunomide, dual or triple csDMARD therapy, or combination of methotrexate plus a TNF inhibitor.Methotrexate is recommended in this patient population due to its established efficacy and low cost. When initiating methotrexate, the oral formulation is preferred over subcutaneous as bioavailability is comparable at initial dosing and ease of use. If patients have issues tolerating oral methotrexate, management strategies include dividing the weekly dose over 24 hours, switching to a subcutaneous route of administration, or increasing folic acid dosing. These are all recommended over switching to an alternative DMARD.3 

    Glucocorticoids:

    The use of glucocorticoids for patients with moderate-to-high disease activity during initiation of csDMARD therapy for short-term (<3 months) or long-term (≥3 months) use is not recommended as the risks of toxicity outweigh the benefits. If a patient is unable to remain at target without glucocorticoids, it is conditionally recommended to add or switch DMARDs.3 

    Low disease activity:

    In patients with low disease activity and are DMARD naive, hydroxychloroquine is conditionally recommended over any other csDMARDs, sulfasalazine is conditionally recommended over methotrexate, and methotrexate is conditionally recommended over leflunomide.3 

    Pharmacological Treatment:

    DMARDs that were mentioned in the guidelines as treatment options for rheumatoid arthritis are listed in tables 3, 4 and 5. Typical dosing, adjustments and additional information are shared below.

    TABLE 4: (download the PDF)


    Recommendations for specific patient populations:

    The 2021 RA guidelines address management of RA in individuals with specific comorbidities. Certain populations are discussed for the first time, including those with subcutaneous nodules, non-alcoholic fatty liver disease, and pulmonary disease.3

    Subcutaneous nodules

    Methotrexate is conditionally recommended over alternative DMARDs if subcutaneous nodules are present in an individual with moderate-to-high disease activity. However, in the presence of progressive subcutaneous nodules, switching to an alternative DMARD is conditionally recommended because methotrexate may be associated with accelerated nodulosis.3, 27 

    Pulmonary disease

    If moderate-to-high disease activity is present, methotrexate is conditionally recommended over alternative DMARDs for individuals with clinically diagnosed mild and stable airway or parenchymal lung disease, or incidental disease detected on imaging.3 Preexisting lung disease is a risk factor for methotrexate-related pneumonitis.28,29 However, its use remains conditionally recommended due to its efficacy and lack of alternatives with similar benefits or superior long-term safety profiles. Those with preexisting lung disease should be educated on their increased risk of methotrexate-related pneumonitis before starting treatment.3

    Heart failure (HF)

    Risk of worsened HF was observed in trials of TNF inhibitors given to individuals with New York Heart Association class III or IV HF without RA.30,31 The low quality of evidence available resulted in the conditional recommendations to follow. If an individual with NYHA class III or IV HF has an inadequate response to csDMARDs, addition of a non-TNF inhibitor bDMARD or tsDMARD is conditionally recommended over addition of a TNF inhibitor. Additionally, if an individual develops HF while taking a TNF inhibitor, switching to a non-TNF inhibitor bDMARD or tsDMARD is conditionally recommended.3

    Lymphoproliferative disorder

    For individuals with moderate-to-high disease activity and history of a previous lymphoproliferative disorder, rituximab is conditionally recommended over other DMARDs because it is not expected to increase risk of recurrence or worsening of these disorders.3

    Hepatitis B infection

    Those at risk for hepatitis B reactivation should be comanaged with a hepatologist. Prophylactic antiviral therapy is strongly recommended over frequent monitoring of viral load and liver enzymes alone for individuals starting rituximab who are hepatitis B core antibody positive, regardless of hepatitis B surface antigen status. If an individual is hepatitis B core antibody positive and hepatitis B surface antigen positive, prophylactic antiviral therapy is strongly recommended over frequent monitoring alone when initiating any bDMARD or tsDMARD. Due to uncertainty regarding benefit versus risk of prophylactic antiviral therapy and cost associated with use, frequent monitoring alone is conditionally recommended for individuals starting a bDMARD (other than rituximab) or a tsDMARD who are hepatitis B core antibody positive and hepatitis B surface antigen negative.3 

    Nonalcoholic fatty liver disease (NAFLD)

    For DMARD-naive individuals with moderate-to-high disease activity and NAFLD with normal liver enzymes, liver function tests, and no evidence of advanced liver fibrosis, methotrexate is conditionally recommended over alternative DMARDs. Consultation with a gastroenterologist or hepatologist should be considered prior to initiating methotrexate in individuals with NAFLD.3 

    Persistent hypogammaglobulinemia without infection

    The clinical significance of hypogammaglobulinemia in individuals without infection remains unknown. Continuation of rituximab for individuals at target is conditionally recommended over switching to an alternative bDMARD or tsDMARD in the setting of persistent hypogammaglobulinemia without infection. It is uncertain if switching to a different DMARD in those who are at target reduces infection risk to a larger degree while maintaining disease control versus continuation of rituximab.3  

    Previous serious infection

    The 2021 guidelines define a serious infection as an infection requiring intravenous antibiotics or hospitalization. Addition of csDMARDs is conditionally recommended versus bDMARD or tsDMARD for individuals with moderate-to-high disease activity who have experienced a serious infection within the past 12 months.3 This conditional recommendation is based on observational data, which suggests a lower risk of infection associated with combination csDMARDs compared to bDMARDs or tsDMARDs.32 

    Nontuberculous mycobacterial (NTM) lung disease

    Due to the variability of NTM lung disease severity and response to treatment, individuals should be closely comanaged with an infectious diseases or pulmonary specialist. Studies suggest an increased risk of NTM lung disease in individuals receiving inhaled or oral glucocorticoids.33,34 Therefore, discontinuation or use of the lowest possible dose of glucocorticoids is conditionally recommended for those with NTM lung disease.3 Due to lower expected risk of NTM lung disease, addition of csDMARDs is conditionally recommended versus bDMARD or tsDMARD for individuals with moderate-to-high disease activity.35 For individuals with NTM lung disease and moderate-to-high disease activity despite use of csDMARDs, abatacept is conditionally recommended over other bDMARDs and tsDMARDs.3 

    Key takeaways and future considerations:

    1. Methotrexate is recommended as monotherapy for most individuals over other DMARDs and should generally be initiated first in those with moderate to high disease activity.3 
    1. Maximize the methotrexate dose prior to adding or switching medications. If an individual is not at target when prescribed oral methotrexate, changing to a subcutaneous route of administration should be considered versus switching to or adding a different DMARD.3
    1. If an individual has low disease activity, use of hydroxychloroquine over other csDMARDs (including methotrexate) is conditionally recommended due to a more favorable side effect profile.3 
    1. Minimize use of glucocorticoids if and when possible. Initiation of a csDMARD without prescribing a short-term course of glucocorticoids is conditionally recommended in those with moderate-to-high disease activity who have not previously taken a DMARD.3 
    1. New and updated recommendations for RA treatment in special populations may help inform clinical decisions.3 
    1. The 2021 RA guidelines are not a comprehensive compilation of current recommendations regarding RA management. Previous guidelines provide additional guidance on information such as pre-treatment screening and routine laboratory monitoring.36-38 
    1. Future guidelines will address approaches to non-pharmacologic treatment and vaccine use.3 

    Take the Quiz for CE

    References: 

    1. CDC. Rheumatoid arthritis (RA). www.cdc.gov/arthritis/basics/rheumatoid-arthritis.html. Accessed October 4, 2021.
    2. Kohler BM, Gunther J, Kaudewitz D, Lorenz HM. Current therapeutic options in the treatment of rheumatoid arthritis. J Clin Med. 2019;8(7):938.
    3. Fraenkel L, Bathon JM, England BR, et al. 2021 American College of Rheumatology guidelines for the treatment of rheumatoid arthritis. Arthritis Care and Res. 2021;73(7):924-939.
    4. Aletaha D, Neogi T, Silman AJ, et al. 2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum. 2010 Sep;62(9):2569-81.
    5. England BR, Tiong BK, Bergman MJ, et al. 2019 Update of the American College of Rheumatology recommended rheumatoid arthritis disease activity measures. Arthritis Care Res (Hoboken). 2019;71:1540–55.
    6. Fransen J, Stucki G, van Riel P. Rheumatoid arthritis measures: Disease Activity Score (DAS), Disease Activity Score-28 (DAS28), Rapid Assessment of Disease Activity in Rheumatology (RADAR), and Rheumatoid Arthritis Disease Activity Index (RADAI). Arthritis Rheum. 2003;49 Suppl:S214–24.
    7. Aletaha D, Nell VP, Stamm T, et al. Acute phase reactants add little to composite disease activity indices for rheumatoid arthritis: validation of a clinical activity score. Arthritis Res Ther. 2005;7:R796–806.
    8. Smolen JS, Breedveld FC, Schiff MH, et al. A simplified disease activity index for rheumatoid arthritis for use in clinical practice. Rheumatology (Oxford) 2003;42:244–57.
    9. Pincus T, Yazici Y, Bergman M. A practical guide to scoring a Multi-Dimensional Health Assessment Questionnaire (MDHAQ) and Routine Assessment of Patient Index Data (RAPID) scores in 10–20 seconds for use in standard clinical care, without rulers, calculators, websites or computers. Best Pract Res Clin Rheumatol. 2007;21:755–87.
    10. Wolfe F, Michaud K, Pincus T. A composite disease activity scale for clinical practice, observational studies, and clinical trials: the patient activity scale (PAS/PAS-II). J Rheumatol 2005;32:2410–5.
    11. Leflunomide. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL.  Accessed October 10, 2021. http://online.lexi.com
    12. Methotrexate. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL.  Accessed October 10, 2021. http://online.lexi.com
    13. Hydroxychloroquine. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL.  Accessed October 10, 2021. http://online.lexi.com
    14. Sulfasalazine. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL.  Accessed October 10, 2021. http://online.lexi.com
    15. Entanercept. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL.  Accessed October 10, 2021. http://online.lexi.com
    16. Adalimumab. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL.  Accessed October 10, 2021. http://online.lexi.com
    17. Certolizumab. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL.  Accessed October 10, 2021. http://online.lexi.com
    18. Golimumab. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL.  Accessed October 10, 2021. http://online.lexi.com
    19. Infliximab. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL.  Accessed October 10, 2021. http://online.lexi.com
    20. Abatacept. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL.  Accessed October 10, 2021. http://online.lexi.com
    21. Tocilizumab. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL.  Accessed October 10, 2021. http://online.lexi.com
    22. Sarilumab. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL.  Accessed October 10, 2021. http://online.lexi.com
    23. Rituximab. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL.  Accessed October 10, 2021. http://online.lexi.com
    24. Tofacitinib. Rituximab. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL.  Accessed October 10, 2021. http://online.lexi.com
    25. Baricitinib. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL.  Accessed October 10, 2021. http://online.lexi.com
    26. Upadacitinib. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL.  Accessed October 10, 2021. http://online.lexi.com
    27. Patatanian E, Thompson DF. A review of methotrexate-induced accelerated nodulosis. Pharmacotherapy. 2002;22:1157–62.
    28. Alarcon GS, Kremer JM, Macaluso M, et al. Risk factors for methotrexate-induced lung injury in patients with rheumatoid arthritis: a multicenter, case-control study. Ann Intern Med. 1997;127:356–64. 
    29. Bartram SA. Experience with methotrexate-associated pneumonitis in northeastern England: comment on the article by Kremer et al [letter]. Arthritis Rheum. 1998;41:1327–8.
    30. Chung ES, Packer M, Lo KH, et al. Randomized, double-blind, placebo-controlled, pilot trial of infliximab, a chimeric monoclonal antibody to tumor necrosis factor alpha, in patients with moderate-to-severe heart failure: results of the anti-TNF Therapy Against Congestive Heart Failure (ATTACH) trial. Circulation. 2003;107:3133–40. 
    31. Mann DL, McMurray JJ, Packer M, et al. Targeted anticytokine therapy in patients with chronic heart failure: results of the Randomized Etanercept Worldwide Evaluation (RENEWAL). Circulation. 2004;109:1594–602.
    32. Ozen G, Pedro S, England BR, Mehta B, Wolfe F, Michaud K. Risk of serious infection in patients with rheumatoid arthritis treated with biologic versus nonbiologic disease-modifying antirheumatic drugs. ACR Open Rheumatol. 2019;1:424–32.
    33. Liu VX, Winthrop KL, Lu Y, et al. Association between inhaled corticosteroid use and pulmonary nontuberculous mycobacterial infection. Ann Am Thorac Soc. 2018;15:1169–76. 
    34. Liao TL, Lin CF, Chen YM, et al. Risk factors and outcomes of nontuberculous mycobacterial disease among rheumatoid arthritis patients: a case-control study in a TB endemic area. Sci Rep. 2016;6:29443.
    35. Brode SK, Jamieson FB, Ng R, Campitelli MA, Kwong JC,  et al. Increased risk of mycobacterial infections associated with anti-rheumatic medications. Thorax. 2015;70:677–82.
    36. Singh JA, Saag KG, Bridges SL Jr, et al. 2015 American College of Rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis Rheumatol. 2016;68:1–26.
    37. Saag KG, Teng GG, Patkar NM, et al. American College of Rheumatology 2008 recommendations for the use of nonbiologic and biologic disease-modifying antirheumatic drugs in rheumatoid arthritis. Arthritis Rheum. 2008;59:762–84.
    38. Singh JA, Furst DE, Bharat A, et al. 2012 update of the 2008 American College of Rheumatology recommendations for the use of disease-modifying antirheumatic drugs and biologic agents in the treatment of rheumatoid arthritis. Arthritis Care Res (Hoboken). 2012;64:625–39.


  • 17 Nov 2021 11:47 AM | Anonymous

    The MSHP R&E Foundation has successfully completed the first occurrence of both our Resident Ground Rounds series and our Preceptor Development Series. 

    Information for the Resident Ground Rounds Series can be found here: https://www.moshp.org/event-4540419

    This series is expected to run routinely (approximately every other week) for the next several months.  We are excited to bring this offering forward to provide a vehicle for residents within the state to continue to hone their presentations skills as well as share new information with other pharmacy practitioners (pharmacists, technicians, and students) throughout the state.  These sessions are available for CE through the Missouri State Board of Pharmacy.

    Our first session of our new Preceptor Development Series occurred on October 26th with MSHP President Christina Stafford as our first presenter.  The event was a success and will be continued with new presenters, different topics, and various presentation methods.  Our goal is to offer this series quarterly, please look for more information via e-blasts in the near future.

    Lastly, it is time to start thinking about nominations for the R&E Foundation annual awards.  Nominations for our three awards (Best Practice Award, Tonnies Preceptor Award, and The Garrison Award) are currently open.  The nomination/submission deadline is January 14th, 2022.

    Information about each award and the respective criteria can be found below:

    MSHP R&E Best Practice Award

    The Best Practice Award recognizes innovation and outstanding performance in health-system pharmacy.  A poster of the program will be highlighted during the Spring Meeting Poster Session.

    Applicants will be judged based on the following criteria:

    • Inventiveness of the project
    • Significance of the project to the health system
    • Demonstration of benefit to patient care as supported by project evaluation data
    • Significance of the project to pharmacy practice
    • Quality of submitted project report
    • Relevance to other institutions

    Applicants must be active MSHP members in a health-system setting such as a large or small hospital, home health, ambulatory clinic, or other health care system.

    Award recipient will receive a $250 honorarium.

    Submission Instructions: A program summary not to exceed 400 words must be submitted with the application and include the following information.

    • Background – description of need for project
    • Goals and specific aims of the project
    • Results - when results are not yet available, include a description of how impact of the project will be measured
    • Conclusion – established and/or expected clinical impact of the project
    • Email your submission to mshp@qabs.com with Best Project Award Submission in the subject line.

    Tonnies Preceptor of the Year Award

    MSHP R&E Foundation is pleased to honor a health system pharmacist for outstanding service to the profession as a preceptor to pharmacy students and/or residents. Below are the Criteria and Procedures to nominate a preceptor for the award.

    Eligibility:

    • Must be a member of MSHP;
    • Must have been a clinical preceptor for minimum of 3 years;
    • Must have not received the award within the last five years; attention will be given to previous nominations.

    Criteria:

    The award will be presented to a health system pharmacist that exemplifies the core values (Professionalism, Desire to educate and share knowledge with students, Willingness to mentor, Willingness to commit the time necessary for precepting, Respect for others, Willingness to work with a diverse student population) and the following characteristics:

    • Partner in education: Is actively involved in instructing and educating in pharmacy practice
    • Role model: Demonstrates willingness to mentor and serve as an example
    • Experience: Has depth of experience and knowledge in area of expertise
    • Coaching: Provides timely and meaningful feedback to the learner
    • Enthusiasm: Demonstrates passion towards the profession and advancement of practice
    • Professionalism: Conducts himself/herself with highest level of dignity and professionalism
    • Teamwork: Facilitates teamwork and approach to patient care
    • Opportunity: Creates innovative learning experiences and opportunities to for growth
    • Research: Makes regular contributions to the profession through papers or presentations
    • Education
    • Evaluation
    • Investment
    • Negotiation

    Garrison Award

    The Garrison award was established in 1985, named after Thomas Garrison for his long-standing support of MSHP (past-president 1974-1976), ASHP (past-president 1984) and numerous professional and academic contributions to Pharmacy. The Garrison Award is presented each year in which a deserving candidate has been nominated in recognition of sustained contributions in multiple areas:

    • Outstanding accomplishment in practice in health-system pharmacy;
    • Outstanding poster or spoken presentation at a state or national meeting;
    • Publication in a nationally recognized pharmacy or medical journal;
    • Demonstrated activity with pharmacy students from St. Louis or the UMKC Schools of Pharmacy;
    • Development of an innovative service in a health-system pharmacy in either education, administration, clinical service, or distribution;
    • Contributions to the profession through service to ASHP, MSHP and/or local affiliates.

    Each letter of nomination must include:

    • Name, work address, and telephone number of nominee;
    • Name, work address, and telephone number of nominator;
    • Sufficient explanation and documentation of the nominee’s accomplishment(s) to allow a proper decision by the selection committee; and Curriculum Vitae of the Nominee.
    • To be considered for the Garrison Award, the nominee must be a current active member of the Missouri Society of Health-System Pharmacists. The winner will be selected by the Board of Directors of the MSHP Research and Education Foundation. Email your nomination to mshp@qabs.com with Garrison Award Submission in the subject line.

    Respectfully submitted,

    Tony Huke, Pharm.D., BCPS
    MSHP R&E Executive Director

  • 14 Oct 2021 7:53 AM | Anonymous

    By: Sreemathi Palanisamy, PharmD Candidate 2022, Thara Kottoor, PharmD Candidate 2022, St. Louis College of Pharmacy at University of Health Sciences and Pharmacy in St. Louis 

    Mentor: Haley N. Johnson, PharmD, BCPS; Assistant Professor, Department of Pharmacy Practice, St. Louis College of Pharmacy at University of Health Sciences and Pharmacy in St. Louis

    The general population is aging as 10,000, “Baby Boomers,” are turning 65 years old each day in the United States. It is predicted that older adults will comprise 20% of the population by the year 2030.1 With the increasing geriatric population, the number of patients with age-related chronic conditions is rising, as well. Elderly patients are prescribed multiple medications to control their chronic illnesses, which increases the risk for adverse events, poor adherence, and direct and indirect healthcare costs.

    Polypharmacy, the use of at least five medications,is a growing peril as our healthcare system is heavily driven by evidence-based medicine.2 Specifically, antihypertensive medications are commonly prescribed in older populations to prevent strokes and cardiovascular diseases. Although efficacious, the agents can also increase the risk of falls, which could potentially be fatal, induce cognitive decline, and decrease overall quality of life. “Deprescribing,” is a method used to adjust medications to their minimum effective dosage or ceasing therapy if the harm outweighs the benefits of treatment. Although best practice recommendations such as the Beers, STOPP, and START criteria, highlight using clinical judgment and taking a patient-specific approach when prescribing antihypertensives in elderly patients, there has been a lack of data and literature noting the long term effects after antihypertensive medications have been deprescribed in the geriatric population.3,4

    The Systolic Blood Pressure Trial (SPRINT) compared two strategies for treating systolic blood pressure (SBP) in reducing the incidence of several cardiovascular events and death, one that targeted a systolic blood pressure (SBP) of <140 mm Hg and another that targeted a more intensive SBP target of <120 mm Hg. Patients who were 50 years or older, had an average baseline SBP ≥ 130 mmHg, and at high cardiovascular risk were included in the study. Although higher rates of adverse events were observed in the intensive treatment group, the study supported an intensive treatment for a target SBP of 120 mm Hg for a significant 34% reduction in fatal and CVD events compared to patients who were treated with a SBP target of 140 mmHg.5 These results were consistent among all the age groups that participated in the study, including patients who are 75 year of age or older.  However, the SPRINT trial did not include geriatric patients with multiple comorbidities including diabetes, dementia, stroke, and other conditions that would reduce participants’ life expectancy, so the study is limited by its lack of generalizability to patients who may experience more adverse events with intensive blood pressure goals.

    Even though medication de-escalation is believed to attenuate efficacy, research has shown that adequate hypertension management can be achieved with fewer drug interventions. Specifically, the Hypertension in Very Elderly Trial (HYVET) found that the antihypertensive indapamide (a thiazide-like diuretic), with or without perindopril (an angiotensin-converting enzyme inhibitor), was beneficial in reducing the risk of fatal or nonfatal stroke, heart failure, and death from stroke or any cause in patients aged 80-89 years old treated to a target blood pressure of 150/80 mm Hg.6 However, the HYVET trial had extensive exclusion criteria, excluding patients with dementia, renal failure, and nursing home residents. 6 Thus, the narrowed participant pool does limit the external validity of the trial’s applicability to a wide range of elderly patients.

    According to the Optimizing Treatment for Mild Systolic Hypertension in Elderly (OPTIMISE) randomized control trial, patients 80 years and older are able to maintain their blood pressure goal with antihypertensive de-escalation via removal of one drug. The randomized, non-inferiority, multicenter study included 569 patients who were aged 80 years and older, had a SBP lower than 150 mm Hg at baseline, and were prescribed at least two antihypertensive medications. Patients were allocated in a 1:1 ratio to the intervention group, or de-escalation group, by removing one antihypertension medication, or the control group, in which patients were continued on their current regimens. The OPTIMISE study highlighted that medication reduction is efficacious to standard therapy as the mean SBP in the intervention group and usual care group were 133.7 mmHg and 130.8 mmHg, respectively.7 The trial only evaluated the benefits of antihypertensive reduction over a 12 week period, so it is not conclusive of long-term clinical outcomes. Additionally, the study was conducted in an unblinded manner, with primary care providers allocating patients to medication de-escalation vs. the control group based on their clinical assessments, decreasing the study’s overall internal validity.The study also focused on a narrow spectrum of patients, 80 years and older, which is not representative of the overall geriatric population. 7 Despite the study’s methodology, the OPTIMISE trial was able to support a “less is more” approach in antihypertensive management in geriatric patients.

    The SPRINT, HYVET, and OPTIMISE trials focused on patients with antihypertensive medications in outpatient settings. However, elderly patients are often prescribed intensified blood pressure regimens to manage their cardiovascular health upon discharge after hospitalizations. Anderson and colleagues conducted a study that looked at clinical outcomes after intensifying antihypertensive therapies upon discharge for geriatric patients who were hospitalized for pneumonia, urinary tract infection, and venous thromboembolism. The retrospective study included patients 65 years and older with hypertension admitted to Veterans Affairs (VA) health systems over a two-year period. Discharge with antihypertensive intensification was defined as receiving a prescription at discharge for a new or at least 20% higher-dose of antihypertensive medication than what was used prior to admission.8 The study found that in patients admitted to the hospital for non-cardiac causes, adding an additional antihypertensive was associated with increased risk of hospital readmissions and serious adverse events rather than improvements in blood pressure and fewer cardiac events following discharge.8 The trial primarily consisted of older male patients hospitalized for non-cardiac events, which is not applicable to all hospitalized elderly patients. Nevertheless, the study highlights the insignificance and potential harm in intensifying antihypertensives in elderly patients during hospital admissions.

    Even though deprescribing antihypertensives is an area in geriatric medicine with lack of robust research, current studies suggest that de-escalating antihypertensive regimens has a positive impact on elderly patients’ quality of life. Geriatric patients are susceptible to medication-related adverse events due to their declining health, so it is rational to provide them with treatment regimens with adequate therapeutic benefits, minimal toxicities, and cost-effectiveness. Based on the current body of literature, it may be more beneficial to have patients on stable and consistent regimens and with close monitoring and follow-up rather than regularly intensifying antihypertensive therapy. Additionally, the inpatient data on antihypertensive escalation at discharge suggests that it is imperative not to modify chronic disease treatments in inpatient settings considering patients’ likelihood of benefit and the interplay of acute hospital conditions. Thus, clinicians should be cognizant of fluctuating blood pressure values which may be transient in the inpatient setting and should not always make medication adjustments accordingly.9

    Pharmacists, specifically, can play a major role in optimizing elderly patients’ antihypertensive medication regimens. Specifically, pharmacists can aid in patients’ transitions of care between inpatient and outpatient settings by performing medication reconciliations to evaluate patients’ likelihood of benefiting from medication reduction. 10 Ambulatory care and community pharmacists can also be proactive in the deprescribing process by having conversations with elderly adults about their medications and consulting with patients’ primary care providers about possibly deprescribing antihypertensive medications.11 Overall, based on current data, pharmacists should feel empowered to have conversations about deprescribing with older patients and healthcare professionals to improve health outcomes in the geriatric population and combat polypharmacy.


    References:

    1. Bureau USC. By 2030, All Baby Boomers Will Be Age 65 or Older. The United States Census Bureau.https://www.census.gov/library/stories/2019/12/by-2030-all-baby-boomers-will-be-age-65-or-older.html. Published May 26, 2021. Accessed July 13, 2021.
    2. Halli-Tierney AD, Scarbrough C, Carroll D. Polypharmacy: Evaluating Risks and Deprescribing. Am Fam Physician. 2019;100(1):32-38.
    3. By the 2019 American Geriatrics Society Beers Criteria® Update Expert Panel. American Geriatrics Society 2019 Updated AGS Beers Criteria® for Potentially Inappropriate Medication Use in Older Adults. J Am Geriatr Soc. 2019;67(4):674-694. doi:10.1111/jgs.15767
    4. O'Mahony D, O'Sullivan D, Byrne S et al. STOPP/START criteria for potentially inappropriate prescribing in older people: version 2 [published correction appears in Age Ageing. 2018 May 1;47(3):489]. Age Ageing. 2015;44(2):213-218. doi:10.1093/ageing/afu145
    5. Wright JT Jr., Williamson JD, Whelton PK, et al. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med. 2015;373:2103–16
    6. Peterson ED, Rich MW. Deprescribing antihypertensive medications for patients aged 80 years or older: Is doing less doing no harm? JAMA. 2020;323(20):2024-2026. doi:10.1001/jama.2020.4841
    7. Sheppard JP, Burt J, Lown M, et al. Effect of antihypertensive medication reduction vs usual care on short-term blood pressure control in patients with hypertension aged 80 years and older: The OPTIMISE randomized clinical trial. JAMA. 2020 May 26;323(20):2039-2051. doi: 10.1001/jama.2020.4871. PMID: 32453368; PMCID: PMC7251449.
    8. Anderson TS, Jing B, Auerbach A, et al. Clinical outcomes after intensifying antihypertensive medication regimens among older adults at hospital discharge. JAMA Intern Med. 2019;179(11):1528-1536. doi:10.1001/jamainternmed.2019.3007
    9. Tinetti ME, Green AR, Ouellet J, Rich MW, Boyd C. Caring for patients with multiple chronic conditions. Ann Intern Med. 2019;170(3):199-200. Epub ahead of print. doi:10.7326/M18-3269
    10. Elbeddini A, Zhang CXY. The pharmacist's role in successful deprescribing through hospital medication reconciliation. Can Pharm J (Ott). 2019;152(3):177-179. Published 2019 Apr 15. doi:10.1177/1715163519836136
    11. Farrell B, Clarkin C, Conklin J, et al. Community pharmacists as catalysts for deprescribing: an exploratory study using quality improvement processes. Can Pharm J (Ott). 2019;153(1):37-45. Published 2019 Nov 9. doi:10.1177/1715163519882969
  • 06 Oct 2021 5:39 PM | Anonymous
    By: Colton Frazer, MBA, PharmaD Candidate 2022
    Mentor: Dr. Paul Juang, PharmD, BCCCP, BCPS, FAHP, FCCM

    The National Transitions of Care Coalition estimated that the United States wastes around 30 to 50 billion dollars in unnecessary medical expenditures to fix transitional care errors each year. Approximately 60% of which are medication related errors. With this in mind, the argument can be made that more emphasis should be placed on pharmacist-led transitions of care (TOC) programs to ensure patients are properly educated on their new medications. Furthermore, this would be a great area for pharmacists to make a positive impact, while expanding our scope of practice. The continuing trend of pharmacists expanding their scope of practice is becoming more and more relevant each year. For example, H.R. 2759/S. 136 is a bill currently in discussion that would add pharmacists to the providers list eligible for Medicare part B service reimbursement. While provider status may continue to elude our profession, pharmacists are the ideal choice to lead TOC programs-- and can successfully implement these programs now. Furthermore, these programs would likely pay for themselves by reducing emergency medical costs paid by health systems.

    To begin, what is a transition of care program? A transition of care (TOC) program consists of a healthcare professional that follows up with a patient via phone call after they are discharged from the healthcare facility to return home. The goal of the program is to ensure the accurate communication of all pertinent healthcare information. This can include things such as discussing barriers, medication adherence, and any new developments in their conditions since discharge.

    Below is an illustration of a standard TOC program timeline as an example:

    The exact process of the TOC program can vary depending on the specific patient and hospital. Despite any difference in TOC follow up protocol, it remains unchanged that transitional follow up is effective for reducing readmission rates among high-risk patients, and reducing overall health care expenditure per patient. By understanding why TOC programs are beneficial, and furthermore, understanding why pharmacists are the ideal candidate to lead these programs, we can advocate for our profession and improve the health outcomes of patients along the way.

    One noteworthy case published in the NCBI in 2016 is a great example of small details going unchecked causing big problems for our patients. The case report follows a geriatric patient who was discharged with the medication thiothixene (Navane) by mistake instead of amlodipine (Norvasc). The patient continued to take thiothixene for 3 months and suffered severe mental and behavioral side effects. The patient's untreated hypertension led to severe chest pain and readmission 3 months later. At that time, a different specialist prescribed the patient citalopram and alprazolam to treat these new mental and behavioral side effects that were labeled as depression and anxiety. A few weeks after this, the patient suffered a fall and was taken to the emergency department where the mistake was finally caught many months later. This case report serves as a great illustration as to why TOC programs are crucial for catching and fixing medication errors. Pharmacist-led TOC programs can cater specifically to the new medications that can be overwhelming for patients to sort out by themselves.

    As stated previously, many problems during transitions of care arise from medication related problems. There are many notable studies that bolster data to suggest that TOC programs have a significant improvement for the outcome of the patient, while also saving the health system on overall expenditures. One study published in The American Journal of Accountable Care in 2018 contacted 90% of the patients enrolled in the intervention group at 72 hours post discharge. From this group, they found that 86.4% of the 185 patients contacted had a medication related issue. (Fig. 1) These medication related issues ranged from not taking their medication correctly, to discontinuing the medication due to the side effect profile. What’s more, the study found that the readmission rate for patients involved in the TOC program compared to routine care (no follow-up) was significantly lower for patients enrolled in the TOC program. These findings were further amplified by the patients all being categorized as high risk for readmission due to receiving more than 10 medications, having a diagnosis of pneumonia or congestive heart failure, or receiving anticoagulation therapy. The study concluded that a system wide TOC program would save the health system $582 per patient.


    Furthermore, a budget impact analysis published in the Journal of Managed Care & Specialty Pharmacy in 2018 set out to determine the impact of regulated pharmacists-led TOC programs for all Medicaid patients. The authors found that pharmacist-led TOC programs could result in a savings of $25 million dollars to Medicaid over a two year time period. This was found by performing a decision tree analysis from the health system payer’s point of view for treatment of high risk patients. (Fig. 2) The main culprit for Medicaid waste was found to be mismanagement of medications leading to costly interventions that could potentially be avoided.


    And finally, a study published in the American Journal of Health-System Pharmacy in 2020 found that the 30 and 90 day readmission rates for chronic heart failure patients were significantly lower when enrolled in a pharmacist-led TOC program. This was in comparison to having no follow-up, and had a difference of 13% of patients readmitted from the TOC group versus 28% from the control group. This highlights the ability of pharmacists to improve health outcomes in this setting.

    With all of the presented data, and the high prevalence of medication related problems during transitional care, it is clear that medication specialists should lead such a crucial step in a patient's health care. Pharmacists are well equipped to be at the helm of this venture. With such a definitive way for pharmacists to make a dramatic impact on the health outcomes of patients, it is clear that pharmacists-led TOC programs are a great option for all pharmacists to pursue to benefit patient health outcomes, while saving the health system money as well.

    References:
    Cua, Yvette M, and Sunil Kripalani. “Medication Use in the Transition from Hospital to Home.” Annals of the Academy of Medicine, Singapore, U.S. National Library of Medicine, Feb. 2008, www.ncbi.nlm.nih.gov/pmc/articles/PMC3575742/.

    Da Silva, B., & Krishnamurthy, M. (2016, September 7). The alarming reality of medication error: A patient case and review of Pennsylvania and national data. Retrieved August 20, 2021, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5016741/

    Tully AP, et al. Evaluation of medication errors at the transition of care from an ICU to non-ICU location. Crit Care Med 2019;47:543-549.

    Melody, Karleen T, et al. “Optimizing Care Transitions: The Role of the Community Pharmacist.” Integrated Pharmacy Research & Practice, Dove Medical Press, 22 Apr. 2016, www.ncbi.nlm.nih.gov/pmc/articles/PMC5741037/.

    Ni, Weiyi & Colayco, Danielle & Hashimoto, Jonathan & Komoto, Kevin & Gowda, Chandrakala & Wearda, Bruce & McCombs, Jeffrey. (2018). Budget Impact Analysis of a Pharmacist-Provided Transition of Care Program. Journal of managed care & specialty pharmacy. 24. 90-96. 10.18553/jmcp.2018.24.2.90.


  • 06 Oct 2021 4:35 PM | Anonymous

    By: Sarah Schriewer and Megan Smith, PharmD Candidates 2023; St. Louis College of Pharmacy at University of Health Sciences and Pharmacy in St. Louis

    Mentor: Roxane Took, PharmD, BCACP; Assistant Professor, Department of Pharmacy Practice, St. Louis College of Pharmacy at University of Health Sciences and Pharmacy in St. Louis; Gateway Apothecary

    Background

    The increased prevalence of heart failure readmissions proves costly for both hospital health systems and patients. More than 20% of hospitalized heart failure patients will return for readmission within a 30-day period.1 Within the last ten years, the Centers for Medicare and Medicaid reduced reimbursement to health systems with excessive 30-day readmission rates in order to curb the climbing occurrence and associated costs of these readmissions.2 This was done to remove incentivizing procedures that may lessen the quality of patient care.3 Many hospitals have established transition of care (TOC) teams composed of various healthcare personnel following this reimbursement limitation.4 The inclusion of the pharmacy profession on the TOC team remains essential, as confirmed by numerous studies that examined the purpose, involvement, and outcomes related to pharmacy specifically. Through performance and accountability measures, the Joint Commission closely examines the efforts of hospitals to improve heart failure patient outcomes.5 Pharmacists play an integral role in improving standards for TOC in heart failure patients.

    Clinical Trial Review

    A single-center, retrospective, quasi-experimental study regarding the impact of pharmacy involvement in heart failure transitions of care found that 30-day readmission rates significantly decreased with the integration of a pharmacist-led TOC team. These TOC services included medication reconciliation performed by the pharmacist, pharmacy residents, or pharmacy interns upon admission and discharge; and patient education with verbal and written components. The majority of patients transitioned from the hospital setting to home, where the patient and caregivers would greatly benefit from written educational materials provided to patients in the intervention group. The study, conducted at Ascension St John Hospital in Detroit, Michigan, focused on 663 patients admitted to cardiac medical floors with a primary or new diagnosis of heart failure. The 333 patients in the intervention group received the pharmacy-led TOC services, whereas the 330 patients made up the control group received TOC services led by other professions. The most common interventions resulting from medication reconciliation involved addition of a medication, dose titration, treatment discontinuation, and duplication avoidance. A total of 17.3% of control group patients had a heart failure readmission within 30 days following discharge whereas only 10.5% of patients in the intervention group experienced a hospital admission within the 30-day window post-discharge.4

    Cohort Study Review

    A monocenter, retrospective, observational cohort study at the Veterans Administration Tennessee Valley Healthcare System determined the outcomes associated with heart failure patient follow-up interviews performed by a clinical pharmacy specialist (CPS). This study was performed to consider the value of  a CPS, especially during a provider shortage. Cohorts were composed of Advanced Heart Failure Clinic (AHFC) patients within this VA health system. Researchers hypothesized that patients receiving care from a CPS would have similar results in comparison to patients following-up with a “familiar provider.” A novel clinical pharmacy telephone clinic was a valuable component in managing medications and reducing 30-day readmission rates. Patients who received the care provided by the CPS had a 10.9% readmission rate. In contrast, patients without the clinical pharmacy interventions had a 12.9% readmission rate within 30 days. Clinical pharmacy specialists in the Veterans Administration health setting are capable of performing more advanced practitioner care, such as limited prescribing and other patient care authorities. This study provides an interesting outlook on the expanding world of pharmacy practice and the impact pharmacists can make on patient outcomes.1

    Management of Implementation

    When implementing TOC teams, it is important to consider the additional time commitments that the pharmacy team will have to make and the best way to spread the added workload out amongst staff. Studies have shown positive results by utilizing pharmacy students in their 3rd and 4th year, PGY1 residents, and paid interns working together.4 Other studies emphasize the successfulness of community pharmacists assisting with heart failure TOC encounters via the Centers of Medicare and Medicaid Services Part D Medication Therapy Management programs. These programs allow pharmacists to bill for counseling patients with multiple high-cost medications for various chronic disease states.6 Some health systems found success with clinical pharmacists working directly with the patients during discharge.1 Although there are many ways to set up a pharmacy-led TOC team, it is important to arrange a team best suited to the staffing abilities of different organizations. 

    Heart failure remains one of the most prevalent disease states in the United States, and, in individuals over the age of 65 year, heart failure remains the most prevalent disease state that causes hospital admissions.7 Data predictions show that more than 8 million adults will be affected, and $69 billion will be spent by 2030 due to the overwhelming amount of hospitalizations.6 The benefits of providing pharmacist-led TOC can help improve these outcomes substantially, and this team can look different based on different preferences. Providing medication reconciliation to patients regarding their heart failure medications is one of the best ways to help improve overall quality of life and decrease the amount of money spent on heart failure readmission by catching discrepancies, titrating doses appropriately, and educating patients on proper use of their medications.7

    Takeaways and Recommendations

    • Many patients transition to the home setting where both the patient and any caregivers need proper educational materials
    • Pharmacists provide valuable services in reducing 30-day readmission rates for heart failure patients through TOC-related counseling
    • Timely follow-up, either in-person or via phone, with a pharmacist is monumentally beneficial

    References

    1. Benge C, Pouliot J, Muldowney JAS 3rd. Evaluation of a Clinical Pharmacist Specialist Transition of Care Pathway to Manage Heart Failure Readmissions During a Provider Shortage. J Pharm Pract. 2021 Jun 1;1-11.
    2. Centers for Medicare and Medicaid Services. Hospital Readmissions Reduction Program (HRRP), 2021. Available from https://www.cms.gov/Medicare/Quality-Initiatives-Patient-Assessment-Instruments/Value-Based-Programs/HRRP/Hospital-Readmission-Reduction-Program [6 August 2021].
    3. Cowie MR, Anker SD, Cleland JGF, Felker GM, Filippatos G, Jaarsma T, Jourdain P, Knight E, Massie B, Ponikowski P, López-Sendón J. Improving care for patients with acute heart failure: before, during and after hospitalization. ESC Heart Fail. 2014 Dec;1(2):110-145.
    4. Neu R, Leonard MA, Dehoorne ML, Scalia SJ, Kale-Pradhan PB, Giuliano CA. Impact of Pharmacist Involvement in Heart Failure Transition of Care. Ann Pharmacother. 2020 Mar;54(3):239-246.
    5. Schmaltz SP, Williams SC, Chassin MR, Loeb JM, Wachter RM. Hospital performance trends on national quality measures and the association with Joint Commission accreditation. J Hosp Med. 2011 Oct;6(8):454-61.
    6. Anderson SL, Marrs JC. A Review of the Role of the Pharmacist in Heart Failure Transition of Care. Adv Ther. 2018 Mar;35(3):311-323.
    7. Milfred-LaForest SK, Gee JA, Pugacz AM, et al. Heart Failure Transitions of Care: A Pharmacist-Led Post-Discharge Pilot Experience. Progress in Cardiovascular Diseases. 2017;60(2):249-258.


  • 24 Sep 2021 3:42 PM | Anonymous

    Program Number:  2021-09-04

    Approved Dates:   October 1, 2021-April 1, 2022

               

    Approved Contact Hours:  One Hour(s) (1) CE(s) per session

    Kids Survive: Evidence Based Management of Pediatric Sepsis

    Author: Victoria H. Anderson, PharmD; PGY-1 Pharmacy Resident (2020-2021)

    Mentor: Jordan E. Anderson, PharmD, BCPS, BCCPS; Pharmacy Clinical Coordinator/PGY-1 Residency Program Director

    University of Missouri Women’s and Children’s Hospital – Columbia, MO

    Objectives

    • 1.      Distinguish features of SIRS, sepsis, severe sepsis, and septic shock.
    • 2.      Describe initial management of pediatric sepsis patients.
    • 3.      Differentiate medications with and without a routine role in pediatric sepsis management.

    Take Assessment Quiz

    The Surviving Sepsis Campaign published updated pediatric sepsis guidelines in February 2020. Prior to these guidelines, pediatric recommendations shared a guideline document with adult recommendations in 2004, 2008, and 2012, and the Surviving Sepsis Campaign only published adult guidelines in 2016.

    Sepsis Considerations: Definitions and Pharmacokinetics

    Early recognition of sepsis and evidence-based care of pediatric sepsis patients are of utmost importance to improve patient outcomes as a study in the UK found that over 50% of pediatric sepsis fatalities occurred in the first 24 hours and approximately half of those fatalities were prior to admission to pediatric intensive care units.1 Adherence to guidelines can improve outcomes and development of protocols including order sets and standardized education can reduce mortality.1 A study of emergency department teams found that only 45% correctly adhered to treatment metrics, so there is certainly room for improved implementation of guideline recommended care.1

    Sepsis is defined as systemic inflammatory response syndrome (SIRS) plus suspected or known infection. SIRS criteria include hypo- or hyperthermia, leukopenia or leukocytosis, brady or tachycardia, and tachypnea (see Figure 1).2 At least two criteria must be met to diagnose SIRS and at least one of those criteria must be the patient’s temperature or leukocyte count.2 Of note, the SIRS criteria and sepsis definitions do not apply to premature infants.2 To qualify for severe sepsis, a patient must have cardiovascular or respiratory dysfunction or dysfunction of at least two other organ systems such as neurologic, hematologic, renal, and hepatic.2 Septic shock is defined as sepsis with cardiovascular organ dysfunction.2 At least 40mL/kg of fluids must be administered over an hour prior to assessing for cardiovascular dysfunction to meet the organ dysfunction criteria.2 It is important to recognize that hypotension may not be present with cardiovascular dysfunction until a patient is near collapse, as pediatric patients often have strong compensatory mechanisms.1 As a result, fluids are very important to management in even normotensive patients as delays can increase ICU and hospital length of stay and increase risk of acute kidney injury(AKI).1 Rather than titrating to blood pressure goals which is often practiced in adults, fluids should be titrated to increased urine output, improved mental status, and decreased capillary refill time as long as patients remain without hepatomegaly or rales.

    Figure 1: 

    Organ function changes are important to note not just for diagnosis of SIRS and subsequently sepsis, but because they also can change the pharmacokinetics of medications administered to these children. Critically ill children often have changes in both synthesis and binding affinity of albumin and alpha-1 acid glycoprotein which can impact unbound fraction of medications.3 Changes in pH whether acidosis or alkalosis can also impact drug levels by impacting ionization which can impact both effective concentration and elimination rates of medications.3 Fluid shifts impact volume of distribution which can lead to changes in concentration, particularly of hydrophilic medications such as vancomycin, so it is important when monitoring vancomycin to consider the impact of fluid resuscitation and maintenance fluids on serum concentrations.3 Renal dysfunction can impact enzyme activity, pH, total body water, and drug clearance, but conversely, sepsis can also lead to augmented renal clearance.3 Mild hepatic dysfunction can modify hepatic blood flow, enzyme activity, drug transport, protein binding, and total body water, impacting the disposition of medication.3 More severe hepatic dysfunction is marked by capillary leak, coagulopathy, renal dysfunction, and hypoglycemia.3 Additionally, inflammatory mediators can decrease P450 enzyme metabolism.3 Changes in blood flow to drug clearing organs may decrease elimination of many drugs.3 Cardiovascular changes can also lead to fluid overload and edema, changing volume of distribution, and increases in alpha-1 acid glycoprotein.3 Abdominal venous congestion can also lead to a decrease in enteral absorption of medication.3 Finally, therapies to compensate for dysfunctional organs such as extracorporeal membrane oxygenation (ECMO) and continuous renal replacement therapy (CRRT) also can impact pharmacokinetics.3 The ECMO circuit tubing binds some medications requiring increased dosing initially until binding sites are saturated.3 ECMO also may increase volume of distribution of some medications secondary to added volume required for the circuit.3 The impact of CRRT varies primarily based on the level of protein binding of the medication with lower protein binding leading to increased removal.3

    It is also important to consider comorbidities that may impact medication therapy. Forty-nine percent of children with sepsis have a comorbidity making them more vulnerable to infection.1 A common comorbidity is cancer which both the condition itself and the treatment can impact pharmacokinetics.3 For example, fluconazole trough concentrations have been found to be significantly lower in pediatric cancer patients.3 All of these changes make careful use and monitoring of medications in these patients of utmost importance.

    Initial Care: Antibiotic and Hemodynamic Management

    Once we have made the presumptive diagnosis of sepsis, rapid protocol-driven treatment is the next important step. Per the Surviving Sepsis Campaign International Guidelines for the Management of Septic Shock and Sepsis-Associated Organ Dysfunction in Children, in patients presenting without shock, antimicrobial therapy should be started within three hours of recognition.4 While blood cultures should be obtained prior to initiation of antibiotics if this will not cause delay, it is important to start treatment with antimicrobials as soon as possible, so timing of antibiotics is not dependent upon availability of blood cultures.4 The guidelines do not address obtaining multiple blood cultures, however, it is common practice to obtain two blood cultures to enhance our ability to detect causative organisms, and to help determine if bacteria found are pathogenic versus a contaminant. If patients have pre-existing intravenous access devices it is prudent to obtain a set of cultures both from the device and from a peripheral site. In addition to blood cultures, cultures should also be obtained from any suspected non-blood site of infection such as urine, cerebrospinal fluid, or wound drainage.4 If a patient presents with shock, guidelines recommend treatment with antimicrobials within one hour of recognition, but for patients without shock, treatment within the first hour has not been found to have a significant impact on mortality as compared to treatment by the end of the third hour.4 This is in contrast to the 2016 adult and 2012 pediatric guidelines which recommended antimicrobials within the first hour for all patients with sepsis regardless of the presence of shock, and the 2008 pediatric guidelines which recommended antibiotics within one hour of recognizing severe sepsis, but after inidicated cultures have been taken without the caveat in more recent guidelines not to delay evidence-based treatment while waiting for cultures.5,6,7 Giving antibiotics sooner than required will clearly not cause harm as long as this is not done at the expense of fully evaluating the patient, so following the older practice of administration within the first hour is not an inappropriate practice when practical.

    These initial antimicrobial agents should be broad spectrum to cover all likely pathogens without excess coverage.4 A previously health child presenting from home should receive a third-generation cephalosporin such as ceftriaxone.4 A child at risk for methicillin-resistant Staphylococcus aureus (MRSA) or presenting from a community with high prevalence of ceftriaxone-resistant pneumococci should additionally receive vancomycin.4 In communities where ceftriaxone-resistant gram negative rods are prevalent, addition of aminoglycosides or substitution of a carbapenem in place of the third generation cephalosporin is recommended.4 If patients have influenza-like illness and influenza is unable to be ruled out, an anti-viral should additionally be given.4 Immunocompromised patients or those with hospital acquired sepsis should receive a beta-lactam covering Pseudomonas aeruginosa.4 Patients with suspected intra-abdominal source of sepsis should receive an antibiotic covering anaerobes, and those with toxic shock syndrome or necrotizing fasciitis should receive clindamycin or lincomycin.4 Neonates should receive ampicillin and if HSV is suspected should additionally receive acyclovir.4 Synergy may be required for device-associated infections, Enterococcal or Staphylococcal endocarditis, group B Streptococcus infections, and carbapenem-resistant Enterobacteriaceaea, but the only patients who should receive double coverage are cancer and transplant patients who are unstable and come from a community with a gram-negative resistance rate of greater than ten percent.4 These patents should receive a second agent covering gram-negatives.4 This is in contrast to the 2016 adult guidelines which recommended empiric combination therapy for patients in shock with de-escalation within the first few days if the patient is clinically improving regardless of results of cultures, but recommended against routinely double covering any particular pathogen in neutropenic patients unless they were presenting with shock.5

    The antimicrobials selected should be dosed based on published pharmacokinetic and pharmacodynamic information to ensure safe and effective use.4 It is important to note that because vancomycin and beta-lactams have time dependent antimicrobial activity, extended infusion times may enhance therapeutic effect in patients with augmented renal clearance in early sepsis.4 Once this initial treatment is selected, it should be re-assessed daily for opportunities to optimize coverage.4 Narrowing of therapy should occur based on culture and sensitivity results, or if unavailable, on site of infection and other patient specific factors.4 Source control, which is physical removal of infection such as draining an abscess, and site and etiology of infection, as well as the patient’s response to treatment should guide duration of treatment for pediatric sepsis, although the 2016 adult guidelines suggest a duration of 7-10 days unless clinical evidence suggests that a longer or shorter course could be indicated.4,5

    Sepsis can cause an array of physiologic changes which may lead to hemodynamic instability and poor organ perfusion. Fluids are therefore another important component of the initial management of a septic patient. Although caution is required in patients presenting with or developing signs of fluid overload, generally in a health care setting with access to intensive care resources, patients should receive up to 40-60mL/kg in 10-20mL/kg doses over the first hour of treatment.4 In settings where intensive care is unavailable, the maximum volume of bolus fluid a child should receive is 40mL/kg in the first hour if hypotension is present, and if hypotension is not present, fluids should be given at a maintenance rate rather than administered as boluses.4 Signs to assess for hydration status include blood pressure, capillary refill and heart rate.4 Caution is required to avoid fluid overload which may present as pulmonary edema or worsening hepatomegaly.4

    While most recommendations on selection of fluids for resuscitation are weak, generally balanced buffered crystalloids such as Lactated Ringer’s or PlasmaLyte solutions are recommended over albumin, normal saline, starches, or gelatin-derived fluids.4 These recommendations balance both cost and safety with cost being the driving factor in recommending against albumin, and safety being the driver of the only strong recommendation to avoid starches as adult data has shown significant risk of both AKI and mortality with the use of hydroxyethyl starch. The adult guidelines, however, give the option of normal saline in place of balanced crystalloids, and recommend use of albumin if patients are requiring significant crystalloids.5 The recommendation to use balanced crystalloids such as Lactated Ringer’s over normal saline in the pediatric guidelines is based on risk of hyperchloremic acidosis, AKI, and coagulopathy with the increased chloride content of normal saline.4,8 Interestingly, the American Academy of Pediatrics clinical practice guideline for maintenance intravenous fluid in children recommends isotonic fluids for maintenance and specifically mentions normal saline and PlasmaLyte, while excluding Lactated Ringer’s solution from their discussion.9 Further studies have evaluated the risks of the supraphysiologic chloride concentrations in normal saline and found that the risk is more significant in bolus fluid administration than slower administration rates, so outside of the bolus phase of treatment switching to normal saline is a reasonable choice although the selection of this fluid for boluses is less clear.8 PlasmaLyte is similar though not identical to Lactated Ringer’s, but is used less often secondary to cost. Per the guidelines, albumin is not a preferred fluid in children secondary to evidence that there is not a mortality benefit and there is a significant cost difference between albumin and crystalloids.4

    For septic shock resistant to fluids or in children who are already at risk of or showing signs of fluid overload, epinephrine and norepinephrine are good first line options recommended over dopamine for blood pressure support.4 This is a change from 2008 and 2012 pediatric guidelines when dopamine and inodilators were recommended prior to initiation of norepinephrine or epinephrine.6,7 While central access is preferred for vasoactive medications, peripheral administration is reasonable during stabilization if central access is not available, and the 2008 and 2012 pediatric guidelines further recommend intra-osseous access if central access is not readily available.4,6,7 If children are on high doses of catecholamines and still in shock, vasopressin may be added, and if hypoperfusion is still present, addition of an inodilator such as milrinone or dobutamine may be a reasonable option.4 This is similar though not identical to the 2016 adult guidelines which recommended norepinephrine first line followed by epinephrine or vasopressin then inodilators.5

    Some patients may also require hydrocortisone. Hydrocortisone is a corticosteroid that decreases inflammation and reverses capillary permeability. In both the 2016 adult guidelines and the 2020 pediatric guidelines, hydrocortisone is recommended in patients who are still hemodynamically unstable after administration of fluids and vasoactive agents, but not those who are stable on those medications.4,5 While hydrocortisone can enhance the activity of norepinephrine by decreasing reuptake, steroids have numerous adverse effects including immunosuppression, hyperglycemia, and neuromuscular weakness, so routine use is clearly not benign.4 Additionally, while hydrocortisone is an evidence-based treatment for primary adrenal insufficiency, stimulation testing or random cortisol levels in the setting of sepsis are not recommended unless there is evidence to enhance concern for adrenal insufficiency such as significant unexplained hyponatremia and hypoglycemia.4

    Continued Care: Drugs with and without Routine Indications

    Patients with sepsis may also require intubation. In these patients, etomidate is not a recommended induction agent secondary to risk of adrenal insufficiency following etomidate exposure.4 The 2008 pediatric guidelines were a bit more specific discouraging etomidate only in meningococcal sepsis.7 This recommendation was broadened to address all pediatric sepsis patients in the 2012 guidelines in which a mortality benefit to avoiding etomidate in meningococcal sepsis was mentioned, and avoiding both etomidate and dexmedetomidine in all sepsis patients was recommended secondary to risk of adrenal suppression.6 The recommendation to avoid dexmedetomidine was not carried forward into the 2020 pediatric sepsis guidelines.4 Future evidence seeks to strengthen recommendations regarding length of neuromuscular blockade for intubated patients which is currently a grey area. Life-threatening Acute Respiratory Failure in Children: to Breathe or Not to Breathe Spontaneously, That’s the Question, is a current study in the Netherlands which started in December 2019 to evaluate rocuronium versus placebo in mechanically ventilated children.10 This study is expected to be completed in mid-2024.10

    While nutrition is important in recovery from any illness, enteral nutrition, particularly gastric nutrition, is preferred over parenteral nutrition for both adult and pediatric sepsis patients.4 The 2008 pediatric guidelines did not address nutrition, but the 2012 pediatric guidelines agree that enteral is preferred if tolerated and additionally address that if not tolerated parenteral feeding with dextrose 10% in a sodium containing solution is recommended.6 If patients are not tolerating full enteral feeds, prokinetic agents such as erythromycin or metoclopramide may be tempting options, however this is a practice that is not evidence-based, not risk-free, and not guideline recommended for pediatric patients despite being recommended in the 2016 adult guidelines.4,5 Even if patients are not tolerating full enteral feeds, total parenteral nutrition (TPN) is not recommended during the first seven days in the PICU.4 Delaying initiation of TPN may improve neurocognitive development without negative impacts on survival or health status.4 The guidelines are not designed to fully address neonatal sepsis, so neonates expected to be unable to tolerate enteral feeding should be an exception to this seven-day delay in TPN. While the benefit of focusing on enteral nutrition seems clear, blood glucose and calcium goals are less well-defined. A blood glucose goal of less than 140mg/dL is not recommended in order to avoid hypoglycemic events, however the pediatric sepsis guidelines do not define a specific blood glucose target.4 American Diabetes Association guidelines for care of hospitalized diabetic patients recommend a blood glucose target of 140-180mg/dL in most critically ill and non-critically ill patients, so this range is a reasonable target.11 This is corroborated with the 2016 adult guidelines which suggest initiating insulin if the blood glucose is greater than 180mg/dL as opposed to more stringent blood glucose targets and the 2012 pediatric guidelines recommending a blood glucose goal less than 180mg/dL.5,6 Calcium goals are even more poorly defined. The prevalence of hypocalcemia in pediatric sepsis may be as high as 75%, yet calcium supplementation has not been evaluated nor is there consensus in the pediatric healthcare community on the management of hypocalcemia in these patients.4 This is further muddied as in the adult critical care population, calcium supplementation has been associated with worsening organ dysfunction, yet in the pediatric population it is known that calcium is associated with improved hemodynamics, particularly in infants with immature cardiomyocytes.4,12

    The pediatric sepsis guidelines specifically recommend against certain nutritional supplements. These include enteral lipid emulsions such as fish oil supplements, selenium, glutamine, arginine, zinc, vitamin C, and thiamine.4 Studies have not found benefit to using these supplements, and some studies have even found harm with arginine.4 Additionally, acute vitamin D replacement is not recommended despite vitamin D deficiency being associated with organ dysfunction.4 While this seems counter-intuitive, vitamin D levels appear falsely low post-resuscitation, and hypervitaminosis D can cause complications leading to death.4 If patients are known to be vitamin D deficient prior to onset of sepsis it is recommended to provide supplementation as recommended outside of sepsis, but measuring of levels during sepsis to guide treatment would not be an acceptable standard of care.4 The 2016 adult guidelines do not comment on as many supplements, but do agree in recommending against selenium, arginine, and glutamine.5 The adult guidelines were unable to make a recommendation for or against carnitine, which is in agreement with pediatric guidelines as carnitine is not mentioned.5

    There is also limited evidence on temperature management in pediatric sepsis patients. The guidelines discuss use of antipyretics or a permissive strategy for fevers.4 Elevated temperature dose have some positive effects on the immune system which are lost if temperature is reduced with antipyretics, however it is not benign, which is most obvious in terms of patient comfort.4 Additionally, comparing antipyretics to physical cooling strategies favors antipyretics for early mortality, so it is clear that cooling is generally not a recommended approach in a pediatric sepsis patient.4 Acetaminophen and ibuprofen are commonly used antipyretics, but acetaminophen is not recommended in patients less than 3 months of age and ibuprofen in patients less than 6 months of age as the difference between effective and toxic doses is much smaller in these patients leading to heightened risk of adverse events. These are not absolute contraindications, and in fact a study in 2018 found that ibuprofen use in patients less than 6 months of age was not associated with greater adverse events than use in patients over 6 months.13 Risk of gastrointestinal and renal adverse events was heightened modestly in patients receiving ibuprofen versus those receiving only acetaminophen, but this risk difference was the same in both age groups.13 However, it is still prudent to use these medications cautiously in our youngest patients.

    In sepsis patients, T3 and T4 level turnover increases and de-iodination of T4 to T3 decreases.4 Additionally, TSH may not be elevated, however, levothyroxine is not recommended for routine use in children with sick euthyroid.4 Although theoretically there may be a role for levothyroxine, studies in critically ill children have found no difference in patients treated with levothyroxine as compared to those who did not receive levothyroxine.4

    Pediatric stress ulcer prophylaxis is a grey area as little research has been published in this area. Hospitals have published protocols, but there are no recent guidelines. A recent observational study found that age, mechanical ventilation, and not receiving enteral nutrition were all independently associated with increased likelihood of the patient receiving stress ulcer prophylaxis.14 These authors also acknowledged that use of vasopressors, corticosteroids, and NSAIDs, presence of coagulopathy, and higher PRISM III score on admission may also be factors in determining need for stress ulcer prophylaxis, but there was not a uniform prescribing practice.14 As stress ulcer prophylaxis is not benign, potentially leading to increased risk of pneumonia and Clostridium difficile infections as well as decreased bone mineral density with longer durations of treatment, it is important to consider risks and benefits of stress ulcer prophylaxis in determining which patients require these medications. It is clear that simply being diagnosed with sepsis or even septic shock is not enough to warrant use of stress ulcer prophylaxis.4 While there is better data in the adult population, the adult guidelines agree that stress ulcer prophylaxis is only indicated if patients have risk factors that would indicate requiring stress ulcer prophylaxis outside of sepsis.5 The 2008 and 2012 pediatric guidelines had no graded recommendations for or against stress ulcer prophylaxis.6,7 As histamine 2 receptor antagonists are more studied in the pediatric population than proton pump inhibitors and have lower rates of adverse events, choosing histamine 2 receptor antagonists over proton pump inhibitors is a good choice though drug selection is not addressed in the sepsis guidelines.

    Venous thromboembolism (VTE) prophylaxis is not routinely indicated in pediatric sepsis patients as VTE is much less common in pediatric patients than it is in adults, but some patients may benefit from VTE prophylaxis.4 This is in contrast to the adult guidelines which recommend both mechanical and pharmacologic VTE prophylaxis in sepsis patients.5 Pediatric sepsis patients most at risk for VTE and therefore most likely to benefit from VTE prophylaxis are those who are post-pubertal and have a central venous catheter.4 As much data on pediatric VTE has been extrapolated from adult data, other risk factors are similar in the two populations including obesity, cancer, use of exogenous estrogens, and renal and cardiac comorbidities.15 Previous pediatric guidelines had similar grey areas in terms of VTE prophylaxis with the 2008 guidelines stating to use VTE prophylaxis in post-pubertal children and primarily addressing heparin bonded central venous catheters rather than administration of LMWH or UFH, but there was no mention of management of children who have not yet reached puberty.7 The 2012 update simply stated no graded recommendations for VTE prophylaxis in pre-pubertal children, again discussed heparin bonded catheters, and did not mention post-pubertal children.6 The medication most often used for VTE prophylaxis in pediatric patients is enoxaparin.

    Intravenous immune globulin (IVIG) may also be indicated in select patients because it enhances passive immunity but evidence has not supported routine use of IVIG in patients with sepsis.4 While IVIG is not routinely recommended for sepsis in pediatric patients, there are a subset of patients for whom IVIG may be a reasonable treatment option.4 Patients with streptococcal toxic shock syndrome are likely to benefit from IVIG.4 Additionally, it may be beneficial to consider IVIG in immunodeficient or immunocompromised patients with low immunoglobulin levels and patients with necrotizing fasciitis.4 While the adult guidelines recommend against IVIG without this caveat of potentially appropriate use, they also suggest that further research may be needed to evaluate the efficacy of IVIG, so with four additional years of research these two guideline statements are essentially in agreement.5 The 2012 pediatric guidelines stated that use of IVIG in toxic shock was unclear, which is a bit incongruent with 2008 pediatric guidelines which suggested IVIG in patients with severe sepsis, not just those with toxic shock.6,7

    Medications that no longer appear in the pediatric sepsis guidelines but have previously been recommended against include recombinant human activated protein C in the 2008 guidelines secondary to findings in clinical trials of no difference between patients receiving activated protein C versus placebo.7 Based on these findings it would be reasonable to assume that despite not being mentioned, continuing to not utilize activated protein C would be appropriate. The 2012 guidelines recommended against long-term propofol for sedation in patients under three years of age secondary to concerns for metabolic acidosis.6 This is another recommendation that while not being mentioned in other iterations of the guidelines continues to seem prudent to follow as it is known that propofol related infusion syndrome is a risk for patients of all ages with extended use of propofol, making propofol a less than ideal agent for patients requiring long-term sedation.

    Conclusions

    Organ dysfunction is useful not only in differentiating sepsis from severe sepsis, but also in considering changes to medication pharmacokinetics. When shock is present antibiotics should be given within one hour. Fluids are an important component of care even in normotensive patients and balanced buffered crystalloids are recommended. Unless patients require hydrocortisone at baseline, it should only be given if fluids and vasoactive medications are insufficient to maintain hemodynamic stability. Nutrition should be provided enterally if possible, and many supplements including zinc, thiamine, and vitamin C are not routinely indicated. Finally, it is important to carefully consider indications for IVIG, stress ulcer prophylaxis, and VTE prophylaxis.

    References

    1. Mathias B, Mira JC, Larson SD. Pediatric sepsis. Curr Opin Pediatr. 2016;28(3):380-387.
    2. Goldstein B, Giroir B, Randolph A; International consensus conference on pediatric sepsis. international pediatric sepsis consensus conference: definitions for sepsis and organ dysfunction in pediatrics. Pediatr Crit Care Med. 2005;6(1):2-8.
    3. Thakkar N, Salerno S, Hornik CP, Gonzalez D. Clinical pharmacology studies in critically ill children. Pharm Res. 2017;34(1):7-24.
    4. Weiss SL, Peters MJ, Alhazzani W, et al. Surviving sepsis campaign international guidelines for the management of septic shock and sepsis-associated organ dysfunction in children. Pediatr Crit Care Med. 2020;21(2):e52-e105.
    5. Rhodes A, Evans LE, Alhazzani W, et al. Surviving sepsis campaign: international guidelines for management of sepsis and septic shock: 2016. Intensive Care Med. 2017;43:304-377.
    6. Dellinger RP, Levy MM, Rhodes A, et al. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock, 2012. Intensive Care Med. 2012;39:165-228.
    7. Dellinger RP, Levy MM, Carlet JM, et al. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med. 2008;36(1):296-327.
    8. Williams V, Jayashree M, Nallasamy K, Dayal D, Rawat A. 0.9% saline versus Plasma-Lyte as initial fluid in children with diabetic ketoacidosis (SPinK trial): a double-blind randomized controlled trial. Crit Care. 2020;24(1):1.
    9. Feld LG, Neuspiel DR, Foster BA, et al. Clinical practice guideline: maintenance intravenous fluids in children. Pediatrics. 2018;142(6):e20183083.
    10. Paediatric ards neuromuscular blockade study (PAN). Clinicaltrials.gov identifier: NCT02902055. Updated December 13, 2019.
    11. American Diabetes Association. 15. Diabetes care in the hospital. Standards of Medical Care in Diabetes-2020. Diabetes Care. 2020;43(Suppl 1):S193-S202.
    12. Averin K, Villa C, Krawczeski CD, et al. Initial observations of the effects of calcium chloride infusions in pediatric patients with low cardiac output. Pediatr Cardiol. 2016;37(3):610-617.
    13. Walsh P, Rothenberg SJ, Bang H. Safety of ibuprofen in infants younger than six months: A retrospective cohort study. PLoS One. 2018;13(6):e0199493.
    14.  Duffett M, Chan A, Closs J, et al. Stress ulcer prophylaxis in critically ill children: a multicenter observational study. Pediatr Crit Care Med. 2020;21(2):e107-e113.
    15. Faustino EV, Raffini LJ. Prevention of hospital-acquired venous thromboembolism in children: a review of published guidelines. Front Pediatr. 2017;5:9.


  • 03 Aug 2021 1:42 PM | Anonymous

    By: Kelly Williams & Jenny Ohnesorge, Pharm.D. Candidates 2023; UMKC SSHP Chapter Presidents

    Despite living and learning in a pandemic, the leadership of UMKC’s SSHP across three campuses (Kansas City, Columbia, and Springfield) persevered by innovating new ways to connect to students and the community. In the Fall of 2020, there were still many unknowns to the pandemic, but the executive teams pushed on and planning was underway for virtual events, a change from previous years. The year kicked off with the New Student Orientation on the lawn of the Health Sciences Building and executive team members were able to talk about what ASHP and SSHP can do for its members. In September, Residency Roundtable was held for the first time ever via Zoom. UMKC’s Residency Roundtable 2020 consisted of discussion-based breakout rooms with the Residency Program Directors and current residents, a keynote presentation, and information about PhorCAS and Midyear. We were able to host a variety of programs from sites that would otherwise be impossible in-person. Many of the programs that attended Residency Roundtable were not from Missouri, but states such as Nebraska, Iowa, Arkansas, Kansas, and Texas. The event was deemed a success from student attendees and the SSHP executive board alike, with talks to continue hosting Residency Roundtable virtually in order to reach a more diverse array of residency programs. Next, in October, we were able to host the Clinical Skills Competition via Zoom as well, where 12 teams of two students competed. The Clinical Skills Competition was held on two separate days, the first day consisting of a written case workup by each team, and the second day consisting of an oral presentation from three semi-finalist teams. Both days were judged by a panel of pharmacy residents. Similar to Residency Roundtable, the Clinical Skills Competition proved to be very successful as it also transitioned to a new virtual structure, with talks to continue this format going forward.

    In both the fall and spring, UMKC’s SSHP held monthly general meetings with speakers from health-systems across Missouri. Topics covered included patient cases and general discussion of the day to day activities as a health-system pharmacist. Additionally, we were excited to host MSHP President Dr. Davina Dell as she presented over ASHP’s Practice Advancement Initiative (PAI) 2030. Furthermore, students were encouraged to attend community service events held at the three campuses; such events consisted of volunteering at Harvester’s and Habitat for Humanity and cleaning up trash alongside roads and highways

    The Columbia SSHP team was able to coordinate one event with MMSHP in the Fall of 2020, including food trucks, drinks, and trivia at a local eatery. Columbia’s SSHP team was also able to arrange a fundraiser selling embroidered UMKC School of Pharmacy jackets and quarter-zips, a feat that raised over $450 for the UMKC SSHP chapter. We hope to continue this fundraiser in the coming years.

    We are excited to once again get creative with our events in the Fall. We look forward to incorporating more virtual events into our schedule, including Residency Roundtable and the Clinical Skills Competition. This summer, the 2021-22 SSHP Executive Team will be hard at work to bring the most valuable experience to its student members. We are very thankful for MSHP’s involvement with SSHP across the three campuses and wish you a restful remainder of your summer!

  • 03 Aug 2021 1:40 PM | Anonymous

    By: Leah Blocker, PharmD Candidate 2023; SSHP President

    At St. Louis College of Pharmacy, our SSHP chapter holds many events that aim to advance and educate pharmacy students. In addition to our ongoing Mentor/Mentee program, some of the events we held this past year included Curriculum Vitae Writing and Review, Resident and Residency Director Roundtables, and a Medical Marijuana Lunch ‘n Learn.

    Our Mentor/Mentee Program is an annual matching program we hold that connects undergraduate or P1 students with professional students. Mentors are able to guide their mentees through their transition from the undergraduate program to the professional program at STLCOP. This program helps younger students face the many new challenges that are associated with the professional program, such as a heavier workload and more independent studies. The mentors in our program are there to offer advice.  Not only that, but our mentor-mentee program also opens up discussion about post-graduate opportunities, such as residency, which many younger students have not yet had time to explore.

    At our Curriculum Vitae Writing and Review events, we aim to educate students on how to create or improve their professional curriculum vitae (CV). CV’s are one of the most important ways a student can promote themselves to residency programs or future job opportunities. At STLCOP, one of our professors, Dr. Jack Burke, leads the CV Writing event. He plays a key role in educating students on the most important aspects of a CV and how to properly structure a CV. For our CV Review event, students were able to submit their CV to us and receive feedback from one of the pharmacist members of StLSHP. This allowed students the opportunity to have a pharmacist review their CV and make suggestions to help improve their chances of standing out in the future.

    Our Resident and Residency Director Roundtable events aim to connect professional students with current pharmacy residents and residency directors in the St. Louis area. The goal is to educate students on the different opportunities available to them after graduation, as well as enlighten them about what residency is like and what to expect. Current residents and residency directors are able to provide students with insight and tips, and students have an open platform to ask questions and receive direct answers.

    Lastly, a new event we held this year included a Medical Marijuana Lunch ‘n Learn. With the ever-changing advancements in legislature and medicine, it is important to keep students up to date and educated on significant topics, such as medical marijuana and its uses in the pharmacy field. Students are only briefly exposed to the topic of medical marijuana in our professional studies, so by offering this event, we hoped to expose more students to the topic in order to better prepare them for their future.

  • 03 Aug 2021 1:19 PM | Anonymous
    By: Elizabeth Nash, St. Louis College of Pharmacy Pharm.D. Candidate 2022 and Morgan Luttschwager Rose, MBA, St. Louis College of Pharmacy Pharm.D. Candidate 2022

    Mentor: Michelle Jeon, Pharm.D., BCACP, Assistant Professor of Pharmacy Practice, St. Louis College of Pharmacy at UHSP

    Epidemiology
    Heparin-induced thrombocytopenia (HIT) is an unusual drug reaction involving heparin exposure. Overall, HIT epidemiology is not well documented; however, reports indicate it will occur in about 0.1-0.5% of patients on heparin therapy including low molecular weight heparin (LMWH) and unfractionated heparin (UF). Based on a population study conducted in 2018, the incidence of HIT diagnosis are relatively low. HIT seems to be more common after cardiac surgeries compared to after orthopedic surgeries.1

    Once HIT occurs, the most common complication is thrombosis, occurring in 30% of cases, with bleeding occurring in 6.2%. In patients that experience bleeding, 25% of patients do not survive regardless of treatment.1

    Pathophysiology
    The pathophysiology of HIT (Figure 1) was identified in the early 1970s, nearly 20 years after the first reported case. The prominent players in the pathophysiology of HIT include platelet factor 4, heparin, platelets, monocytes, factors VII, IX, X, and thrombin.

    Once heparin is administered, it binds to naturally occurring platelet factor 4 due to ionic forces—this binding halts heparin’s action. The immune system responds by creating IgG antibodies that attack the PF4/heparin complex. The immunocomplex then binds to the surface of platelets and monocytes. This binding triggers their activation through the cross-linking of FcgIIA receptors. Platelet activation then leads to aggregation and stimulation of procoagulant activity. Monocyte activation stimulates tissue factor (TF) generation. TF binds with factor VII to activate factors IX and X, which in turn stimulate thrombin formation. Thrombin leads to known clinical problems associated with HIT, such as pulmonary embolism, mesenteric ischemia, ischemic limb necrosis, acute myocardial infarction, and stroke.2 

    Figure 1. Pathophysiology of heparin-induced thrombocytopenia2


    Risk Factors
    All patients receiving any form of heparin should to be monitored for HIT with routine labs including platelets. However, there are some specific scenarios in which increased risk may be present and extreme caution should be used. Risk factors for HIT include:

    • Heparin therapy used for a duration longer than five days, regardless of dose or indication
    • Type of heparin used, unfractionated heparin carries the largest risk
    • Surgical and trauma patients
    • Female patients3
    • Increasing age beyond the age of 50 years old1
    • COVID-19 infection - Further information in “COVID-19 Considerations”4,5,6

    Patients under these circumstances may require closer monitoring; however, there is still a risk for HIT in patients who do not have these risk factors.

    Diagnosis and Clinical Presentation
    Although HIT is rare, patients with suspected signs and symptoms should be evaluated for probability of the disease. As indicated in Figure 2, the 4Ts test considers thrombocytopenia, timeframe of platelet decreasing, thrombosis, and other causes of thrombocytopenia. If these tests reveal intermediate or high probability, an immunoassay, which identifies antibodies against PF4 or heparin should be conducted. If the immunoassay is positive, a functional platelet activation assay (e.g. serotonin release assay) should subsequently be performed, which shows antibodies that specifically induce heparin-dependent platelet activation3. If again positive, HIT is likely and treatment options should be considered. Typical clinical presentation of HIT includes platelet count decreased from baseline by greater than 50% and platelet nadir greater than or equal to 20,000/mm2. Patients with HIT typically have an onset within 5-14 days or less than one day with recent heparin exposure3. These patients may also have a confirmed thrombosis, necrosis of the skin at injection site, adrenal hemorrhage, or anaphylactoid reaction after heparin bolus. Patients with suspected HIT should have no other probable causes of thrombocytopenia.  

    Figure 2. Diagnosis for HIT3


    Treatment and Management
    The most critical information for practicing pharmacists regarding HIT is perhaps the treatment and management. Patients with HIT should be treated with non-heparin anticoagulants. The American Society of Hematology5 (ASH) suggests argatroban, bivalirudin, fondaparinux, or a direct-acting oral anticoagulant (DOAC). Patient-specific factors such as comorbidities, ease of administration, cost, route, etc., play a role in helping to select the best medication. If the patient is clinically stable, treatment with fondaparinux or any of the DOACs are best due to the ease of administration and the lack of routine labs required to monitor for safety. In situations where a short-acting anticoagulant is needed – such as in critical illness, increased bleed risk, or the potential for an urgent procedure – argatroban or bivalirudin are ideal. DOACs should be avoided in the case of life or limb-threatening thrombosis because they have not been thoroughly tested in this population. In a matter of such thrombosis, argatroban, bivalirudin, or fondaparinux are recommended for use. If patients also have moderate to severe hepatic dysfunction – defined as Child-Pugh Class B and C – bivalirudin, or fondaparinux are recommended over other options. If necessary, a lowered dose of argatroban may be appropriate in the case of hepatic impairment.3


    Monitoring Parameters
    HIT requires monitoring for signs and symptoms of thrombosis, bleeding and platelet recovery no matter which therapy option is chosen. Baseline aPTT levels should be drawn, if possible, to establish when thrombin levels have returned to normal. Several treatment options rely on platelet levels to determine duration of therapy. Signs and symptoms of bleeding such as bruising, weakness, and decreased blood pressure should be monitored daily. Patients diagnosed with HIT and a hemorrhage have a poor prognosis, with a 25% mortality rate regardless of treatment. The best chance to counter those odds is to catch the bleed early on with close monitoring.

    Drug-specific monitoring parameters can vary, especially between the newer DOACs and older agents. DOACs typically require less laboratory monitoring, which can be favorable for patients.

    COVID-19 Considerations
    The pathology of heparin-induced thrombocytopenia relies significantly on the platelet factor 4/heparin (PF4/H) complex and the antibodies developed against it. In the case of patients infected with the SARS-CoV-2 virus, the presence of these antibodies is increased.4, 5 Once infected, patients develop antibodies against the COVID-19 virus; however, these antibodies resemble the PF4/H antibodies so closely they can activate the B cells associated with HIT. Thrombotic complications associated with COVID-19 infection, therefore, share pathology with HIT. The SARS-CoV-2 infection is strongly related to thromboembolic events, perhaps due to the resemblance of the antibodies, making anticoagulation therapy common in hospitalized patients. When using heparin as anticoagulant therapy in infected patients, extreme caution should be used as the risk for HIT is increased.5

    Role of a Pharmacist
    Pharmacists can significantly impact the treatment of heparin-induced thrombocytopenia; they are on the front line to recognize the drug-induced reaction of HIT. Pharmacists should determine whether or not non-heparin products are an appropriate therapy for anticoagulant use. The risk factors of HIT could guide treatment selection and the level of monitoring needed. Pharmacists can use patient-specific factors to choose the best anticoagulation therapy for a patient. Pharmacists can also recognize when heparin is in lower concentrations in products such as heparin flushes, hematopoietic stem cell products, some total parenteral nutrition products, and prothrombin complex. As the drug experts, pharmacists can be the first to identify someone has HIT by evaluating side effects of the drug. Pharmacists should participate in an interdisciplinary approach to help manage HIT with exemplary patient-centered care.

    References:

    1. Dhakal B, Kreuziger LB, Rein L, et al. Disease burden, complication rates, and health-care costs of heparin-induced thrombocytopenia in the USA: a population based study. Lancet Haematol. 2018;5(5):e220-e231.
    2. Patriarcheas V, Pikoulas A, Kostis M, Charpidou A, Dimakakos E. Heparin-induced thrombocytopenia: pathophysiology, diagnosis and management. Cureus. 2020;12(3):e7385.
    3. Pishko AM, Linkins LA, Warkentin TE, Cuker A. Diagnosis and management of heparin-induced thrombocytopenia (HIT) a pocket guide for the clinician. Am Soc of Hematology. 2018;2(22):3226-3256.
    4. Zhu W, Zheng Y, Yu M, et al. SARS-CoV-2 receptor binding domain-specific antibodies activate platelets with features resembling the pathogenic antibodies in heparin-induced thrombocytopenia. Research Square. 2021;rs-3.
    5. Favaloro EJ, Henry BM, Lippi G. The complicated relationships of heparin-induced thrombocytopenia and platelet factor 4 antibodies with COVID-19. Int J Lab Hematol. 2021;00:1-12.
    6. Madala S, Krzyzak M, Dehghani S. Is COVID-19 an independent risk factor for heparin-induced thrombocytopenia. Cureus. 2021;13(2):e13425.
    7. Argatroban. Packa a pocketge Insert. LGM Pharma. 2011.
    8. Beiderlinden M, Treschan TA, Görlinger K, et al. Argatroban anticoagulation in critically ill patients. Ann Pharmacother. 2007;41(5):749-54.
    9. Bivalirudin. Package Insert. International Technidyne Corporation. 2016.
    10. Fondaparinux. Package Insert. GlaxoSmithKline. 2010.
    11. Agnelli G, Buller HR, Cohen A, et al. AMPLIFY investigators. oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med. 2013;369(9):799-808.
    12. Eliquis. Package Insert. Bristol-Myers Squibb Company and Pfizer Inc. 2021.
    13. Pradaxa. Package Insert. Boehringer Ingelheim Pharmaceuticals. 2015.
    14. Xarelto. Package Insert. Janssen Pharmaceuticals. 2016.
  • 03 Aug 2021 11:51 AM | Anonymous

    By: Jaynika Patel, PharmD Candidate 2023; University of Health Sciences and Pharmacy at St. Louis College of Pharmacy, Saint Louis, Missouri

    Mentor: Priyam Patel, PharmD; Aurora St. Luke’s Medical Center, Milwaukee, Wisconsin

    Background
    Obesity is a prevalent condition in the United States (U.S.) with nearly one in every three adults being affected.1 The body mass index (BMI) is utilized to determine the weight classification of an individual and can be calculated by dividing the weight in kilograms by the height in meters squared. Obesity is defined as a BMI of 30.0 kg/m2 or above and is further classified into three subcategories: class I (BMI 30-34.9 kg/m2), class II (35-39.9 kg/m2), and class III (≥ 40 kg/m2). Morbidly obese patients are considered Class III based on their BMI.

    Obesity presents as a risk factor for venous thromboembolism (VTE).2 Venous thromboembolism is a serious, yet preventable medical condition which refers to blood clots in the veins and could lead to a serious illness or death.3 It is estimated that the annual incidence of VTE in the U.S is 1 to 2 per 1000 of the population.3 Due to the high morbidity and mortality risk, the prevention and treatment of VTE have become a growing concern.

    Per the American College of Chest Physicians (CHEST) guidelines, the favorable treatment option for patients with VTE and no cancer diagnosis are direct oral anticoagulants (DOACs) over vitamin K antagonist (VKA) therapy.4 However, the guideline by the Scientific and Standardization Subcommittee of International Society on Thrombosis and Haemostasis (ISTH) advises that DOACs should not be administered for BMI greater than 40 kg/m2 or weight greater than 120 kg due to inadequate drug exposure, short half-lives, and lower peak concentrations in this patient population.5 The remainder of this article will evaluate landmark trials and recent studies followed by the key takeaways.

    Landmark Trials and Recent Studies
    Each DOAC, supported by its landmark trial(s), has been evaluated for its efficacy and safety in the treatment of VTE. The outcomes measured in these trials include, but are not limited to, recurrence of VTE and major bleeding. The results of these studies concluded that DOACs in VTE are as effective for anticoagulation as VKA, such as warfarin.


    One limitation, as it pertains to this article, is that these landmark trials were conducted in a general population, which had a low enrollment of morbidly obese patients. The enrollment for the highest weight/BMI categories reported in these trials is summarized in Table 1. Recent studies aim to determine the efficacy and safety of DOAC use in morbidly obese patients.  

    Elshafei et al. performed a systematic review followed by a meta-analysis of trials that compared efficacy and safety of DOAC use to warfarin for acute VTE in morbidly obese patients.12 Four observational studies assessed the efficacy and safety outcomes. The primary efficacy outcome of VTE recurrence rate in morbidly obese patients determined that DOAC use compared to warfarin was non-inferior (OR 1.07, 95% CI 0.93 to 1.23, Q=1.45, I2=0%) with a low I2, indicating the results were homogenous. In regard to major bleeding events, the analysis identified a non-significant risk reduction by 20% in the DOAC group (OR 0.80, 95% CI 0.54 to 1.17, Q=0.16, I2=0%). This study provided evidence that DOAC use as an alternative to warfarin in morbidly obese patients is effective and safe.

    Spyropoulos et al. conducted a retrospective 1:1 propensity score-matched cohort study that analyzed morbidly obese patients diagnosed with a VTE who received rivaroxaban or warfarin.13 Two analyses were conducted in this study to observe continual anticoagulant use: intent-to-treat (ITT) and on-treatment (OT). In the ITT analysis, the risk of recurrent VTE in the rivaroxaban group (16.8%) versus the warfarin group (15.9%) was not significantly different (OR 0.99, 95% CI 0.85 to 1.14, P=0.8443). However, major bleeding events in the treatment group (1.8%) in comparison to the warfarin group (2.5%) were significant lower (OR 0.66, 95% CI 0.45 to 0.98, P = 0.0388). In the OT analysis, the risk of recurrent VTE for rivaroxaban (14.8%) versus warfarin (13.4%) was not statistically significant (OR 1.02, 95% CI, 0.87 to 1.20, P=0.8343). Major bleeding events for rivaroxaban (1.4%) and warfarin (1.8%) also did not occur at a statistically different rate (OT: OR 0.75, 95% CI 0.47 to 1.19, P=0.2266). The two analyses provided consistent results in concluding that rivaroxaban has comparable efficacy to warfarin in this study population.

    Coons et al. also performed a retrospective matched cohort study analyzing the effectiveness and safety of DOACs for acute VTE treatment in morbidly obese patients in comparison to warfarin.14 The primary outcome was the recurrence of VTE within 12 months after the index admission date. Of the patients with a diagnosis of acute VTE and weight threshold of 100 kg to 300 kg, 632 patients had received a DOAC, while 1208 patients had received warfarin. Rivaroxaban was the primary DOAC administered, representing 91.8% of the patient population. The recurrence of VTE occurred in 6.5% of patients in the DOAC group versus the 6.4% of patients in the warfarin group, which was not a statistically significant difference (P=0.93). The incidence of the primary outcome in the apixaban, rivaroxaban, and warfarin groups were 2.1%, 2%, and 1.2%, respectively (P=0.74). Bleeding events in the DOAC group (1.7%) and warfarin group (1.2%) were also not statistically significant (P=0.31). Based on the data, the authors of the study support the treatment of acute VTE in morbidly obese patients with DOACs.

    A retrospective single-center cohort study by Patil et al. analyzed the efficacy and safety of DOACs versus warfarin in the morbidly obese Veteran patient population.15 In the DOAC group, apixaban was administered to 61.68% of the patients, rivaroxaban to 32.71%, and dabigatran to 5.61%. The primary outcome measure was a composite of VTE and stroke/transient ischemic attack. The results of the annual incidence rate of the primary outcome were not statistically significant between the DOAC group (1.61%) and warfarin group (3.91%) (RR 2.436, 95% CI 0.776 to 10.08, P=0.1543). The secondary outcome measuring major bleeding based on the ISTH guidelines had similar annual incidence rates between the two groups (warfarin: 3.13% vs. DOACs: 3.21%, RR 0.97, 95% CI 0.36 to 2.75, P=0.9438). Overall, the study results demonstrated that the administration of DOACs in comparison to warfarin is a viable alternative in morbidly obese patients. 

    Conclusion 
    The recent studies discussed above suggest that DOAC use in the treatment of VTE in morbidly obese patients may be efficacious in preventing recurrent VTE. The non-inferiority studies still hold warfarin to be a viable treatment option for patients. Regarding safety, DOACs demonstrated similar or slight variations in the rates of bleeding events compared to warfarin which may be contributed from patient-specific factors or inconsistent monitoring. The results of these studies were strengthened by the study design which included a diverse population, relevant subgroup of patients, and large databases for research. 

    One major limitation found amongst the retrospective studies was that they relied on accurate documentation that may not have considered other factors at that time, such as specific comorbidities or concomitant use of other high bleeding risk medications. Additionally, the predominance of one DOAC in a study analyzing all DOACs does not provide a balanced comparison. Thus, prospective clinical trials studying the effects of all DOACs for the treatment of VTE in morbidly obese patients are needed to determine which DOAC is superior and most appropriate to recommend. 

    References

    1. Defining adult overweight & obesity. Centers for Disease Control and Prevention. https://www.cdc.gov/obesity/adult/defining.html. Updated June 7, 2021. Accessed June 9, 2021.
    2. Overweight and obesity. National Heart, Lung, and Blood Institute. https://www.nhlbi.nih.gov/health-topics/overweight-and-obesity. Accessed June 3, 2021.
    3. What is venous thromboembolism? Centers for Disease Control and Prevention. https://www.cdc.gov/ncbddd/dvt/facts.html. Updated February 7, 2020. Accessed June 1, 2021.
    4. Kearon C, Akl EA, Ornelas J, et al. Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report. Chest. 2016;149(2):314-352.
    5. Martin K, Beyer-Westendorf J, Davidson BL, Huisman MV, Sandset PM, Moll S. Use of the direct oral anticoagulants in obese patients: guidance from the SSC of the ISTH. J Thromb Haemost. 2016;14(6):1308-1313.
    6. Schulman S, Kearon C, Kakkar AK, et al.; RE-COVER Study Group. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med. 2009;361(24):2342-52.
    7. Schulman S, Kakkar AK, Goldhaber SZ, et al.; RE-COVER II Trial Investigators. Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis. Circulation. 2014;129(7):764-72. 
    8. EINSTEIN Investigators, Bauersachs R, Berkowitz SD, Brenner B, et al. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010;363(26):2499-510. 
    9. EINSTEIN–PE Investigators, Büller HR, Prins MH, Lensin AW, et al. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med. 2012;366(14):1287-97.
    10. Agnelli G, Buller HR, Cohen A, et al.; AMPLIFY Investigators. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med. 2013;369(9):799-808.
    11. Hokusai-VTE Investigators, Büller HR, Décousus H, Grosso MA, et al. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med. 2013;369(15):1406-15.
    12. Elshafei MN, Mohamed MFH, El-Bardissy A, et al. Comparative effectiveness and safety of direct oral anticoagulants compared to warfarin in morbidly obese patients with acute venous thromboembolism: systematic review and a meta-analysis. J Thromb Thrombolysis. 2021;51(2):388-396.
    13. Spyropoulos AC, Ashton V, Chen YW, et al. Rivaroxaban versus warfarin treatment among morbidly obese patients with venous thromboembolism: Comparative effectiveness, safety, and costs. Thromb Res. 2019;183:159-166.
    14. Coons JC, Albert L, Bejjani A, Iasella CJ. Effectiveness and safety of direct oral anticoagulants versus warfarin in obese patients with acute venous thromboembolism. Pharmacotherapy. 2020;40(3):204-210.
    15. Patil T, Lebrecht M. A single center retrospective cohort study evaluating use of direct oral anticoagulants (DOACs) in morbidly obese veteran population. Thromb Res. 2020;192:124-130. 

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