• 17 Nov 2017 11:16 AM | Deleted user

    Vancomycin Utilization in the Obese Population and Future Monitoring Strategies

    Authors: Ryan Buckman, UMKC Pharm.D. Candidate, 2018
    Kathryn Burnett, Pharm.D., Kansas City VAMC PGY-2 Infectious Diseases Pharmacy Resident

    Vancomycin was isolated in 1957 by an Eli Lilly chemist, Dr. E.C. Kornfield, from a soil sample collected in the jungle of Borneo.1,2 The sample was isolated from a fungus that yielded bactericidal activity against Staphylococci. The U.S. Food and Drug Administration (FDA) fast tracked the compound, due to concerns over growing resistance of Staphylococci. The compound was given the generic name vancomycin, a term derived from the word vanquish.1,2 Fast forward nearly 60 years and there is still controversy surrounding the optimal dose monitoring parameters for vancomycin.

    Vancomycin is a glycopeptide antibiotic widely used in the United States for serious gram-positive infections involving methicillin resistant Staphylococcus aureus (MRSA). Vancomycin exhibits multicompartmental pharmacokinetics. Several strategies have been studied to determine pharmacokinetic and pharmacodynamics monitoring parameters for predicting vancomycin outcomes. Strategies for dose monitoring include: percentage of time the dosing interval that the drug concentration remains above the minimum inhibitory concentration (T>MIC), the area under the concentration-time curve (AUC): MIC ratio, and the maximum concentration: MIC (Cmax: MIC) ratio. Optimal dosing and monitoring for vancomycin will assist in reducing the occurrence of subtherapeutic and supratherapeutic levels leading to resistance and/or toxicity.

    In 2009, the American Society of Health-System Pharmacists (ASHP), Infectious Diseases Society of America (ISDA), and the Society of Infectious Diseases Pharmacists (SIDP) addressed vancomycin therapeutic drug monitoring.11 The panel recommended that trough serum vancomycin concentrations, as a marker for AUC, as the most accurate and practical method at monitoring vancomycin effectiveness (Level of evidence II, Grade B). Trough concentrations should be measured at steady-state, which occurs approximately before the fourth dose. Dosing is based on actual body weight and concentrations of 15-20mg/kg every 8-12 hours to be utilized in complicated infections for most patients (normal renal function) to achieve target concentrations.11 Trough concentrations of 15 to 20 μg/mL to achieve efficacy in complicated infections while maintaining trough concentrations > 10 μg/mL to prevent the development of resistance.

    According to the current consensus recommendation, vancomycin dosages should be calculated on adjusted body weight (ABW) for all patients, including the obese population, and then adjusted based on serum vancomycin concentrations to achieve therapeutic trough concentrations.

    Challenges with Vancomycin Dosing in Obese Patients A 2009-2010 National Health and Nutrition examination survey revealed more than 78 million (35.7%) adults in the United States are obese (body mass index (BMI) > 30kg/m2).5 Projections for 2030 estimate more than half of adults in the U.S. will be obese.8 These numbers are concerning because obesity is associated with an increased risk of infection, as well as increased morbidity and mortality.5,6 Vancomycin dosing for obese and extremely obese patients provides challenges. Increase in body weight can affect vancomycin pharmacodynamics and pharmacokinetics. It has been observed that obese patients display physiological changes that include increased adipose tissue and muscle mass that can alter vancomycin’s volume of distribution.1,2 Additionally, increased kidney mass, increased renal blood flow, increased creatinine clearance and increased vancomycin clearance.1,2,4 Due to the altered physiological changes and dosing challenges, obese patients may be at greater risk for nephrotoxicity.

    Dosing Strategies
    Divided load strategy
    Denetclaw and colleagues developed a divided-load dosing strategy for obese patients. The study was designed as an 8-month prospective, uncontrolled analysis of 54 patients at a single community hospital. Patients initially received 750mg, 1000mg, or 1250mg dose intravenously every 6 hours. The initial dose given was based upon patient’s ideal body weight ≥ 137% and body weight ±83 kg IBW (Table 1). The first trough concentration was drawn before the third dose. If the first pre-steady state trough concentration was within target range, then the initial dose was maintained and frequency was altered according to estimated creatinine clearance using the modified Cockcroft-Gault equation (Table 2 and 3). If first pre-steady state trough concentration was below range then the initial frequency was maintained and a second pre-steady state trough concentration was drawn before the fifth dose. If the second trough was within goal range then they followed the previous mentioned strategy of maintaining dose and adjusted the frequency of administration (Table 4). If either of the two troughs were above target range the dose was held and then restarted with the same initial dose but change in frequency according to estimated creatinine clearance and followed traditional dosing guidelines. They found that 89% of patients exhibited pre-steady-state concentrations between 10 to 20 µg/mL with 12 hours after dose initiation. The mean non-steady-state concentration was 14.5 ± 3.2 µg/mL.

    Based upon the study protocol developed by Denetclaw and colleagues, Dr. Burnett implemented a divided-load dosing strategy in morbidly obese patients assessed in an urban hospital. The study sought to determine the safety and efficacy of the alternative dosing strategy. The study was designed as a retrospective study that examined patients who met inclusion criteria between December 2015 and March 2016 for a baseline group and from December 2016 to March 2017 for divided dose implementation group.

    Utilizing the primary outcome measure of percentage of time in therapeutic range after maintenance regimen had been initiated, 36 of 99 patients reached target trough concentrations and were in the therapeutic range 41.9% ± 22.5% in the pre-implementation group. In the divided-dose group 11 of 19 patients reached target trough concentrations and were in the therapeutic range 24.4% ± 26.1%. The results revealed no statistical significance between the two groups (pre 41.9 + 22.5% vs post 35.6 + 34.4; p=0.579). A limitation of small sample size was due to patients missing doses, levels not drawn per protocol and vancomycin therapy being discontinued prior to a level being drawn during the maintenance regimen. The results were not anticipated for the divided-dose patients based upon the study done by Denetclaw et al.

    Allometric strategy
    Brown and colleagues examined allometric versus consensus dosing strategies to achieve target vancomycin trough concentrations.7 Allometric dosing aims to optimize empirical therapy across all body weights by improving the attainment of target drug concentrations. Allometric theory can be used to extrapolate drug dosing that utilizes a two-variable mathematical power to approximate doses according to body size. Dosing was based upon allometric equation, which is expressed as follows: allometric dose (mg) = average dose (mg) X {TBW (kg) / average TBW (kg)] β, where β is the allometric exponent that is scaled according to patient’s body size.7 The trial was a retrospective pre-and post-protocol implementation from January to June 2013 and January to June 2014. The primary outcome measure was percentage of patients achieving initial vancomycin trough concentrations between 10-20 mg/L. Eighty-one patients were included in each group. Allometric dosing resulted in 77% of patients achieving vancomycin trough concentration targets versus 57% for consensus guideline dosing.7 Since allometric dosing adjusts for patient’s body size, use could be considered for obese patients.

    Conclusion
    Even though vancomycin has been around for decades, dosing methods have varied and leaders in the area are still determining the best strategy. The 2009 consensus statement recommended trough levels to determine vancomycin effectiveness because of its practicality and relative accuracy. Although this model can be applied to most patients with reliable results, in obese patients dosing provides challenges due to physiological changes that can alter vancomycin volume of distribution. Dr. Burnett and others have studied divided dosing in obesity with mixed results but more data needs to be obtained to determine utility of this strategy in therapy. The updated consensus statement for vancomycin will include AUC/MIC as the preferred monitoring method over trough concentrations based on discussion from Michael Ryback, PharmD, MPH at IDWeek 2017. This method of dosing and monitoring will hopefully obtain better outcomes for all subsets of patients and reduce the development of resistance.

    References:

    1. Davies SW, Efird JT, Girdry CA, et al. Vancomycin-associated nephrotoxicity: The obesity factor.
    2. Denetclaw TH, Yu MK, Moua M, et al. Performance of a divided-load intravenous vancomycin dosing strategy for obese patients. Annals of Pharmacotherapy. 2015; 49(8): 861-868.
    3. Rybak MJ, Lomaestro B, Rotschafer JC, et al. Therapeutic monitoring of vancomycin in adults: Summary of consensus recommendations from the American Society of Heath-System Pharmacists, the Infectious Diseases Society of America, and Society of Infectious Diseases Pharmacists. Am J Health-Syst Pharm. 2009; 66: 82- 98.
    4. Grace E. Altered vancomycin pharmacokinetics in obese and morbidly obese patients: What we have learned over the past 30 years. J Antimicrob Chemother. 2012; 67; 1305-1310.
    5. Ogden CL, Carrol MD, Kit BK, Flegal KM. Prevalence of obesity in the United States, 2009-2010. United States Department of Health and Human Services: Centers for Disease Control and Prevention. National Center for Health Statistics. Available at www. Cdc.gov/nchs/data/databriefs/db82.pdf Accessed 08/22/2017.
    6. Wang YC, McPherson K, Marsh T, et al. Health and economic burden of the projected obesity trends in the USA and the UK. Lancet. 2011; 379 (9793): 815-825.
    7. Brown ML, Hutchison AM, McAtee AM et al. Allometric versus consensus guideline dosing in achieving target vancomycin trough concentrations. Am J Health-Syst Pharm. 2017; 74: e312-e320.
    8. Holmes NE, Tumidge JD, Munchof WJ et al. Vancomycin AUC/MIC ratio and 30-day mortality in patients with Staphylococcus aureus bacteremia. Antimicrobial Agents in Chemotherapy. 2013; 57(4): 1654-1663.
    9. Moellering RC. Vancomycin: A 50-year reassessment. Clin Infect Diseases. 2006; 42: s1-4.
    10. Morill HJ, Caffrey AR, Noh E, et al. Vancomycin dosing considerations in a real-world cohort of obese and extremely obese patients. Pharmacotherapy. 2015; 35(9): 869-875.
    11. Moise-Broder PA, Forrest A, Birmingham MC, et al. Pharmacodynamics of vancomycin and other antimicrobials in patients with Staphylococcus aureus lower respiratory tract infections. Clin Pharmacokinet. 2004;43(13):925-42.
    12. Rubinstein E, Keynan Y. Vancomycin revisted-60 years later. 2014; 217(2): 1-7.
  • 17 Nov 2017 11:03 AM | Deleted user

    Authors:
    Megan Griffey; UMKC PharmD Candidate, Class of 2018,
    Diane McClaskey, RPh, BCPS: Assistant Director of Experiential Learning-UMKC at MSU,
    Valerie Ruehter, PharmD, BCPP; Director of Experiential Learning-UMKC

    The role of a pharmacist in the health care system continues to evolve at a rapid pace. Pharmacists are becoming more involved in every aspect of patient care. While, many pharmacists across the nation may be utilizing the similar guidelines, dosing protocols, and thought processes, until 2014 there was not an agreed upon consistent patient care process. The vision of the Joint Commission of Pharmacy Practitioners (JCPP) is to see patients achieve optimal health and medication outcomes with pharmacists as essential and accountable providers within patient-centered, team-based healthcare. The JCPP, seeing a need for consistency in the profession, developed the standardized Pharmacists’ Patient Care Process (PPCP).

    The PPCP was developed to be a contemporary and comprehensive approach to promote consistency across the profession and encourage collaboration with other members of the health-care team. The PPCP is applicable to a variety of patient care services and provides a framework for delivering patient care in any setting. An active patient-pharmacist relationship and open effective communication with patients, family and caregivers are vital components to patient-centered care. Pharmacists must continuously collaborate and communicate with other health care providers and provide thorough documentation to ensure patients receive optimal care. The patient care process can be further improved by efficient interoperable information technology systems.

    The Pharmacists’ Patient Care Process

    Collect: The pharmacist assures the collection of necessary subjective and objective information about the patient in order to understand the relevant medical/medication history and clinical status of the patient.

    Assess: The pharmacist assesses the information collected and analyzes the clinical effects of the patient’s therapy in the context of the patient’s overall health goals in order to identify and prioritize problems and achieve optimal care.

    Plan: The pharmacist develops an individualized patient-centered care plan, in collaboration with other health care professionals and the patient or caregiver that is evidence-based and cost-effective.

    Implement: The pharmacist implements the care plan in collaboration with other healthcare professionals and the patient or caregiver.

    Follow-up (Monitor and Evaluate): The pharmacist monitors and evaluates the effectiveness of the care plan and modifies the plan in collaboration with other health care professionals and the patient or caregiver as needed.

    The Pharmacists’ Patient Care Process can be applied to countless services pharmacists practice on a daily basis. One example includes during a comprehensive medication review you must collect a medication history, assess the information collected and identify drug-related problems. You then develop a Medication-Related Action Plan, communicate and collaborate with the patient’s prescriber, then follow-up with the patient to monitor and evaluate any changes. IV to PO medication conversions require pharmacists to investigate and assess the appropriateness of a particular dosage form, make changes when necessary and properly communicate those changes with all health care professionals involved as well as the patient. Pharmacists collect demographic and disease state information from patients and assess whether they are in need of immunizations or other preventative care services. Chronic disease state management should involve this process at every patient encounter. Identifying drug related problems at the counseling window of a community pharmacy employs the PPCP and provides a process for effective interventions to be made. Even a medication reconciliation at any transition of care utilizes the Pharmacists’ Patient Care Process. Many pharmacists may be utilizing components of this process already, but strategically applying the PPCP to the services offered will ensure consistency and logical flow to patient-centered care.

    As a quality improvement exercise, you may evaluate your existing patient care services to ensure all aspects of the PPCP are being met. To begin, select an existing patient care service and rate how it aligns with the components of the PPCP. Rate items with low alignment as level 1. Rate items with high alignment as level 3. For any rating less than 3, develop strategies for improvement and an implementation timeline.

    Once you recognize how the PPCP can be applied to the services you provide patients, you can begin incorporating pharmacy student-interns and residents into this process. Early in the pharmacy school curriculum students learn the basics of patient health and medication assessment as well as identifying potential drug related problems and barriers to adherence. Involve students in the Collect and Assess stages of the PPCP through direct instruction and modeling to help them develop good professional communication skills and organization. As students progress through the curriculum mentor them through the critical assessment, plan, implement and follow-up stages. Emphasize the importance of evidence-based recommendations and detailed documentation and follow-up. After gaining an understanding of the baseline knowledge and experience of an APPE student, allow them to work independently through each of the PPCP stages providing coaching and facilitating when appropriate. High level learners, like pharmacy residents, can help teach and precept younger learners.

    The Pharmacists’ Patient Care Process provides a standardized approach to patient care promoting consistency across the profession. Learning to implement the Pharmacists’ Patient Care Process in a variety of different pharmacy services will help achieve optimal team-based patient-centered care. Developing learners’ ability to understand and effectively use the PPCP will ensure pharmacists remain an essential member of the health care team.

    References:

    • Pharmacy Collaborating for a Healthier America. (n.d.). Retrieved August 30, 2017, from https://jcpp.net/
    • Bennett, M., & Kliethermes, M. A. (2015). How to implement the pharmacists patient care process. Washington, DC: American Pharmacists Association.
    • O'Sullivan, T. A., PharmD, & Lau, C., PharmD. (2017). Analysis of the Student Experience in an Attending Pharmacist Model General Medicine Advance Pharmacy Practice Experience. American Journal of Pharmaceutical Education, 81(4), 66th ser., 1-11. Retrieved June 26, 2017, from http://www.ajpe.org/
  • 17 Nov 2017 10:26 AM | Deleted user

    Author: Sarah Cook, PharmD (Clinical Pharmacist at SSM Health St. Joseph’s Hospital – St. Charles)

    On the path to obtaining a residency, candidates are invariably faced with constructing a CV, writing letters of intent, and interviewing with programs. To help you succeed in your pursuit, several Residency Program Directors from programs across Missouri have generously offered their advice! (For those reading who are not pursuing residency, many of these tips easily transfer to obtaining your ideal job as well.) Below are some tips for putting your best foot forward:

    Crafting your CV:
    Remove items from your CV that you cannot speak to.
    It is important that the content of your CV highlights your achievements and involvement, and you should be able to speak to what is on it in a meaningful way. If you have a journal club or presentation listed, you should be able to highlight the take-home points. If you cannot, remove it. The content of your CV should show your interests, strengths, and uniqueness – the quality of the content is more important than the quantity. In fact, having too much “fluff” can distract from what you want to showcase about yourself, rather than impressing programs with the amount that you have done. For more information on crafting a CV (for residency and throughout your career), go to: https://www.ashp.org/pharmacy-student/pharmacy-student-forum/career-development/cv-development.

    Formatting tip: Use tables in Microsoft Word when formatting your CV and then hide the gridlines.
    This will allow you to have a neat, organized CV with multiple columns without having to waste time tabbing and spacing to try to get everything aligned just right. It also will save you from the struggle of having to realign text when you make edits to CV throughout your career.

    Have as many people as possible peer-review your CV.
    Seek out mentors, peers, and/or ASHP reviewing systems to look over your CV. This will reduce the chance for errors within your CV and will give you the chance to get feedback on its organization, readability, and content.

    Writing Letters of Intent:
    Make your letters of intent as specific to each program as possible.
    Prior to interviews, programs must rely primarily on the content of the application packet to decide who to invite for interviews. When writing your letters of intent, showcase your interests and skills and how they align with that specific program. Also, include how the program aligns with your short and long-term goals. Furthermore, some programs have specific guidance on what they desire to see in your letter or have additional materials which they want you to submit. Be sure to submit what each program asks for, as not doing so will indicate that you likely did not fully research the program.

    Showcasing yourself during interviews:
    Wear a suit!Although interview attire may be changing in certain occupations, wearing a suit to residency program interviews is still standard practice.

    Research interview questions and practice prior to interview day.
    Your interview should feel natural and non-rehearsed. However, it is also important to highlight your uniqueness and set yourself apart from other candidates. Practicing interviewing and researching interview questions allows you to think about your experiences and strengths so that you will be able to give specific, meaningful examples come interview day rather than generic, forgettable answers. Additionally, having an in-person practice interview with a mentor or other experienced individual will give you an opportunity to get feedback on how you convey yourself – including potentially distracting mannerisms, overuse of filler words like “um”, etc.

    Be professional and respectful.
    Even if you are interviewing at a place you are very familiar with or are currently employed at, showing professionalism and respect throughout the day is important and expected.

    Ask meaningful questions!
    It is not only important that interviewers get a good feel for how you will fit in with their program but also that you can assess if the program is a good fit for you. Asking questions that are specific to the program will also show that you have done your research on the program and that you have a genuine interest in the residency.

    For additional preparation for residency interviews, consider reading the following article detailing a Residency Program Director’s perspective on the ideal resident, which was published in an issue of Hospital Pharmacy: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3859286/pdf/hpj4810-825.pdf .

    Special thanks to the Residency Program Directors who contributed to this article: Nicole Gattas, Tony Huke, Allison King, Stephanie Lager, and Chelsea Landgraf.

    Finally, if you have a best practice which you feel others in the state would benefit from reading about, please contact me – Sarah Cook, Vice Chair of the MSHP Newsletter Committee – at Sarah.Cook@ssmhealth.com.

  • 17 Nov 2017 10:16 AM | Deleted user

    Author: Elaine Ogden, PharmD, BCPS, BC-ADM 
    MSHP Secretary

    Fall was an exciting time for the board of directors. We have finalized our strategic initiatives for the year and have dug right in! Over the next several months, the board will be reviewing and updating all the policies and procedures for MSHP.


    September BOD Updates

    • The Resident Workgroup has been established and will be chaired by Kerry Yamada…more to come!
    • Out-of-State Affiliate Membership is now available. Check out our membership page for more information.
    • Fall meeting planned and executed!! Four hours of GREAT pharmacist CE presented and a student session. See the Preceptor Development section of the newsletter, which features highlights of one of the presentations.

    October BOD Updates

    • MSHP BOD is working alongside with MPA to meet Governor Greitens’s request for all Missouri boards to review each regulation. Please see the public policy review update for more information
    • Planning for the joint Spring meeting with KCHP is in full swing! Watch for a call for poster presentations!
    • The Website committee has been working diligently to improve the content of MSHP’s website. Take a gander and let us know what you think!
    • The Resident work group has been working CE presentations for pharmacy technicians to expand access to quality CE presentations.
  • 17 Nov 2017 10:03 AM | Deleted user

    MSHP Public Policy Committee

    Author: Bert McClary, RPh (retired)

    The Public Policy Committee met by telephone conference in its scheduled monthly meetings on October 5 and November 2.

    During discussion of the practice advancement legislation proposal the committee was told that although MHA is very interested in supporting this and has agreed to help draft bill language, their regulatory staff is very busy at this time with DHSS rules and other legislation proposals. Discussion was held regarding possibly asking MPA again to write the bill language since the proposed changes were agreed on last spring, but this would be a decision to be made by the practice advancement group.

    The technician legislation proposal has been facilitated with MHA by individual pharmacists, and MSHP has also expressed support. MHA has agreed to provide draft bill language for pharmacy groups to review, but has not had time to do so. The goal of the proposal is to provide open language regarding technician qualifications and scope of practice that can accommodate future changes in pharmacy practice. The scope of the legislation will be limited to hospitals and hospital facilities. Discussion included whether or not it would be advantageous to also develop a DHSS hospital licensing rule using similar criteria. PP Committee volunteers will develop draft language for promotional materials that provides evidence of both increased patient safety and economic advantages of advanced technician scope of practice.

    Both of these proposals will need fast review and turnaround by interested pharmacy groups in order to select sponsors, file the bills and begin promotion by lobbying partners. Pre-filing of bills for the 2018 legislative session begins December 1, and lobbyists often begin promoting bills during November.

    Other agenda discussion topics included:

    • BOP meeting summaries
    • Review of SB 501 and DHSS hospital licensing rules
    • CMS/MoHealthNet proposed reimbursement changes for 340B pharmacies
    • Opioid epidemic
    • Federal provider status legislation

    Practice Advancement Legislation Group

    This voluntary multidisciplinary practice group, which is described in the January and September Newsletters, is preparing a legislative proposal to grant authority for pharmacists to prescribe drugs and controlled substances through MTS protocol agreements with physicians. This will enable improved patient medication management by pharmacists who are allowed to practice not only at the top of their license but also at the top of their competency.

    A core group of participants met by telephone conference on September 21 to review the current status of the proposal, make recommendations for finalizing the language, and make recommendations for promoting the bill to the legislature and to interested persons and organizations. Discussions included the following:

    • The colleges are preparing a summary of clinical practices in ambulatory care settings for use in promoting the bill.
    • The potential to include authority for ordering/performing/interpreting laboratory testing related to drug use. Also, the gray area of interpreting lab test results vs diagnosing, which is prohibited in the current statute. It was determined best to not make the bill too broad in scope, and that authority for testing should be determined based on current law and scope of practice standards.
    • Direct discussion of the proposal has been held with the Missouri Hospital Association. Additional contact will be made to request moving forward with preparation of bill language.
    • Additional efforts will be made to encourage participation by chain pharmacies and long term care pharmacies.
    • Members were encouraged to provide examples and ideas for promotional documents.
    • Promotion of the bill through MHA, MPA and health system lobbyists.
    • It is possible that MPA will want changes to current suggested language. Discussion also included the possibility of compromise during legislative hearings, and that compromise criteria should not be determined now, but the group should be aware of the possibility.

    During later discussions about this proposal at the BOP Hospital Advisory Committee meeting and the BOP open session, it was stated that MHA is extremely busy with other regulatory issues, but hoped to have bill language ready in November. It was also noted that BOP has discussed this proposal with MHA.

  • 17 Nov 2017 9:48 AM | Deleted user

    Author: Bert McClary, RPh (retired)

    The HAC met on October 12 in Jefferson City. Proposed pharmacy legislation was discussed, including the BOP technician registration proposal and the pharmacy practice advancement proposal. Committee members provided information about the technician registration proposal related specifically to hospital practice that is being developed in cooperation with the Missouri Hospital Association. Members also provided a brief review of the practice advancement proposal that is being discussed with MHA.

    Discussion was held regarding the implications of SB 501 and SB 50, which have identical language relating to DHSS hospital licensing rules. Any DHSS hospital licensing rules that are duplicative of or conflict with CMS Conditions of Participation will become invalid July 1, 2018. DHSS and MHA have begun a review process to determine which current rule language should be retained and if any new language should be added. Current law allows DHSS to promulgate rules which provide a higher degree of patient safety over CMS COPs, and recommendations for retention of current language or addition of new language will be proposed as new rules.

    HAC previously reviewed the proposed DHSS 19 CSR 30-100 Pharmacy Services and Medication Management rule that was proposed by a multidisciplinary DHSS rule review committee several years ago but has not been promulgated. HAC previously made recommendations for changes and DHSS accepted those recommendations. Since DHSS has no staff pharmacy expertise they are now requesting another thorough HAC review to determine which parts of the proposal are not duplicative of or in conflict with CMS COPs. They will give priority consideration to promulgating these based on providing a higher level of patient safety.

    The DHSS hospital licensing rules also address all other hospital functions. Almost 20 of those rules have either specific language or a significant effect on pharmacy/medication management, such as definitions, anesthesiology, medical staff, construction standards, medical records and respiratory therapy. Most of the medication related language was proposed to be deleted in favor of the revised pharmacy/medication management rule. Since the proposed language was never promulgated, the current language remains the same.

    Initial recommendations were to not retain most of the current or proposed rule language for the sections reviewed on October 12. Recommendations were made to retain partial language from the current rule or the proposed changes, or to provide revised language, pertaining to the following topics:

    • Technician education, training and authorized activities
    • Compounding, repackaging and dispensing records
    • Medication storage conditions
    • Controlled substance inventories and discrepancy reporting
    • Patient medication records
    • Receiving medications from outside pharmacy suppliers

    Rule topics that will likely be considered at the next HAC meeting November 14 include:

    • DHSS hospital premises definition
    • Medical staff privileges and membership for pharmacists
    • Distribution within the hospital and to outside locations
    • Distribution to patients when pharmacist is not available
    • Who may order medications, and medication order requirements
    • Who may administer medications, and training requirements
    • Medication use monitoring
    • Infection prevention and control
    • Quality assessment/performance improvement
    • CMS COPs for Critical Access Hospitals
  • 17 Nov 2017 9:23 AM | Deleted user

    Author: Bert McClary, RPh (retired)

    The Board of Pharmacy held an additional public session on September 13 in Jefferson City, and the regularly scheduled meeting on October 25 at St. Louis College of Pharmacy.

    According to the Governor’s Executive Order 17-03, all Missouri administrative rules are being reviewed and the additional session was necessary in order to keep the BOP rule review on schedule. The following rules were among those considered for the first time, and a recommendation was made to open them for further discussion by the Board for possible revisions:

    • PRN Refills 20 CSR 2220-2.110
      o Quantities remaining on refills
    • Transfer of Prescription Information 20 CSR 2220-2.120
      o Consider current technology, special types of transfers
    • Drug Repackaging 20 CSR 2220-2.130
    • Automated Filling Systems 20 CSR 2220-2.950
      o Compare language with other automated system rules
    • Patient Counseling 20 CSR 2220-2.190
      o Use of remote technology for counseling, other language considerations

    Continuing discussion was held on the following rules from previous meetings:

    • Pharmacy Standards of Operation 20 CSR 2220-2.010
      o Mandatory name tags for pharmacy staff
      o Print or electronic versions of required reference materials
      o Technician pictures allowed in binder vs posted publicly
      o Humidity control requirements
      o Use of the term medication vs drug
      o Content and retrievability of records for all legend drugs received and distributed
      o Possession of steroids by a home health agency
      o Security requirements
    • Pharmacy Supervision 20 CSR 2220-2.012
      o Technician activities during pharmacist’s temporary absence
      o Technician activities when pharmacist is not on site, including accepting prescriptions and compounding
      o Who is responsible for negative events when pharmacist is not present
      o Differentiate between security issues and oversight of duties
      o Define discretionary vs non-discretionary work
      o Clear definition of permit area
      o Subcommittee will prepare recommendations for discussion
    • Administration by Medical Prescription Order 20 CSR 2220-6.040
      o Qualification requirements
      o Board approval of training programs
      o Requirement for patient to remain in pharmacy after vaccine administration
      o Vaccine information statements
      o Reporting to DHSS ShowMeVax system
      o Mileage requirements
      o Will file for rulemaking
    • Administration of Vaccines per Protocol 20 CSR 2220-6.050
      o Requirement for obtaining or creating a prescription to document dispensing
      o Will refer to BOHA for approval, then file for rulemaking
    • Pharmacist-In-Charge 20 CSR 2220-2.090
      o Necessity of PIC requirement
      o Division of responsibility between PIC and permit holder
    • Electronic Prescriptions 20 CSR 2220-2.085
      o Digital signatures
      o Controlled substances in accordance with state and federal law
      o Will proceed with final rulemaking
    • Shared Services 20 CSR 2220-2.650
      o No additional changes suggested
      o Will file for rulemaking

    The BOP proposed legislation for technician registration changes is not a high priority for the Governor’s office as it does not reduce regulatory burden. An alternate proposal that would apply only to hospital pharmacy and hospital clinic sites is being considered by a hospital based group.

    The Governor’s Task Force on Boards and Commissions has recommended combining certain health profession boards, but has not recommended combining BOP with any other board. There was discussion of adding a technician member.

    The Governor is concerned that rule review meetings are not being held in all parts of the state by all agencies. The Board considered the utility of meeting in other areas of the state for rule review as well as for regularly scheduled meetings to provide more opportunity for public comment. The rule review requirements are causing a significant increase in workload for both Board members and staff, and this is expected to continue for the next couple of years. The Board will also focus on the Governor’s emphasis on timely clearing of investigation cases. The Board currently meets quarterly for open sessions and at least monthly in email and telephone conference meetings. Recommendations for adding an additional open meeting and the meeting schedule for the coming calendar year were discussed.

  • 22 Sep 2017 3:53 AM | Anonymous

    Authors:

    Kristine Reckenberg, PharmD Candidate 2018: St. Louis College of Pharmacy
    Christine Kelso, Pharm.D., BCPS, AE-C: Barnes-Jewish Hospital

    Cardiovascular disease (CVD) is responsible for approximately one out of every three deaths in the United States (US).1        One major indicator, considered a predictor of cardiovascular health by the American Heart Association (AHA), is cholesterol. Thirty-three percent of Americans have elevated low density lipoprotein (LDL) cholesterol.1 LDL and other lipoproteins containing apolipoprotein B (apoB) may accumulate within the intima of arteries, ultimately leading to plaque formation and atherosclerotic cardiovascular disease (ASCVD).4 This increase in LDL is an established biomarker and modifiable risk factor for CVD, included in the current ASCVD risk assessment tool.3 Non-high density lipoprotein cholesterol (non-HDL-C) measures the cholesterol content of all atherogenic lipoproteins that contribute to this ASCVD development.10 However, conflicting evidence exists regarding whether non-HDL-C or LDL has a more significant impact on CVD development. Thus, whether or not to treat to an LDL target is the subject of debate and variations in guidelines.2 Due to this conflicting evidence, it leads to a discussion as to whether treating to an LDL target is appropriate.

    Currently there are three guidelines for the management of hyperlipidemia in the US, comprised of those from the American College of Cardiology/American Heart Association (ACC/AHA), American Association of Clinical Endocrinologists and American College of Endocrinology (AACE), and National Lipid Association (NLA). Table 1 provides a brief summary of the goals and risk stratification for these major US recommendations. As outlined below, all organizations recommend similar initial treatment and differ primarily in the time of therapy initiation and treatment goals.7.8.9 Notably, not all guidelines endorse a target LDL goal. While the AACE and NLA promote this endpoint in their recommendations, the ACC/AHA instead focuses on a percent reduction in LDL achieved with statin therapy. Additionally, HDL levels have been shown to contrast with those of LDL elevation. Measured HDL is inversely proportional to atherosclerotic cardiovascular events, but no major landmark trials have shown success in pharmacologic interventions increasing HDL and reducing these incidents.5 Further exploration into this topic is warranted.

    As previously mentioned, LDL targets are a source of much controversy within the guidelines. Overall there is no evidence to support targeting a specific LDL and the safety of this approach has not been scientifically proven.6 Moreover, targeted LDL therapy increases patient costs, as it requires more than the annual fasting lipid panels recommended in the ACC/AHA guidelines.7 While acknowledging that no large randomized controlled trials designed to test this are available, the NLA guidelines suggest, with expert panel consensus, that providing a targeted goal for patients allows the individual and practitioner to understand progress in their treatment which has shown to be the standard of practice for healthcare professionals throughout history.9 Similarly, the AACE guidelines endorse the use of LDL targets with a strong recommendation with strong evidence.8 In sum, further studies are needed on LDL targeted therapy in order to make a more conclusive recommendation regarding this approach.


    Download Full Page Table

    References:

    1. Benjamin EJ, Blaha MJ, Chiuve SE et al. Heart disease and stroke statistics-2017 update: a report from the American Heart Association. Circulation. 2017;135(10):146-603. 

    2. Harari G, Green MS, Magid A et al. Usefulness of non–high-density lipoprotein cholesterol as a predictor of cardiovascular disease mortality in men in 22-year follow-Up. Am J Cardiol. 2017;119(8):1193-98.

    3. Ference BA, Ginsberg HN, Graham I et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society consensus panel.  Eur Heart J. 2017.

    4. Shapiro MD, Fazio S. Apolipoprotein B-containing lipoproteins and atherosclerotic cardiovascular disease. F100Research. 2017;6:134.

    5. Ali KM, Wonnerth A, Huber K et al. Cardiovascular disease risk reduction by raising HDL cholesterol – current therapies and future opportunities. Br J Pharmacol. 2012;167(6):1177-94.

    6. Hayward RA, Krumholz HM. Three reasons to abandon low-density lipoprotein targets: an open letter to the Adult Treatment Panel IV of the National Institutes of Health. Circ Cardiovasc Qual Outcomes. 2012;5(1):2-5.

    7. Andrus B, Lacaille D. 2013 ACC/AHA guideline on the assessment of cardiovascular risk. J Am Coll Cardiol. 2014;63(25 Pt A).

    8. Jellinger PS, Handelsman Y, Rosenblit PD et al. American association of clinical endocrinologists and American college of   endocrinology guidelines for management of dyslipidemia and prevention of cardiovascular disease. Endocr Pract. 2017;23(Suppl 2):1-87.

    9. Jacobson TA, Ito MK, Maki KC et al. National lipid association recommendations for patient-centered management of dyslipidemia: part 1-full report. J Clin Lipidol.2015;9(2):129-69.

    10. Virani AA, Coulter SA. Non-HDL cholesterol as a metric of good quality of care: opportunities and challenges. Tex Heart Inst J. 2011;38(2):160-62.


  • 21 Sep 2017 10:56 AM | Anonymous

    Authors:

    Sara Massey, PharmD Candidate 2018: UMKC School of Pharmacy
    Kylie Barnes, PharmD, BCPS: Clinical Assistant Professor at UMKC School of Pharmacy

    Pregnant women have an estimated 4- to 5-fold increased risk of thromboembolism when compared with non-pregnant women.1 Complicating the risk, pregnancy is also associated with physiologic and anatomic changes that increase a woman’s risk of thromboembolism. Those risks include hypercoagulability, increased venous stasis, decreased venous outflow, compression of the inferior vena cava and pelvic veins by the enlarging uterus, and decreased mobility.2 The increased risk begins in the first trimester, and intensifies throughout the third trimester and postpartum period, with the highest risk occurring during the first week postpartum. Personal history of thrombosis or increased hypercoagulable state is also an important risk factor to consider.

    Women with a mechanical heart valve are at particularly increased risk for a thromboembolic event during pregnancy. The risk of thromboembolic event differs from patient to patient, and depends upon the type and location of the valve, as well as the patient’s clinical presentation and other baseline risk factors. Women with a history of a prior thromboembolic event, atrial fibrillation, prosthesis in the mitral position, or multiple prosthetic valves are at the highest risk of an event.3 Regardless of the valve type or position, all women with a mechanical heart valve are recommended to be treated with therapeutic anticoagulation throughout pregnancy to reduce the risk of complications. Maternal thromboembolic complications during pregnancy may lead to required valve replacement or result in maternal death, which can also lead to fetal loss.3 Unfortunately, due to lack of adequate prospective controlled trials, the optimal anticoagulant therapy may vary and often depends on patient presenting factors, history, and personal preferences.

    Determining the most appropriate anticoagulant for a pregnant patient can be challenging, especially for practitioners who do not routinely care for patients throughout the antepartum period. According to the American Heart Association and American College of Cardiology (AHA/ACC) Valvular Heart Disease guidelines and the American Congress of Obstetricians and Gynecologists (ACOG) guidelines, warfarin, low molecular weight heparin (LMWH), and unfractionated heparin (UFH) are all potential treatment options for pregnant patients with a mechanical heart valve, depending upon the anticoagulation indication and gestation of the patient.2,4 Before starting an anticoagulation medication, patients should fully understand the importance of treatment and the potential associated risks with each treatment option. 

    Of the three treatment options, warfarin is the most effective agent in preventing valve thrombosis and thromboembolism. A systematic review of 28 studies, including 976 women with 1234 pregnancies from 1966 to 1997 evaluated the risks of maternal and fetal complications in women with mechanical heart valves treated with different anticoagulation regimens during pregnancy. Women treated with warfarin throughout pregnancy were associated with the lowest risk of valve thrombosis (3.9%; 95% CI, 2.9-5.9%). In comparison, heparin use during weeks 6 to 12 gestation, followed by warfarin for the remainder of pregnancy was associated with an increased risk of valve thrombosis (9.2%; 95% CI, 5.9-13.9%).5 Unfortunately, none of the included studies were randomized, and close to half of the women had older model valves, that are known to be more thrombogenic at baseline, compared to current valves used, making it difficult to assimilate the risks to current practice. Additionally, compliance was not reported in all of the included studies, and poor compliance and subtherapeutic regimens could have potentially contributed to the higher rate of valve thrombosis.

    There are no randomized controlled trials comparing LMWH use verses warfarin or UFH in pregnant patients with a mechanical heart valve. One retrospective review including 16 studies and 81 pregnancies from 1996 to 2003 reported thromboembolic complications occurred in 12.3% of pregnancies. When including only women who received therapeutic doses of LMWH, the incidence of thromboembolic complications decreased to 2.7%, suggesting the increased risk may be associated with use of subtherapeutic doses of LMWH, inadequate anti-Xa monitoring, and/or poor patient compliance with LMWH therapy.6 When comparing LMWH use to heparin, LMWH has a more predictable dosing regimen to attain therapeutic levels.

    When considering which anticoagulant to use, it is important to also consider maternal and fetal safety with each agent. Warfarin crosses the placenta, and is associated with an increased risk of late fetal loss.3 Exposure during the first trimester is associated with a pattern of congenital malformations termed the fetal warfarin syndrome that occurs in roughly 25% of exposed fetuses.  Additionally, warfarin has been linked to increased risk of spontaneous abortion, stillbirth, and neonatal death. In total, only 70% of pregnancies exposed to warfarin use are expected to result in a normal, healthy infant at delivery.7 However, lower doses of warfarin, less than or equal to 5 mg per day, have shown a reduction in potential fetal risks. From 1987 to 1997, one study investigated fetal and pregnancy risks of dosing warfarin less than or equal to 5mg daily or greater than 5 mg daily throughout 58 pregnancies. Pregnant patients receiving greater than 5 mg per day resulted in 3 full term deliveries and 22 fetal complications (spontaneous abortion, fetal growth retardation, warfarin embryopathy, stillbirth, or ventricular septal defect), whereas, pregnant patients who received less than or equal to 5 mg of warfarin daily resulted in 28 healthy deliveries and only 5 fetal complications.8 It has been theorized that warfarin embryopathy and fetal loss impact is dose-dependent, and patients should be treated with doses < 5 mg / day when appropriate. The clinical relevance of this finding can be lacking, as warfarin dosing is guided by therapeutic international normalized ratio monitoring to achieve adequate anticoagulation.  

    UFH is unable to cross the placenta, and has no known direct harm to the fetus.  According to the AHA/ACC guidelines, only continuous infusion UFH, not subcutaneous UFH, is recommended in this pregnant population, due to increased protection against thromboembolic events.3,4 Long-term use of UFH may cause bone loss due to reduced bone mineral density. One study, including 184 women, evaluated the effects of long-term treatment with heparin during pregnancy. Osteoporotic vertebral fractures were found in 2.2% of the women.9 Bone mineral density is thought to recover after heparin is discontinued, but the long-term impact is unclear.  UFH also has an increased risk for bleeding and thrombocytopenia, which is another potential risk in pregnant women with mechanical heart valves.10 LMWH also does not cross the placenta, and is associated with less effect on bone mineral density, less bleeding, and less thrombocytopenia when compared to UFH. However, LMWH has a longer half-life than UFH, and does not have a full reversal agent in the event the patient goes into labor.

    Anticoagulation management during pregnancy in the presence of a mechanical valve is complex. Warfarin, UFH, and LMWH are all potential anticoagulation treatment options in this population, and treatment decisions are guided, based on individual patient scenarios. Warfarin has clinically been the most effective in this patient population, however carries significant concerns to fetal development and safety. Below, the chart from the AHA/ACC Valvular Heart Disease guidelines, shows a general anticoagulation treatment approach for pregnant women with a mechanical heart valve.4 It is important to fully inform patients regarding the importance of therapeutic anticoagulation and continued medication compliance and monitoring throughout pregnancy. Additionally, patients must be informed of the maternal and fetal risks associated with each anticoagulation treatment option, and participate in the decision making process.

    Figure from the 2014 AHAACC Management of Patients with Valvular Heart Disease Guidelines4

    Figure from the 2014 AHA/ACC Management of Patients with Valvular Heart Disease Guidelines4

    References:

    1. Heit JA, Kobbervig CE, James AH et al. Trends in the incidence of venous thromboembolism during pregnancy or postpartum: a 30-year population-based study. Ann Intern Med 2005;143:697-706.
    2. Thromboembolism in pregnancy. ACOG Practice Bulletin No. 123. American College of Obstetricians and Gynecologists. Obset Gynecol 2011;123:987-96. doi: 10.1097/AOG.0000000000000230.
    3. North RA, Hunt B, Gaasch WH. Management of pregnant women with prosthetic heart valves. UpToDate 2017;8126(16).
    4. Nishimuara RA, Otto CM, Bonow RO, et al. 2014 AHA/ACC Guideline for the Management of Patients with Valvular Heart Disease: Executive Summary. American Heart Association Journals 2014;129:e521-643. 
    5. Chan WS, Anand S, Ginsberg JS. Anticoagulation of pregnant women with mechanical heart valves: a systemic review of the literature. Arch Intern Med 2000;160:191.
    6. Oran B, Lee-Parritz A, Ansell J. Low molecular weight heparin for the prophylaxis of thromboembolism in women with prosthetic mechanical heart valves during pregnancy. Thromb Haemost 2004;92:747.
    7. Briggs GG, Freeman RK, Towers CV, et al. Drugs in Pregnancy and Lactation, 11th ed. Philadelphia, PA: Lippencott Williams & Wilkins 2015:341-344.
    8.  Vitale N, Feo MD, De Santo LS, et al. Dose-dependent fetal complications of warfarin in pregnant women with mechanical heart valves. Journal of American College of Cardiology 1999;33(6):1637-41.
    9. Dahlman TC. Osteoporotic fractures and the recurrence of thromboembolism during pregnancy and the puerperium in 184 women undergoing thromboprophylaxis with heparin. Am J Obstet Gynecol 1993;168:1265.
    10. Hull RD, Garcia DA. Heparin and LMW heparin: dosing and adverse effects. UpToDate 2017;1348(60).
  • 20 Sep 2017 3:57 PM | Anonymous

    Authors:

    Emily Shor, PharmD Candidate 2018: St. Louis College of Pharmacy
    Jerrica Shuster, PharmD, BCPS, AQ-Cardiology: Barnes-Jewish Hospital
    Eli Deal, PharmD, FCCP, BCPS: Barnes-Jewish Hospital


    End-stage renal disease (ESRD), venous thromboembolism (VTE), and atrial fibrillation (AF) are continuously growing disease states worldwide. AF greatly impacts over 20% of ESRD patients, and AF patients on hemodialysis (HD) have 1.72 times higher one-year mortality rates than those not on HD.1,2 Additionally, HD patients are at a six-fold increased predisposed risk of ischemic or hemorrhagic stroke compared with the general population.2 Warfarin has served as the main oral anticoagulant for the general AF population.  However, it lacks randomized, controlled trials comparing it to placebo in patients on HD.2 Results from cohort studies have been inconsistent and limit warfarin’s utility in the HD population.2 Recently developed direct oral anticoagulants (DOACs) offer several advantages in comparison to warfarin while remaining as or more safe and effective. Similar data is still needed in the HD population to establish efficacy and safety. This review will evaluate the available literature in regards to DOACs in non-valvular atrial fibrillation (NVAF) patients requiring HD.

    Dabigatran
    Dabigatran, a direct thrombin inhibitor, was FDA-approved in October 2010 for the prevention of stroke and systemic embolism in patients with NVAF. Dabigatran 75 mg twice daily, a 50% dose reduction, is recommended in patients with NVAF and severe renal impairment (CrCl 15-29 mL/min).3 The landmark NVAF trial, RE-LY, excluded patients with severe renal impairment (CrCl < 30 mL/min).4 A pharmacokinetic (PK) study determined the appropriate dose adjustment in patients with severe renal impairment, but did not explore dosing recommendations in patients undergoing HD.5 However, Stangier, et al. found a two-fold increase in drug exposure in six patients undergoing HD and receiving a single 50 mg dose in comparison to healthy subjects. In addition, HD removed 62-68% of the dose in contrast to excretion of 80% of a dose in the urine with normal renal function.6 The use of dabigatran in HD should be avoided until steady-state PK studies or prospective clinical trials provide more insight due to the two-fold increase in drug exposure, and decreased removal with HD, identified by the single-dose PK study.6

    Rivaroxaban
    Rivaroxaban, a direct factor Xa inhibitor, was FDA-approved in November 2011 for the reduction of stroke and systemic embolism in patients with NVAF. Per manufacturer labeling, NVAF patients with CrCl 15 to 50 mL/min or on HD, a dose reduction to rivaroxaban 15 mg is recommended.7 However, the landmark trial, ROCKET-AF, excluded patients with CrCl less than 30 mL/min.8 The dose adjustment recommendation in HD for NVAF is based on a single-dose PK study consisting of eight patients that found a 56% increase in drug exposure following post-dialysis administration of rivaroxaban 15 mg when compared to healthy patients. In addition, drug clearance decreased by approximately 35% in ESRD patients.9 However, a multiple-dose PK study found that a 10 mg daily dose of rivaroxaban in HD patients without NVAF or VTE resulted in similar drug exposure when compared to a 20 mg daily dose in healthy patients with normal renal function. This dose contrasts the currently recommended dose reduction to rivaroxaban 15 mg in patients with NVAF and ESRD.10 A dose reduction to rivaroxaban 10 mg daily should be considered in HD patients with NVAF due to the renal accumulation indicated with the recommended 15 mg dose in PK studies.

    Apixaban
    Apixaban, a direct factor Xa inhibitor, was FDA-approved in December 2012 for the reduction of stroke and systemic embolism in patients with NVAF. Currently, manufacturer labeling recommends in NVAF a dose reduction to apixaban 2.5 mg twice daily in ESRD patients (SCr > 1.5 g/dL) if they are also either > 80 years old or have a body weight < 60 kg. However, patients with ESRD requiring HD, but not meeting the dose reduction criteria, are recommended to receive the unadjusted dose of 5 mg twice daily.11 Both landmark trials, ARISTOTLE and AVERROES, excluded patients with CrCl < 25 mL/min or SCr > 2.5 mg/dL.12,13 A single-dose PK study including eight patients determined that the administration of apixaban 5 mg to HD patients resulted in 36% increase in drug exposure compared to patients with normal renal function. Additionally, this study revealed that dialysis removed only 14% of apixaban, indicating that HD would not be an effective method to remove apixaban in the event of an overdose or bleed.14 However, the results of these studies cannot be confidently extrapolated to patients receiving multiple doses. Recently, Mavrakanas, et al. assessed apixaban PK at steady state in HD patients and found that HD patients receiving apixaban 2.5 mg twice daily had comparable drug exposure when compared to patients with preserved renal function receiving the standard dose (5 mg twice daily). This study did not discuss whether age or weight impacted the results. In HD patients, apixaban 5 mg twice daily, the recommended dose for HD patients not meeting dose reduction requirements, led to supratherapeutic drug exposure, which may be associated with adverse events, such as bleeding.2 Based on these findings, an apixaban dose reduction to 2.5 mg twice daily may be cautiously considered in HD patients with NVAF while monitoring for potential adverse events, as opposed to the labeled recommendations.

    Edoxaban
    Edoxaban, a direct factor Xa inhibitor, was FDA-approved in January 2015 for the prevention of stroke and systemic embolism in patients with NVAF. Per manufacturer labeling for NVAF patients with CrCl 15 to 50 mL/min, a dose reduction to edoxaban 30 mg daily is recommended.15 However, the ENGAGE AF-TIMI 48 Trial excluded patients with CrCl < 30 mL/min.16 No recommendations are currently available in HD. The use of edoxaban is contraindicated in patients with CrCl greater than 95 mL/min.15 A single-dose PK study assessed a 15 mg dose in patients in ESRD without NVAF, and found that HD resulted in a slight decrease in total exposure when compared to patients off dialysis (AUC0–›∞ 676.2 v. 691.7 ng·h/mL), and HD only accounted for one-fourth of the total clearance in healthy patients, indicating that edoxaban was not effectively cleared by HD.17 Further studies providing additional, reliable guidance including steady state dosing in HD are needed prior to utilizing edoxaban in this population.

    Betrixaban
    Most recently, betrixaban, a direct factor Xa inhibitor, was FDA-approved in June 2017 for prophylaxis of VTE in hospitalized adults. The landmark APEX trial excluded patients with CrCl < 15 mL/min or requiring HD.18 The comparison of betrixaban and warfarin in the setting of atrial fibrillation is still being explored. Therefore, without safety and efficacy data, betrixaban should not be utilized in HD patients with NVAF.

    Conclusion
    Overall, consistent pharmacokinetic and pharmacodynamic evidence supporting the use of DOACs in HD is lacking. While single-dose studies exist for the majority of DOACs, they do not describe the potential impact of administering the medications as long-term anticoagulation. These single-dose studies also describe that HD does not affect the clearance of most DOACs, which indicates the potential for drug accumulation. Of the available DOACs, reduced doses of apixaban 2.5 mg twice daily and rivaroxaban 10 mg daily can be considered as alternatives in NVAF patients undergoing HD based on multiple-dose studies rather than the manufacturer labeling recommendations, which were based on single dose studies. Until large, prospective, clinical trials evaluate the efficacy and safety of these drugs in HD, DOACs should be used with extreme caution due to the limited evidence available.


    References

    1. United States Renal Data System. 2016 USRDS annual report: Epidemiology of kidney disease in the United States. National Institutes of Health, National Institutes of Diabetes and Digestive and Kidney Diseases. Bethesda, MD, 2016.
    2. Mavrakanas TA, Samer CF, Nessim SJ, et al. Apixaban pharmacokinetics at steady state in hemodialysis patients. J Am Soc Nephrol. 2017;28(7):2241-48.
    3. Pradaxa (dabigatran) [prescribing information]. Ridgefield, CT: Boehringer Ingelheim; November 2015.
    4. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361(12):1139-51.
    5. Hariharan S, Madabushi R. Clinical pharmacology basis of deriving dosing recommendations for dabigatran in patients with severe renal impairment. J Clin Pharmacol. 2012;52(1 Suppl):119S-25S.
    6. Stangier J, Rathgen K, Stähle H, Mazur D. Influence of renal impairment on the pharmacokinetics and pharmacodynamics of oral dabigatran etexilate: an open-label, parallel-group, single-centre study. Clin Pharmacokinet. 2010;49(4):259-68.
    7. Xarelto (rivaroxaban) [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals, Inc; August 2016. 
    8. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365(10):883-91.
    9. Dias C, Moore KT, Murphy J, et al. Pharmacokinetics, Pharmacodynamics, and Safety of Single-Dose Rivaroxaban in Chronic Hemodialysis. Am J Nephrol. 2016;43(4):229-36.
    10. De Vriese AS, Caluwé R, Bailleul E, et al. Dose-finding study of rivaroxaban in hemodialysis patients. Am J Kidney Dis. 2015;66(1):91-8.
    11. Eliquis (apixaban) [prescribing information]. Princeton, NJ: Bristol-Myers Squibb; July 2016.
    12. Granger CB, Alexander JH, Mcmurray JJ, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365(11):981-92.
    13. Connolly SJ, Eikelboom J, Joyner C, et al. Apixaban in patients with atrial fibrillation. N Engl J Med. 2011;364(9):806-17.
    14. Wang X, Tirucherai G, Marbury TC, et al. Pharmacokinetics, pharmacodynamics, and safety of apixaban in subjects with end-stage renal disease on hemodialysis. J Clin Pharmacol. 2016;56(5):628-36.
    15. Savaysa (edoxaban) [prescribing information]. Parsippany, NJ: Daiichi Sankyo, Inc.; September 2016.
    16. Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2013;369(22):2093-104.
    17. Parasrampuria DA, Marbury T, Matsushima N, et al. Pharmacokinetics, safety, and tolerability of edoxaban in end-stage renal disease subjects undergoing haemodialysis. Thromb Haemost. 2015;113(4):719-27.
    18. Cohen AT, Harrington RA, Goldhaber SZ, et al. Extended Thromboprophylaxis with Betrixaban in Acutely Ill Medical Patients. N Engl J Med. 2016;375(6):534-44.


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