• 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.


  • 20 Sep 2017 12:52 PM | Anonymous

    Authors:

    Fangzheng Yuan, PharmD Candidate 2018: St. Louis College of Pharmacy
    Hannah Pope, PharmD, BCPS: Barnes-Jewish Hospital

    Dual antiplatelet therapy (DAPT) is the mainstay of treatment in acute coronary syndromes (ACS). The use of DAPT is crucial in those who undergo percutaneous coronary intervention (PCI) and coronary artery stent implantation.1 DAPT consists of low-dose aspirin and an oral P2Y12 receptor inhibitor such as clopidogrel, prasugrel, or ticagrelor.2 Premature discontinuation of DAPT has been associated with an increased risk of adverse events, including stent thrombosis and mortality.2 Mortality rates of 19-30 % have been observed in patients who had DAPT discontinued early for a surgical procedure.3-5 Studies have shown that over 4% of patients on DAPT will require non-cardiac surgery within one year after stent implantation.6 The optimal approach for managing the risk of potential catastrophic perioperative stent thrombosis and bleeding in patients requiring surgery during the recommended duration of DAPT remains uncertain.

    In non-emergent cases, American College of Cardiology/American Heart Association recommended that DAPT be discontinued 5-7 days prior to surgical intervention. Current guidelines recommend that all elective surgeries be postponed until DAPT is complete.1 Per these recommendations, non-cardiovascular, elective surgeries should be delayed for at least 30 days after bare metal stent (BMS) and 6 months after drug eluting stents (DES).2 However, this is not always feasible and temporary administration of a short-acting antiplatelet agent, also known as bridging anti-platelet therapy, is warranted to minimize ischemic and bleeding events. 

    An ideal bridging agent should achieve platelet inhibition similar to the oral P2Y12 receptor inhibitors, with a rapid onset and short duration of action.7 Off-label use of the GPIIb/IIIa inhibitors, tirofiban and eptifibatide, as bridging agents has been advocated as an alternative to oral DAPT therapies, due to their pharmacokinetic profiles (Table 1).7-10 Current evidence for this indication is limited and the optimal duration of therapy is unknown.

    Cangrelor is an intravenous, non-thienopyridine adenosine triphosphate analogue that directly and reversibly binds to the P2Y12 receptor.8 This differs from oral thienopyridines such as clopidogrel and prasugrel that require metabolic activation and bind irreversibly. Although not FDA approved for bridging therapy, the pharmacokinetic profile of cangrelor makes it an ideal bridging agent. It has a faster onset and offset than other agents considered for bridging (Table 1).8-10 Due to its rapid inactivation in the circulation via dephosphorylation, cangrelor is less likely to accumulate and does not require renal dosing when compared to GPIIb/IIIa anti-platelet agents, which are eliminated as unchanged drug or partial metabolites.8-10

    Table 1. Pharmacokinetic profiles of bridging agents8-10

    Cangrelor

    Tirofiban

    Eptifibatide

    Administration

    IV

    IV

    IV

    Onset of action

    Immediate

    Immediate

    Immediate

    Mechanism of action

    P2Y12 inhibition

    GPIIb/IIIa inhibition

    GPIIb/IIIa inhibition

    Plasma t ½

    3-5 min

    2 hours

    2.5 hours

    Offset of action

    1 hour

    4-8 hours

    4-6 hours

    Renal dosing

    No

    Yes

    Yes

    To date, cangrelor is FDA approved as an adjunct to PCI. However, the phase II randomized, double-blind trial, Bridging anti-platelet therapy with cangrelor in patients undergoing cardiac surgery (BRIDGE trial), evaluated the hypothesis that cangrelor may be a safe and effective option to bridge patients from irreversible platelet P2Y12 inhibitors to cardiac surgery.11 Patients were randomized to cangrelor or placebo after an initial open-label, dose-finding phase that determined the dose of 0.75 mcg/kg/minute was necessary to achieve appropriate platelet inhibition in 10 patients. In stage 2 of the study, a greater proportion of patients (98.8%) treated with cangrelor achieved the goal of platelet reactivity units (PRU) <240 throughout the entire treatment period compared with placebo (RR=5.2, 95% CI 3.3-8.1, P<0.001). In addition, no significant differences were found in excessive coronary artery bypass grafting (CABG) surgery-related bleeding or major bleeding prior to surgery. However, minor bleeding episodes were numerically higher with the cangrelor group. Angiolio, et al. concluded that the cangrelor group had a higher rate of maintenance of platelet inhibition than the control group.11

    Firstenberg, et al. assessed the effects of preoperative cangrelor on the incidence of perioperative complications in the BRIDGE trial.12 All patients received 2-7 days of therapy (cangrelor or control) and the therapy was discontinued 1-6 hours before the planned CABG. Pre- and post-operative outcomes, bleeding values, and transfusion rates were compared between the cangrelor and placebo groups. A multivariable logistic model was used to quantify bleeding risks. No significant difference was found in the rate of CABG-related bleeding (P=0.763) or in serious post-operative adverse events (p=0.454) between the cangrelor group and placebo group. Bridging patients with cangrelor prior to CABG effectively maintained platelet inhibition at <240 P2Y12 PRU without increasing post-CABG bleeding or infusion needs. This analysis further suggests that cangrelor treatment is a potential strategy for bridging patients to a procedure and surgery.12

    Overall, the pharmacokinetic profile and data from the BRIDGE trial suggest that cangrelor is a potential treatment option in patients that require DAPT discontinuation prior to a procedure or surgery. Cangrelor can be initiated at the dose of 0.75 mcg/kg/minute through IV administration until 1-6 hours before surgery. Signs and symptoms of bleeding should be monitored during therapy and the procedure. DAPT with an oral antiplatelet agent should be resumed as soon as possible post-surgery.

    References

    1. Levine GN, Bates ER, Bittl JA et al. 2016 ACC/AHA guideline focused update on duration of dual antiplatelet therapy in patients with coronary artery disease: a report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines. J Thorac Cardiovasc Surg. 2016; 152(5):1243-1275. 
    2. Song JW, Soh S, Shim J-K. Dual antiplatelet therapy and non-cardiac surgery: evolving issues and anesthetic implications. Korean Journal of Anesthesiology. 2017; 70(1):13-21.
    3. Wilson SH, Fasseas P, Orford JL, et al. Clinical outcome of patients undergoing non-cardiac surgery in the two months following coronary stenting. J Am Coll Cardiol. 2003; 42(2):234-240.
    4. Eisenstein EL, Anstrom KJ, Kong DF, et al. Clopidogrel use and long-term clinical outcomes after drug-eluting stent implantation. JAMA. 2007; 297(2):159-168.
    5. Ferrari E, Benhamou M, Cerboni P, Marcel B. Coronary syndromes following aspirin withdrawal: A special risk for late stent thrombosis. J Am Coll Cardiol. 2005; 45(3):456-459.
    6. Berger PB, Kleiman NS, Pencina MJ et al. Frequency of major noncardiac surgery and subsequent adverse events in the year after drug-eluting stent placement results from the EVENT (Evaluation of Drug-Eluting Stents and Ischemic Events) Registry. JACC Cardiovasc Interv. 2010; 3(9):920-927.
    7. Capodanno D, Angiolillo DJ. Management of antiplatelet therapy in patients with coronary artery disease requiring cardiac and noncardiac Surgery. Circulation. 2013; 128:2785-2798.
    8. Cangrelor. Lexicomp Online, Lexi-Drugs Online, Riverwoods. IL. 2017; July 15, 2017.
    9. Tirofiban. Lexicomp Online, Lexi-Drugs Online, Riverwoods. IL. 2017; July 15, 2017.
    10. Eptifibatide. Lexicomp Online, Lexi-Drugs Online, Riverwoods. IL. 2017; July 15, 2017.
    11. Angiolio DJ, Firstenberg MS, Price MJ, et al. Bridging anti-platelet therapy with the intravenous agent cangrelor in patients undergoing cardiac surgery. JAMA. 2012; 307(3):265-274. Firstenberg MS, Dyke CM, Angiolillo DJ, et al. Safety and efficacy of cangrelor, an intravenous, short-acting platelet inhibitor in patients requiring coronary artery bypass surgery. Heart Surg Forum. 2013.


  • 19 Sep 2017 12:38 PM | Anonymous

    Authors:
    Diane McClaskey, RPh, BCPS: Assistant Director of Experiential Education-UMKC at MSU

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

    Whether a pharmacy student or resident desiring to set themselves apart or a practicing pharmacist desiring to contribute in a broader way to the medical community, writing review articles for publication in a medical journal may be a desirable opportunity.  Megan Musselman, PharmD, MS, BCPS, BCCCP is a Clinical Pharmacist Specialist in Emergency Medicine/Critical Care at North Kansas City Hospital and has generously shared her best practices for developing, writing, and successfully submitting a literature review paper.  We hope this information will be helpful to those contemplating and actively working on research articles.  If you have any questions regarding the topic, please sent them to Sarah.Cook@ssmhealth.com and they will be forwarded on to Dr. Musselman. 

    What is the best method of choosing a topic for a review article?
    When choosing a topic for a review article, it is best to choose an area you have interest in and to identify an audience you are familiar with.  If you are interested in the topic, it will help you keep momentum as you work your way through the process.  In addition, if you identify a target audience, it helps you streamline your outline and appropriately highlight specific areas of that topic.  Oftentimes, the best review articles developed are secondary to your own review of the available literature when trying to answer a question that applies to your practice. 

    How should you start the process of writing a literature review paper?
    Start by conducting a thorough literature search and downloading relevant papers.   When conducting your search, keep track of your search terms so they can be replicated, if needed.  Tips for a successful search include using different keywords and database sources (i.e., Google Scholar, Medline, Scopus).  Additionally, look through the references of the articles that you have selected to find any additional literature that may pertain to your topic.

    What are important steps to take while reading and evaluating the available literature?
    When choosing and evaluating literature, be up-to-date but don’t forget the older studies.   Be careful using other published reviews as a frame of reference for your current review; it can sway your evaluation and critique of the available studies on the topic.  Try to maintain objectivity when writing your review, reducing any bias on the subject matter.  Most importantly, take notes while reading.  This will help you remember which literature you used when drafting your publication.  Nothing is more frustrating than when you cannot remember which body of literature you used for a specific section of your paper.

    How do you choose which journal to pursue for publication?
    It is always good to research which journals are out there that are tailored to your specific topic, and most importantly, which journals take review articles.  Some journals do not accept review articles and other journals only accept review articles from authors they have invited to write the review.  Also, it is usually a good choice to choose a journal that you are familiar and read often.  This will make formatting easier.

    What is the next step once you have identified your target journal for submission?
    A good review should have the following elements: it is worth the reader's time, timely, systematic, well written, focused, and critical. It also needs a good structure. The structure is usually dictated by the journal’s specific requirements.  Overall, a general introduction of the content and, toward the end, a recap of the main points covered along with take-home messages makes sense in terms of structuring reviews. For systematic reviews, there is a trend towards including information about how the literature was searched including which database, number of keywords, and time frame used to conduct the search.

    What is necessary to effectively write a literature review article?
    A good review does not just summarize the literature.  It takes it a step farther and discusses it critically, identifies methodological problems, and points out current gaps in the literature.  One thing to keep in mind when writing your review is to ask yourself if your publication will provide the reader with the major achievements in the reviewed field, the main areas of controversy or debate, and what outstanding research questions still exist.  While focus is an important feature of an effective review, this requirement has to be balanced with the need to make the review relevant to a broad audience. 

    What are some successful tips to ensure final acceptance of your publication?
    Normally all journals are peer-reviewed.  After your initial submission, feedback will be provided on ways to improve your publication.  Feedback is vital to writing a good review, and should be sought from a variety of colleagues and disciplines.   While the feedback process is vital to the final product being exemplary, it is oftentimes hard to be open-minded to the criticism.  Keep in mind that this may lead, in some cases, to conflicting views on the merits of the paper and on how to improve it, but such a situation is better than the absence of feedback.

    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.  


  • 19 Sep 2017 11:43 AM | Anonymous

    Author: Barb Kasper, PharmD, BCACP
    MSHP Newsletter Committee Chair

    The Newsletter Committee has compiled the results of our 2017 Newsletter Survey.  A total of 57 members responded to the survey.  Approximately 64% of respondents read the newsletter at least 75% of the time.  Of the recurring newsletter content, members read the featured clinical topics, public policy updates, and announcements most frequently.  A strong majority of respondents were interested in obtaining pharmacist CE through the MSHP Newsletter.  Areas for improvement included the overall presentation of content and consistent distribution to all members. 

    The Newsletter Committee wishes to thank members for taking the time to provide feedback to enhance the newsletter.  The following changes have already taken place, or will be forthcoming, to better meet the needs of our members:

    1. The Jul/Aug 2017 Newsletter utilized a new format designed to enhance the overall presentation and readability of content.
    2. The Nov/Dec 2017 Newsletter will feature pharmacist CE.
    3. The 2018 featured clinical topics are as follows:
    • Jan/Feb: Endocrinology
    • Mar/Apr: Psychiatry
    • May/Jun: Critical Care/Pulmonary/Emergency Medicine
    • Jul/Aug: Pain
    • Sept/Oct: Cardiology/Anticoagulation
    • Nov/Dec: Infectious Disease

    The Newsletter Committee welcomes continued member feedback, questions, or concerns.  Additionally, if you are interested in becoming a member of the Newsletter Committee, please direct correspondence to the Newsletter Committee Chair.  We appreciate your support of the MSHP Newsletter and look forward to continuing to serve the needs of our membership!

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