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  • 16 Sep 2018 11:15 PM | Anonymous

    Overview and Management of Local Anesthetic Systemic Toxicity (LAST) Based on Updated 2017/18 ASRA Practice Guidelines

    Author:  Alexander Spillars, Pharm.D. Candidate 2019, St. Louis College of Pharmacy
    Preceptor: Rachel C. Wolfe, Pharm.D, BCCCP

    Overview
    Local anesthetic therapy has become an increasingly utilized component of multimodal analgesia.1 Potential benefits include decreasing opioid exposure, decreasing postoperative nausea and vomiting, improving patient satisfaction, decreasing hospital length of stay, improving the quality of recovery from surgery, and reducing the risk of chronic postoperative pain.2 Despite the potential benefits, administration of local anesthetics can lead to a rare and potentially fatal event known as local anesthetic systemic toxicity (LAST). Organ systems affected by LAST include the cardiovascular system and/or central nervous system (CNS). The treatment, management, and prevention of LAST is multifactorial and involves multiple pharmacological interventions with lipid emulsion administration as the cornerstone of therapy.

    Incidence
    The reported incidence of LAST and its major complications (i.e. seizures and cardiac arrest) is low with data being derived from registry studies, administrative databases, and case reports/case series.3 In 2017, Mörwald et al4 examined the incidence of LAST using an administrative database, surrogate markers, and the International Classification of Disease Codes in nearly 238,500 patients receiving a peripheral nerve block for total joint arthroplasty at over 400 hospitals between 2006 and 2014. The overall incidence of LAST, as defined by the occurrence of cardiac arrest, seizure and/or the administration of lipid emulsion on the day of surgery, was 1.8 per 1000 patients. During the 9-year study period, the overall incidence of LAST trended down, from 8.2 per 1000 in 2006 to 2.5 per 1000 in 2014. Advances in localization techniques, such as ultrasound guided blocks, and implementation of safety steps that reduce intravascular injection of local anesthetics is thought to contribute to this decline. In comparison to administrative databases, a recent review (2018) of clinical registries by Gitman and Barrington claimed a reported incidence of LAST to be 0.3 per 1000 peripheral nerve blocks.5 Though the frequency of LAST is low based on these studies, each institution or clinic utilizing local anesthetics must be prepared to manage such an event, should it occur.

    Pharmacology and Pharmacokinetics of Local Anesthetics
    All local anesthetics have the potential to cause LAST and it can occur with any route of administration. Pharmacologically, these agents exert their primary effect by blocking voltage-gated sodium channels at the alpha-subunit inside the channel, preventing sodium influx, depolarization, and action potential generation. Blocking this conduction prevents pain transmission from neuronal cells to the cerebral cortex, ultimately producing analgesia and anesthesia.6 Cardiac toxicity occurs when local anesthetics inhibit sodium channels in the myocardium leading to conduction disturbances, ventricular arrhythmias, contractile dysfunction, and ultimately cardiac arrest.7, 8 Neurotoxicity occurs when local anesthetics bind to thalamocortical neurons in the brain. This leads to altered mental status, paresthesia, visual changes, muscle twitching, and seizures.9

    The toxicities associated with LAST may present in various ways based on the physiochemical, pharmacokinetic, and pharmacological properties of the local anesthetics. Physiochemical properties such as pKa, lipophilicity, and protein binding contribute to individual pharmacokinetic differences and toxicities among the clinically used agents. A lower pKa indicates a greater proportion of the drug exists in the uncharged state at physiological pH allowing for more drug transfer across the lipophilic cellular membrane to the effector site, which impacts onset time. Lipophilicity correlates to potency. Increased potency of local anesthetics correlates with increased cardiac toxicity, as higher lipophilicity allows for better lipid bilayer penetration to the target receptor. For example, bupivacaine is considered a more potent local anesthetic (higher lipophilicity) versus lidocaine and is therefore more cardiotoxic. Finally, a higher affinity for protein binding decreases the circulating levels of free local anesthetic translating to an increased duration of action (Table 1).10


    Clinical Presentation
    Systemic toxicity from local anesthetic overdose often occurs due to accidental intravascular injection, absorption from a tissue depot, or administration of repeated doses of local anesthetics without balanced elimination. Symptoms of local anesthetic toxicity classically emerge as a progression of adverse effects. Classical symptoms appear as CNS excitement (i.e. prodromal symptoms) followed by seizures then CNS depression. Symptoms then progress to the cardiovascular system, initially presenting as cardiac excitability or depression then leading to arrhythmias and cardiac arrest (Table 2).2, 3 Clinical presentations of LAST do not always follow the classical symptom progression as described above and instead target exclusively either the cardiovascular system or the CNS.


    A review of systemic toxicity cases over a 30-year period published by Di Gregorio et al12 revealed that 60% of cases were classic in terms of rapid onset presenting with CNS signs/symptoms followed by cardiovascular signs/symptoms (as outlined in Table 2). Gitman and Barrington5 found that the most common presenting symptom of local anesthetic toxicity was seizures, occurring in 53% and 61% of case reports and registries, respectively. This was followed by combined cardiovascular and CNS symptoms, and lastly by isolated cardiovascular symptoms. Overall, the clinical presentation of LAST is highly variable and should be suspected whenever physiologic changes occur after local anesthetic administration. Heightened vigilance is crucial to detecting toxicity.

    Prevention3
    The American Society of Regional Anesthesia (ASRA) practice advisory guidelines recommends specific strategies and techniques in order to prevent the occurrence of LAST during local anesthetic administration3, these include:

    • Using the lowest effective dose of local anesthetic
    • Using incremental injection of local anesthetics (administer 3 to 5 mL aliquots, pausing 15 to 30 sec between each injection)
    • Aspirating the needle or catheter before each injection
    • Administering a test dose of local anesthetic with 10 to 15 mcg/mL of epinephrine prior to injecting potentially toxic doses of local anesthetic – see maximum dose in Table 1 (an increase in heart rate > 10 bpm or increase SBP > 15 mmHg within 20 to 40 seconds may indicate inadvertent intravascular administration, although beta-blockers may confound these effects)
    • Using ultrasound guidance for placement of peripheral nerve blocks

    Prevention techniques and active vigilance should always be performed while administering local anesthetics as toxicity could develop, requiring proper treatment and management.

    Treatment and Management3, 13
    Updates from the 2017/18 ASRA practice advisory guidelines recommend the use of IV lipid emulsion therapy as the cornerstone of LAST treatment. The precise mechanism of lipid emulsion therapy in LAST is not fully understood. Current research believes that it acts as a carrier to remove local anesthetic from high blood flow organs that are sensitive to local anesthetics, such as the heart and brain. The complex is then redistributed to organs that store and detoxify the drug, such as the muscle and liver.14 This is known as the “shuttling effect” as positively charged, fat-soluble local anesthetic molecules bind to negatively charged lipid particles.

    Updates from the 2017/18 ASRA practice advisory guidelines recommend discontinuing the local anesthetic at the first sign of LAST, managing the airway (to prevent hypoxia, hypercapnia, and acidosis), and then administering lipid emulsion therapy as follows:

    • Bolus 20% lipid emulsion over 2 to 3 minutes followed by a continuous infusion:
      • < 70 kg: 1.5 mL/kg bolus followed by an infusion at 0.25 mL/kg of ideal body weight (IBW)/min
      • > 70 kg : 100 mL bolus followed by an infusion of 200 to 250 mL over 15 to 20 min
    • If circulatory stability is not attained, consider administering an additional bolus or double the infusion rate to 0.5 mL/kg of IBW/min for patients < 70 kg and to 400 to 500 mL for patients > 70 kg
    • Continue infusion for at least 10 min after hemodynamic stability is attained
    • Maximum dose of 12 mL/kg is recommended per FDA as the upper limit for initial dosing              
    • Do not substitute 20% lipid emulsion with propofol

    The pharmacological treatment of LAST is different from other cardiac arrest scenarios and following ACLS recommendations are not warranted. If cardiac arrest occurs the following recommendations should be utilized per ASRA:

    • Small initial doses of epinephrine (< 1 mcg/kg) are preferred
    • Avoid vasopressin, calcium channel blockers, and beta-blockers
    • If ventricular arrhythmias develop, amiodarone is preferred; avoid local anesthetic based antiarrhythmics (i.e., lidocaine or procainamide)
    • Failure to respond to lipid emulsion and epinephrine therapy should prompt initiation of cardiopulmonary bypass

    If seizures develop, priority should be placed on initiating lipid emulsion therapy which results in the shuttling of local anesthetic away from the thalamocortical neurons. In addition to lipid emulsion therapy, ASRA guidelines recommends treatment with benzodiazepines. If seizures persist despite benzodiazepine therapy, then administering small doses of propofol is acceptable. Though large doses of propofol should be avoided, as this can further depress cardiac function. Monitoring should occur 4 to 6 hours post-treatment in a patient with a significant cardiovascular event and 2 hours if the event is limited to CNS symptoms that resolve quickly.

    Summary
    Though LAST is an overall rare event, it can occur after administration of any local anesthetic via any route and can result in potentially fatal cardiac and CNS toxicities. Healthcare practitioners should be aware of the additive nature of these agents, as local anesthetic are often administered to the same patient by different clinicians. Additionally, the use of local anesthetic continuous infusions as part of multimodal analgesic regimens predispose patients to the development of toxicity. Prevention of LAST through proper anesthetic techniques and monitoring of the patient during and after completion of local anesthetic therapy for physiologic and/or hemodynamic changes is key to prompt recognition and treatment of LAST. Lipid emulsion rescue should be readily available in settings in which local anesthetics are utilized to avoid potential fatal events. Pharmacists can assist in updating protocols, electronic medical records, and infusion pump libraries in accordance with the new lipid emulsion dosing in the updated 2017/18 ASRA guidelines to aid in the prevention, treatment, and management of LAST.

    References:

    1. Chou R, Gordon DB, Leon-Casasola OAD, et al. Management of postoperative pain: a clinical practice guideline from the American Pain Society, the American Society of Regional Anesthesia and Pain Medicine, and the American Society of Anesthesiologists Committee on Regional Anesthesia, Executive Committee, and Administrative Council. J Pain. 2016;17:131-157. 
    2. Dickerson DM, Apfelbaum JL. Local anesthetic systemic toxicity. Aesthet Surg J. 2014;34:1111-1119.
    3. Neal JM, Barrington MJ, Fettiplace MR, et al. The third American Society of Regional Anesthesia and Pain Medicine practice advisory on local anesthetic systemic toxicity. Reg Anesth Pain Med. 2018;43:113-123.
    4. Mörwald EE, Zubizarreta N, Cozowicz C, Poeran J, Memtsoudis SG. Incidence of local anesthetic systemic toxicity in orthopedic patients receiving peripheral nerve blocks. Reg Anesth Pain Med. 2017;42:442–445.
    5. Gitman M, Barrington MJ. Local anesthetic systemic toxicity: a review of recent case reports and registries.  Reg Anesth Pain Med. 2018;43:124-130.
    6. Catterall WA. Voltage-gated sodium channels at 60: structure, function and pathophysiology. J Physiol. 2012;590:2577-2589.
    7. Butterworth J. Models and mechanisms of local anesthetic cardiac toxicity: a review. Reg Anesth Pain Med. 2010;35:167-176.
    8. Wolfe JW, Butterworth JF. Local anesthetic systemic toxicity: update on mechanisms and treatment. Curr Opin Anaesthesiol. 2011;24:561-566.
    9. Meuth SG, Budde T, Kanyshkova T, et al. Contribution of TWIK-Related Acid-Sensitive K Channel 1 (TASK1) and TASK3 channels to the control of activity modes in thalamocortical neurons. J Neurosci. 2003;23:6460-6469.
    10. Lirk P, Picardi S, Hollmann MW. Local anaesthetics: 10 essentials . Eur J Anaesthesiol. 2014;31:575-585
    11. Gadsden J. Local Anesthetics: Clinical Pharmacology and Rational Selection. The New York School of Regional Anesthesia. https://www.nysora.com/local-anesthetics-clinical-pharmacology-and-rational-selection. Published May 24, 2018.
    12. Di Gregorio G, Neal JM, Rosenquist RW, et al. Clinical presentation of local anesthetic systemic toxicity: a review of published cases. 1979 to 2009. Reg Anesth Pain Med. 2010;35:181-187.
    13. Burch MS, Mcallister RK, Meyer TA. Treatment of local-anesthetic toxicity with lipid emulsion therapy. Am J Health Syst Pharm. 2011;68:125-129.
    14. Fettiplace MR, Lis K, Ripper R, et al. Multi-modal contributions to detoxification of acute pharmacotoxicity by a triglyceride micro-emulsion. J Control Release. 2015;198:62 – 70.
  • 16 Sep 2018 11:11 PM | Anonymous

    Andexanet Alfa: A Novel Reversal Agent for Factor Xa Inhibitors
    Author:  Christopher Kimes, Pharmacy Student, University of Kansas School of Pharmacy
    Preceptor:  Amy Sipe, PharmD, Kansas City VA Medical Center

    Background
    In recent years, direct acting oral anticoagulants (DOACs) have been gaining increased utilization due to fewer drug and food interactions and less frequent blood monitoring required than the traditional anticoagulant of choice, warfarin. However, like warfarin, DOACs still possess a risk for acute major bleeds.

    Portola Pharmaceuticals’ andexanet alfa (Andexxa®) has recently garnered significant attention for being the first FDA-approved reversal agent for the factor Xa (fXa) inhibitor class of DOACs.1 Given the limited real-world experience in the use of this drug, this overview may serve as useful source for providers to feel more comfortable with its use in practice.

    Pharmacology/Mechanism of Action2,3
    fXa inhibitors produce anticoagulant effects by inhibiting the serine active site of fXa, which is responsible for the conversion of prothrombin into activate thrombin during secondary hemostasis. Direct fXa inhibitors (apixaban, rivaroxaban, edoxaban, betrixaban) act by directly inhibiting the serine active site. Indirect fXa inhibitors (fondaparinux, enoxaparin) act by changing the structure of antithrombin III, which makes it more effective at binding and inhibiting the serine active site (Figure 1).

    Figure 1. Interaction of Andexanet Alfa with Drugs and Proteins Involved in the Regulation of fXa Activity.


    Andexanet reverses the effects of fXa inhibitors by sequestering these drugs away from fXa, allowing fXa to convert prothrombin into thrombin (Figure 1). Andexanet accomplishes this because it is a modified human fXa protein that acts as a decoy for fXa inhibitors. An important part of andexanet’s design was the removal of the procoagulant properties of fXa (Figure 2). During clinical trials, andexanet was found to possess a procoagulant effect that would potentially increase the risk of thromboembolic events in patients, however, the consequences of this property on clinical outcomes have not been fully studied.3

    Figure 2. Comparison of Andexanet Alfa with Factor Xa

    Indication
    Currently, andexanet is FDA-approved for the reversal of anticoagulant effects in the event of life-threatening or uncontrolled bleeding for patients on either apixaban or rivaroxaban therapy.1,4 This indication was based largely on the results of the phase III ANNEXA trials, in which test subjects were given only apixaban or rivaroxaban prior to reversal by andexanet.5 Consequently, the FDA did not approve labeling of andexanet as a reversal agent for all fXa inhibitors. Although other fXa inhibitors had been used in animal studies and phase II trials, the FDA cited differences in pharmacokinetic, pharmacodynamic, and in-vivo/ex-vivo properties between anticoagulants as a reason for limiting andexanet use to agents studied in the phase III trials.3

    Andexanet received breakthrough designation from the FDA, which accelerated approval based on phase III trials using healthy volunteers and surrogate biomarker as primary efficacy endpoint.  The clinical efficacy of andexanet is currently being studied through the prospective, open-label, single-group Phase IV ANNEXA-4 trial.6 Researchers intend to determine the hemostatic efficacy of andexanet in patients suffering an acute major bleed within 18 hours of taking a fXa inhibitor. To assess efficacy, the researchers have established a rating system to classify hemostasis. Given that institutions and providers may disagree with what constitutes excellent or good hemostasis, a review of this rating system is prudent prior to consideration of andexanet use (Table 1).

    Table 1. Rating system for assessing hemostatic efficacy utilized in the ANNEXA-4 trial.

    Based on this rating system, preliminary data from the phase IV trial indicates an 83% efficacy of achieving excellent or good hemostasis for patients of all bleed types.7 However, most patients suffered from intracerebral (61%) or gastrointestinal (27%) bleeds. Although this satisfies the FDA’s desire for the manufacturer to study the effects of andexanet in patients suffering from an intracerebral hemorrhage,1 it limits the efficacy and safety data for other types of bleeds.

    Dosage and Administration
    The current FDA recommended dosing guidelines were ascertained during the phase II trials and confirmed in the phase III trials. The phase II trials found that the decline in the anti-fXa activity caused by andexanet was correlated to the decline in plasma concentration of the fXa inhibitor.2 This is consistent with andexanet’s mechanism of action. Therefore, the optimal dose of andexanet is dependent upon the steady-state concentration and the volume of distribution of the fXa inhibitor.8 This led to the adoption of using a high dose regimen or low dose regimen of andexanet based on the expected plasma concentration of the fXa inhibitor (Table 2).

    Table 2. Andexanet regimens developed in clinical trials and approved for use by the FDA4

    Phase III trials proved that andexanet could significantly reverse the anti-fXa activity of apixaban and rivaroxaban. Andexanet showed reduced anti-fXa activity by -94% in apixaban subjects compared to -21% for placebo and by -92% for rivaroxaban subjects compared to -18% for placebo5 (Graph 1). The reduction in anti-fXa activity only took 2-5 minutes after completion of bolus infusion to reach its nadir. This reversal effect was only maintained for the duration of the infusion. Therefore, a continuous infusion after the bolus administration is necessary to maintain a sustained reduction in anti-fXa activity.

    Graph 1. Anti-fXa activity of subjects over time during phase III trials. Graph 1 displays the anti-fXa activity of patients with steady state concentrations of apixaban from the phase III trials receiving either (A1) IV bolus of andexanet alone, (A2) IV bolus followed by a continuous IV infusion of andexanet, and (P) placebo. As the graph demonstrates, anti-fXa activity rapidly returns to placebo levels after cessation of andexanet infusion. 


    Based on efficacy data from phase III trials, FDA labeling recommends that andexanet alfa be given as an initial IV bolus followed by a 120-minute continuous IV infusion4 (Figure 3). None of the clinical trials measured the effectiveness or safety of multidose administration or infusion administration beyond 2 hours, therefore, no efficacy or safety data exists for situations requiring infusions over that 2-hour period

    Figure 3. Algorithm based on FDA package insert for andexanet4

    Safety
    Current data from the phase IV trial indicate that 11% of patients suffer a thromboembolic event, while 12% died within 30 days of receiving andexanet. Citing these events and the unexpected ability of andexanet to inhibit TFPI, the FDA issued a Black Box Warning that andexanet was associated with arterial and venous thromboembolic events, ischemic events (including myocardial infarction and ischemic stroke), cardiac arrest, and sudden death.3 The FDA advises that patients given andexanet are monitored for these conditions and that patients should resume anticoagulant therapy as soon as medically appropriate. 

    There is limited efficacy or safety data for certain patient populations due to the design of the clinical trials. The Phase III trials were performed using only healthy test subjects. The phase IV trials excluded patients who possessed certain medical conditions or were on certain drug therapies.6 The FDA package insert takes into consideration a certain number of these exclusions, however, it does not describe all exclusions in detail. Therefore, it is important for institutions and providers to be familiar with the medical conditions that were excluded from these trials when considering andexanet use (Table 3).

    Table 3. Exclusion Criteria for the ANNEXA-4 Trial

    Product Availability and Cost4
    Andexanet is produced from Chinese hamster ovary cells by two biotechnology companies: CMC Biologics (Copenhagen, Denmark) and Lonza (Visp, Switzerland). Concerns with manufacturing capacity and an inability to produce adequate drug quantities was a factor that prevented andexanet from gaining FDA approval in 2016.2 These concerns were addressed in subsequent reviews, however, andexanet will be produced in very limited quantities. Therefore, only a select number of medical facilities (ranging from as low as 10 to as much as 50) will carry this medication.9,10 The manufacturer has stated that andexanet will most likely be limited to medical facilities that participated in ANNEXA-4 trials. There is a possibility that a select few level 1 trauma centers and comprehensive stroke centers will be able to receive this product.9

    Andexanet is produced as 100 mg lyophilized powder in single-use vials. It is sold in a package of four vials. The current estimated cost for a single package of four 100mg vials is $11,000.11 At this price point, a low and high dose andexanet regimen will cost $24,750 and $49,500, respectively.

    Comparison to Other Available Treatments
    Despite andexanet’s niche role as the first FDA-approved reversal agent for fXa inhibitors, bleeding caused by fXa inhibitors have previously been controlled through other pharmacological agents.12,13 While the procedure for treating bleeds varies by institution, the two most commonly recommended agents include four-factor prothrombin complex concentrates (4FPCC) and activated charcoal. A table containing information on the drug properties, FDA indications, off-label use, current recommend dosing, and research data on these two products are presented below to serve as a reference.14

    Table 4. Information on off-label treatments for major bleeds caused by fXa inhibitors.15-22


    Conclusion

    Despite accelerated approval by the FDA, andexanet remains undergoing scrutiny, as the ANNEXA-4 trial is still underway with no final results or completion. Furthermore, the FDA felt that andexanet’s ability as a reversal agent for fXa inhibitors would be best suited for treating intracranial hemorrhages. Consequently, it has mandated the manufacturer to conduct a postmarketing study to determine the hemostatic efficacy and safety of andexanet on patients suffering from intracranial hemorrhages to be completed by October 31, 2022. 

    Andexanet alfa garnered significant attention for its novelty. For many, the approval suggested a new era in which life-threatening bleeds caused by fXa inhibitors could be easily reversed with an antidote. However, an overview of andexanet’s drug design, indication, dosing regimen, safety data, and manufacturing logistics seems to paint a more complex picture. Furthermore, ever increasing research data on the off-label use of more easily accessible products may diminish the enthusiasm for the drug. Institutions and practitioners may need to consider these issues when they are reviewing andexanet for use in their patients.

    References:

    1. Food and Drug Administration. Approval Letter - ANDEXXA. 2018; https://www.fda.gov/downloads/BiologicsBloodVaccines/CellularGeneTherapyProducts/ApprovedProducts/UCM606693.pdf.
    2. Kaatz S, Bhansali H, Gibbs J, Lavender R, Mahan CE, Paje DG. Reversing factor Xa inhibitors - clinical utility of andexanet alfa. J Blood Med. 2017;8:141-149.
    3. Food and Drug Administration. Clinical Review Memo - ANDEXXA. 2018; https://www.fda.gov/downloads/BiologicsBloodVaccines/CellularGeneTherapyProducts/ApprovedProducts/UCM610008.pdf.
    4. Andexxa® [package insert]. San Francisco, CA: Portola Pharmaceuticals, Inc. 2018.
    5. Siegal DM, Curnutte JT, Connolly SJ, et al. Andexanet Alfa for the Reversal of Factor Xa Inhibitor Activity. N Engl J Med. 2015;373(25):2413-2424.
    6. Connolly SJ, Milling TJ, Jr., Eikelboom JW, et al. Andexanet Alfa for Acute Major Bleeding Associated with Factor Xa Inhibitors. N Engl J Med. 2016;375(12):1131-1141.
    7. Andexxa-An Antidote for Apixaban and Rivaroxaban. JAMA. 2018;320(4):399-400.
    8. Cuker A, Husseinzadeh H. Laboratory measurement of the anticoagulant activity of edoxaban: a systematic review. J Thromb Thrombolysis. 2015;39(3):288-294.
    9. Blank C. Why a New Anticoagulant Reversal Agent Is Significant. Drug Topics June 1, 2018; http://www.drugtopics.com. Accessed June 26, 2018.
    10. Palmer E. Portola's Andexxa bleeding antidote wins FDA nod but will see limited release. FiercePharma May 7, 2018; https://www.fiercepharma.com, June 26, 2018.
    11. AndexXa. (2018). IBM Micromedex® RED BOOK®. Retrieved June 26, 2018, from https://www.micromedexsolutions.com. Ann Arbor, MI: Truven Health Analytics.
    12. Lai S, Kalantari A, Mason J, Grock A. When Anticoagulants Become a Bloody Mess. Ann Emerg Med. 2017;70(6):949-952.
    13. Gulseth MP. Overview of direct oral anticoagulant therapy reversal. Am J Health Syst Pharm. 2016;73(10 Suppl 2):S5-S13.
    14. Tomaselli GF, Mahaffey KW, Cuker A, et al. 2017 ACC Expert Consensus Decision Pathway on Management of Bleeding in Patients on Oral Anticoagulants: A Report of the American College of Cardiology Task Force on Expert Consensus Decision Pathways. J Am Coll Cardiol. 2017;70(24):3042-3067.
    15. Kcentra® [package insert]. King of Prussia, PA: CSL Behring, Inc. 2013.
    16. Levy JH, Moore KT, Neal MD, et al. Rivaroxaban reversal with prothrombin complex concentrate or tranexamic acid in healthy volunteers. J Thromb Haemost. 2018;16(1):54-64.
    17. Schultz NH, Tran HTT, Bjornsen S, Henriksson CE, Sandset PM, Holme PA. The reversal effect of prothrombin complex concentrate (PCC), activated PCC and recombinant activated factor VII against anticoagulation of Xa inhibitor. Thromb J. 2017;15:6.
    18. Schenk B, Goerke S, Beer R, Helbok R, Fries D, Bachler M. Four-factor prothrombin complex concentrate improves thrombin generation and prothrombin time in patients with bleeding complications related to rivaroxaban: a single-center pilot trial. Thromb J. 2018;16:1.
    19. Chyka PA, Seger D, Krenzelok EP, et al. Position paper: Single-dose activated charcoal. Clin Toxicol (Phila). 2005;43(2):61-87.
    20. Yeates PJ, Thomas SH. Effectiveness of delayed activated charcoal administration in simulated paracetamol (acetaminophen) overdose. Br J Clin Pharmacol. 2000;49(1):11-14.
    21. Kcentra. (2018). IBM Micromedex® RED BOOK®. Retrieved June 26, 2018, from https://www.micromedexsolutions.com. Ann Arbor, MI: Truven Health Analytics.
    22. Activated Charcoal. (2018). IBM Micromedex® RED BOOK®. Retrieved June 26, 2018, from https://www.micromedexsolutions.com. Ann Arbor, MI: Truven Health Analytics.
  • 16 Sep 2018 11:06 PM | Anonymous

    Direct-Acting Oral Anticoagulants (DOACs) use in Patients with Chronic Kidney Disease

    Authors:  Kaily Kurzweil, Pharm.D. Candidate UMKC School of Pharmacy and Andrew Smith, Pharm.D., FCCP, BCPS, UMKC School of Pharmacy

    Background
    Since the approval of the first direct-acting oral anticoagulant (DOAC), dabigatran in 2010, the management of oral anticoagulation in patients has significantly changed.  In the years following its approval, four more agents were approved as well: rivaroxaban, apixaban, edoxaban, and betrixaban.1-5  The introduction of these drugs into practice provides an alternative to warfarin, which has historically been the only option for oral anticoagulation in patients.  Where warfarin requires monitoring every 2-4 weeks and frequent regimen modifications, the DOACs do not have any monitoring requirements and rarely require dose adjustments.1-5  The DOACs also have notably less interactions with diet and other medications or supplements.  These qualities make the DOACs a more patient and provider-friendly option to those requiring anticoagulation.

    The populations that predominantly benefit from the DOACs are patients at risk for a venous thromboembolism (VTE) and those diagnosed with nonvalvular atrial fibrillation (AF) for the prevention of stroke and systemic embolism.1-5  Patients that concurrently have a diagnosis of chronic kidney disease (CKD) or end stage renal disease (ESRD) are a high-risk population that has largely been excluded from the potential benefits of the DOACs due to limited data regarding use in patients with poor renal function.   It has been established that patients with CKD have increased likelihood of developing AF, believed to be due to poor kidney function.  Patients who develop AF with CKD are five times more likely to suffer from a stroke which often leads to mortality in these patients.6 

    In an effort to assess the use of DOACs in patients with impaired renal function, many post-marketing studies and analyses have been completed.  This article examines new evidence supporting dosing strategies for renal insufficiency in rivaroxaban and apixaban, as pharmacokinetically these agents are more reasonable for use in kidney impairment due to decreased renal clearance in comparison to the other agents in the class.1-4  Due to the newness of betrixaban to the market, there is not enough comparative data to include it in this assessment.5 

    Clinical Trial Review

    The Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET-AF) trial was the study that established rivaroxaban’s efficacy in patients with atrial fibrillation.  Rivaroxaban was shown to be non-inferior to dose-adjusted warfarin in terms of prevention of stroke and systemic embolism.   Major and non-major clinically relevant bleeding rates were similar in both arms, rivaroxaban did show less frequent cases of intracranial hemorrhage, critical bleeding, and fatal bleeding.7  The ROCKET-AF trial did show that the rivaroxaban group had more gastrointestinal bleeding, but post-market studies have not confirmed this.8  The initial safety and efficacy of rivaroxaban was only assessed and approved in patients with a creatinine clearance (CrCl) of 30 ml/min or greater, including a dose reduction to 15mg daily for patients with CrCl between 30-49 ml/min.7  After post-market sub-studies of patients with renal impairment the 15mg daily dose was approved for patients with a CrCl of 15 ml/min or greater.8  In a sub-analysis of patients with a CrCl < 50 ml/min both groups had comparable rates of stroke or systemic embolism as well as major and non-major clinically relevant bleeding.  However, fatal bleeding was less frequent in the rivaroxaban group.7 

    A small study looked further into the pharmacokinetics (PK) and pharmacodynamics (PD) in patients on hemodialysis without residual kidney function.  This study looked to assess potential accumulation, levels of anti-Xa activity, and the timing of the dose in relation to dialysis treatments.  The study found that rivaroxaban 10mg resulted in similar exposure to that of a healthy patient taking rivaroxaban 20mg and that rivaroxaban was not eliminated via dialysis.9  This study was set up as a phase I or phase II trial and studies of similar size and design have been completed since, showing that dialysis does not affect the PK and PD properties of rivaroxaban.10  These results are encouraging but larger, randomized studies still need to be performed to more conclusively study the safety and efficacy of rivaroxaban in CKD and ESRD.

    Apixaban currently is FDA approved for use in hemodialysis patients despite limited safety data.3  Initially, apixaban was not recommended in patients with a CrCl less than 25 ml/min as the safety and efficacy of apixaban was not studied in this population.  A sub-group analysis of the ARISTOTLE trial focused on the impact renal function had on outcomes and it was noted that apixaban significantly decreased stroke and systemic embolism as well as major bleeds regardless of renal function.11  These trends have led to further studies looking at apixaban use in comparison to warfarin in patients with renal function that would be classified as more severe than mild or moderate impairment. 

    A large retrospective cohort study that compared over 600 patients with advanced CKD receiving apixaban or warfarin was recently published.  All of the patients included in outcome measurements had stage 4 or stage 5 CKD and patients including those concurrently on hemodialysis.  The primary outcome analyzed major bleeding at 3 months after enrollment.  At 3 months there was no difference in the number of patients with a major bleed in the apixaban and warfarin groups (8.3% vs. 9.9%; p= 0.48).  The secondary outcome of major bleeds at  3-6 months showed a continued trend towards improvement with apixaban, but did not achieve statistical significance (apixaban 1.4% vs warfarin 4%; p= 0.07).  Apixaban did show an improvement in major bleeding after 6-12 months (apixaban 1.5% vs. warfarin 8.4%; p<0.001) No differences in stroke or thromboembolism was seen between groups.  Based on this study, one could conclude that apixaban may be an acceptable alternative to warfarin long-term in patients with late stage kidney disease.12  It must be considered that retrospective cohort studies are not capable of providing conclusive results, therefore randomized trials should be evaluated before using this data to revise current recommended standard of care.

    Currently, large trials are in the recruiting phase looking at anticoagulation strategies in patients with AF and CKD.  The RENAL-AF trial (NCT02942407) is measuring time to first major bleeding/non-major clinically relevant bleeding event in a comparison of apixaban versus warfarin in patients on hemodialysis with ESRD as well as AF.13  The XARENO trial (NCT02663076) is looking at patients with both AF and CKD who are treated with VKA or rivaroxaban as their anticoagulation agent.  Primary outcomes will look at bleeding and thrombotic events, all-cause mortality, change in eGFR, major cardiovascular events, and net-clinical benefit.14  Results for these trials will likely not become available until later in 2019 but will hopefully bring some clarity to managing AF patient who have concomitant kidney dysfunction. 

    Conclusion

    In summary, current guidelines still do not offer much support for the use of DOACs in patients with both AF and severe renal dysfunction.  Strong and conclusive evidence supporting the use of DOACs in this patient population is still lacking, but there is encouraging research becoming increasingly available to help guide clinicians in making decisions regarding anticoagulation in this patient population.  The evidence is beginning to suggest a benefit in the use of rivaroxaban or apixaban in patients with more advanced kidney disease and as more information becomes available we may see the treatment guideline governing bodies implement changes in current practice to how we manage anticoagulation in AF patients with CKD or ESRD.   

    References:

    1. Pradaxa®[package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc.; 2015.
    2. Xarelto®[package insert]. Titusville, NJ: Janssen Pharmaceutical Companies; 2011.
    3. Eliquis®[package insert]. Princeton, NK: Bristol-Myers Squibb Company; 2012.
    4. Edoxaban®[package insert]. Tokyo, Japan: Daiichi Sankyo, Inc.; 2015.
    5. Bevyxxa®[package insert]. South San Francisco, CA: Portola Pharmaceuticals, Inc. 2017.
    6. Palabindala V, Salim SA, Pamarthy A, Malhotra B, Ahuja S. Incidence and Prevalence of Atrial Fibrillation (AF) in End Stage Renal Disease (ESRD) Patients. SM Journal of Nephrology and Therapeutics 2017; 2(1): 1006
    7. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus Warfarin in Nonvalvular Atrial Fibrillation. New England Journal of Medicine 2011; 365:883-891. DOI:10.1056/NEJMoa1009638
    8. Sanmartin-Fernandex M, Marzal-Martin D. Safety of Non-Vitamin K Antagonist Oral Anticoagulants in Clinical Practice: Focus on Rivaroxaban in Stroke Prevention in Patients With Atrial Fibrillation. Clinical and Applied Thrombosis/Hemostasis 2017; 23(7): 711-724. DOI:10.1177/1076029616668404.
    9. De Vriese AS, Caluwe R, Bailleul E, et al. Dose-Finding Study of Rivaroxaban in Hemodialysis Patients. American Journal of Kidney Disease 2015; 66(1): 91-98.
    10. Dias C, Moore KT, Murphy J, et al. Pharmacokinetics, Pharmacodynamics, and Safety of Single-Dose Rivaroxaban in Chronic Hemodialysis. American Journal of Nephrology 2016; 43:229-236. DOI:10.1159/000445328.
    11. Hohnloser SH, Hijazi Z, Thomas L, et al. Efficacy of apixaban when compared with warfarin in relation to renal function in patients with atrial fibrillation: insights from the ARISTOTLE trial. European Heart Journal 2012; 33: 2821-2830. DOI:10.1093/eurhearth/ehs274.
    12. Schafer JH, Casey AL, Dupre KA, Staubes BA. Safety and Efficacy of Apixaban Versus Warfarin in Patients With Advanced Chronic Kidney Disease. Annals of Pharmacotherapy 2018; DOI:10.1177/1060028018781853.
    13. ClinicalTrials.gov. Trial to Evaluate Anticoagulation Therapy in Hemodialysis Patients With Atrial Fibrillation (RENAL-AF). Available at: https://clinicaltrials.gov/ct2/show/NCT02942407.  Accessed July 4, 2018.
    14. ClinicalTrials.gov. Factor XA - Inhibition in RENal Patients With Non-valvular Atrial Fibrillation (XARENO). Available at https://clinicaltrials.gov/ct2/show/study/NCT02663076. Accessed July 4, 2018.
  • 16 Sep 2018 11:03 PM | Anonymous

    The Role of Extended Thromboprophylaxis in Acutely Ill Medical Patients
    Author: Yasmine Zeid, PharmD

    Background
    Venous thromboembolism (VTE) encompasses two interrelated conditions that are part of the same spectrum: deep vein thrombosis (DVT) and pulmonary embolism (PE).1 A DVT is a venous blood clot that typically forms in the veins of the lower extremities. A PE occurs when part of a DVT breaks off and travels to the lungs, where partial or complete occlusion of blood flow can be fatal.2 VTE affects about 900,000 patients in the United States every year.3 The risk of VTE remains even after diagnosis and treatment, with one-third of patients diagnosed with a VTE having a recurrence within 10 years. It is estimated that over 50% of hospitalized medical patients are at risk for VTE, with VTE being the second most common medical complication that can occur during a patient’s hospital stay. The total annual cost per patient for secondary diagnosis of DVT is $7,594, and the total annual cost per patient for secondary diagnosis of PE is $13,018.3-6 Early recognition of patients who are at an increased risk of developing VTE is imperative to reduce the medical and economic burden of this complication.

    Assessing Risk
    Virchow’s Triad is a theory that describes three broad factors that are thought to increase the likelihood of VTE formation: alterations in blood flow, hypercoagulability, and vascular endothelial injury.7 Alterations in blood flow can also be referred to as venous stasis, or the slowing or stopping of blood flow.8 One of the most common contributors to venous stasis is immobilization following long-haul traveling or hospitalization. Polycythemia, a disease state that results in hyperviscosity of the blood, can also lead to slowing of blood flow. Hypercoagulability encompasses both hereditary and acquired risk factors. Factor V Leiden disease leads to a hypercoagulable state due a variant in factor V that cannot bind to protein C. Acquired risk factors include pregnancy, oral contraceptive use, obesity, and cancer. Vascular endothelial injury result from physiologic shear stress and disease states such as hypertension.9-10

    There are risk assessment tools available to objectively aid in determining a patient’s risk of developing a VTE. The most commonly used one is the Padua Prediction Score Risk Assessment Tool.11 The Padua Prediction Score is comprised of 11 risk factors, both anatomic and hereditary, with each risk factor assigned a point value based on its relative contribution to risk of VTE formation. A total score of <4 means the patient has a low risk of VTE, while a score ≥4 indicates a high risk of VTE.2 Appendix A includes a complete Padua Prediction Score Risk Assessment Tool.

    The 2012 American College of Chest Physicians (ACCP) guidelines address VTE prevention in hospitalized medical patients.2 Recommendations for thromboprophylaxis are based upon the calculated risk of VTE using the Padua Prediction Score Risk Assessment Tool while also taking into account a patient’s risk of bleeding. The guidelines recommend against thromboprophylaxis for patients with a low risk of VTE, chemical thromboprophylaxis for patients with a high risk of VTE and low bleeding risk, and mechanical thromboprophylaxis for patients with a high risk of VTE and a high risk of bleeding. Patient-specific factors must be taken into account when caring for high-risk patients so that the risks and benefits of treatment can be adequately weighed.

     

    Chemical Thromboprophylaxis
    There are three medications with FDA approval for the chemical prophylaxis of VTE.2 All three medications have shown to be superior to both placebo and mechanical devices used for thromboprophylaxis. Unfractionated heparin (UFH) is administered subcutaneously at a dose of 5000 units three times a day. Low molecular weight heparins (LMWH) include agents such as enoxaparin, which are also administered subcutaneously. Enoxaparin’s traditional dosing is 40 mg once daily, with dose adjustments required for patients with a creatinine clearance less than 30 mL/min, as well as in obese patients. Fondaparinux, a synthetic factor Va inhibitor, is traditionally dosed subcutaneously at 2.5 mg once daily. Dose adjustments are required in patients with renal dysfunction defined as creatinine clearance less than 30 mL/min; use is contraindicated in patients weighing less than 50 kg.

    Extended-Duration Thromboprophylaxis
    The 2012 ACCP guidelines recommend that VTE prophylaxis be continued throughout a patient’s acute hospital stay for the duration of patient immobilization. The guidelines go further to recommend against extending the duration of treatment beyond this time.2 The question arises as to whether or not the risk of developing a VTE is eliminated at hospital discharge, as patients may have risk factors that persist for weeks or even months after hospital discharge. The concept of extended-duration thromboprophylaxis refers to thromboprophylaxis that continues beyond its initial course.

    Evidence to support extended-duration thromboprophylaxis is strongest in hospitalized surgical patients, specifically in patients who have undergone total hip arthroplasty and total knee arthroplasty.12 The 2012 ACCP guidelines recommend a minimum duration of 10-14 days of thromboprophylaxis, with a recommendation for up to 35 days of thromboprophylaxis from the day of surgery.2 Appendix B includes a table with commonly prescribed agents for extended-duration thromboprophylaxis in surgical patients.

    The risk of VTE extending beyond hospitalization has been demonstrated in several studies. The MEDENOX study, a randomized-controlled trial that granted enoxaparin its FDA indication for standard-duration thromboprophylaxis, demonstrated that 8% of total VTEs occurred between days 15 and 110.13 In an observational study in 2011, data from over 15,000 patients in the International Medical Prevention Registry on Venous Thromboembolism (IMPROVE) study was analyzed to determine the incidence of VTE for 3 months after admission. The risk of VTE post-discharge was 45%.5 Moreover, an observational study published in 2012 examining the risk of VTE following hospitalization found that 56.6% of all VTE events occurred after discharge.14

    Enoxaparin
    To date, there are four large randomized controlled trials that have evaluated short-term versus extended-duration thromboprophylaxis in the acutely ill medical population. A table summarizing these four trials is included in Appendix C. The EXCLAIM trial, published in 2010, evaluated extended-duration thromboprophylaxis versus standard-duration with enoxaparin. All enrolled patients initially received open-label subcutaneous enoxaparin (40 mg once daily) for 10±4 days. Upon successfully completing open-label prophylaxis, patients were randomized in a 1:1 ratio to receive either subcutaneous enoxaparin (40 mg once daily) or placebo for an additional 28±4 days. The primary efficacy outcome was a composite of VTE events during the double-blind treatment period, and the primary safety outcome was major hemorrhagic complications. The EXCLAIM trial found that extended-duration enoxaparin did reduce the frequency of VTE events while also increasing the incidence of major bleeding. A subgroup analysis for two endpoints of the study, VTE at day 28 and major bleeding events, was completed looking specifically at three factors: age, sex, and immobility levels. In female patients age >75 years with level 1 immobility (defined as total bed rest without bathroom privileges), the risk of VTE at day 28 was significantly lower in the extended-duration thromboprophylaxis group.15

    Apixaban
    The ADOPT trial, published in 2011, evaluated extended-duration thromboprophylaxis with apixaban following standard-duration prophylaxis with enoxaparin. Patients were randomly assigned in a 1:1 ratio to receive apixaban, administered orally at a dose of 2.5 mg twice daily, or enoxaparin, administered subcutaneously at a dose of 40 mg once daily, during their stay in the hospital, for a minimum of 6 days. After 6 days, the decision to discontinue the parenteral study drug was made at the discretion of the investigators, and patients continued treatment up to 30 days with either apixaban 2.5 mg twice daily or an oral placebo. Notably, the dose of apixaban that was utilized in the ADOPT study was 2.5 mg twice daily, which is FDA-approved dose for extended-duration thromboprophylaxis in patients undergoing total hip and total knee arthroplasty. The primary efficacy outcome was a composite of VTE events during the 30-day treatment period, and the primary safety outcome was major bleeding. Extended-duration apixaban was not found to be superior to standard-duration thromboprophylaxis with enoxaparin, and a significant increase in major bleeding events was observed.16

    Rivaroxaban
    The MAGELLAN study, published in 2013, evaluated extended-duration thromboprophylaxis with rivaroxaban versus standard-duration prophylaxis with enoxaparin. Patients were assigned in a 1:1 ratio to one of the following therapies: rivaroxaban 10 mg once daily orally for 35±4 days plus subcutaneous placebo for 10±4 days; or, enoxaparin 40 mg once daily subcutaneously for 10±4 days plus an oral placebo for 35±4 days. Similarly to the dose of apixaban in the ADOPT study, this 10 mg once daily dose of rivaroxaban was based upon the FDA-approved dose of the medication for extended-duration prophylaxis in total hip and total knee arthroplasty patients. The primary efficacy outcome was a composite of VTE events, with a non-inferiority analysis up to day 10 (compared standard-duration prophylaxis with rivaroxaban to standard-duration enoxaparin) and a superiority analysis up to day 35 (compared extended-duration rivaroxaban to standard-duration enoxaparin). The primary efficacy outcome was a composite of major bleeding or clinically relevant nonmajor bleeding events. Rivaroxaban was found to be noninferior to enoxaparin for the standard duration of therapy; additionally, extended-duration rivaroxaban was superior to standard enoxaparin prophylaxis. A significantly higher risk of major bleeding and clinically relevant nonmajor bleeding was observed in the rivaroxaban group versus the enoxaparin group.17

    Betrixaban
    The APEX trial, published in 2016, is the most recent study examining extended-duration thromboprophylaxis in the acutely ill medical population. It evaluated extended-duration thromboprophylaxis with the newest FDA-approved factor Xa inhibitor, betrixaban, versus standard-duration prophylaxis with enoxaparin. Patients were divided into three patient cohorts: cohort 1 included patients with elevated baseline D-dimer level greater than 2x upper limit of normal; cohort 2 included patients in cohort 1 plus patients ≥75 years of age; and cohort 3 included the overall study population. Patients were then randomized in a 1:1 ratio to receive either enoxaparin 40 mg once daily subcutaneously for 10±4 days plus placebo once daily for 35 to 42 days; or, subcutaneous placebo for 10±4 days plus oral betrixaban. Betrixaban was administered as a 160 mg loading dose followed by 80 mg once daily for 35-42 days. The primary efficacy outcome was a composite of VTE events, and the primary safety outcome was the occurrence of major bleeding. Extended-duration prophylaxis with betrixaban reduced overall VTE events compared to standard-duration enoxaparin in cohort 1, but this finding was not found to be statistically significant. While cohorts 2 and 3 did demonstrate a statistically significant reduction in VTE events, because the first cohort failed to show statistical significance, all subsequent analyses were considered to be exploratory. The efficacy results of the APEX trial were later analyzed using a modified intent-to-treat analysis (mITT) for patients who took at least 1 dose of study drug and had a follow-up assessment of VTE. Major bleeding was not significantly increased in any of the patient cohorts; however, major or clinically relevant nonmajor bleeding was significantly increased in all three patient cohorts.18-19

    Betrixaban was granted FDA-approval in June 2017, and it is the first and only anticoagulant with approval for both hospital and extended thromboprophylaxis of VTE in acutely ill medical patients. The recommended dosing is 160 mg on day 1 of therapy, following by 80 mg daily for 35-42 additional days. In patients with a creatinine clearance of 15-30 mL/min and/or receiving concurrent treatment with P-glycoprotein inhibitors, the dose is reduced to 80 mg on day 1, followed by 40 mg daily for 35-42 additional days. Betrixaban must be taken at the same time every day with food to avoid high concentrations.19 The average wholesale price (AWP) for 35 days of therapy with betrixaban is about $650, compared to about $260 dollars for standard-duration enoxaparin.20

    Based on the evidence available at this time, as well as current guideline recommendations, extended-duration thromboprophylaxis in the acutely ill medical population should not be routinely practiced until the potential risks and benefits have been evaluated on an individual patient-case basis. Although betrixaban is now approved for this indication, its efficacy has not yet been well established. Even though its use did not demonstrate an increase in major bleeding in the APEX trial, an increase in major or clinically relevant nonmajor bleeding was still observed. Extended-duration thromboprophylaxis may be beneficial in a niche patient population (female, age ≥75, immobilized, elevated D-dimer), and more studies are needed to better characterize this population.

    References:

    1.       Turpie AG, Chin BS, Lip GY. Venous thromboembolism: pathophysiology, clinical features, and prevention. BMJ 325 2002;7369:887–90.

    2.       Kahn SR, Lim W, Dunn AS, et al. Prevention of VTE in nonsurgical patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141:e195S.

    3.       Fernandez MM, Hogue S, Preblick R, Kwong WJ. Review of the cost of venous thromboembolism. Clinicoecon Outcomes Res. 2015;7:451–62.

    4.       Spyropoulos AC, Lin J. Direct medical costs of venous thromboembolism and subsequent hospital readmission rates: an administrative claims analysis from 30 managed care organizations. J Manag Care Pharm. 2007; 13: 475-486.

    5.       Spyropoulos AC, Anderson FA Jr, Fitzgerald G, et al. Predictive and associative models to identify hospitalized medical patients at risk for VTE. Chest 2011; 140:706.

    6.       Hull RD, Hirsh J, Sackett DL, Stoddart GL. Cost-effectiveness of primary and secondary prevention of fatal pulmonary embolism in high-risk surgical patients. Can Med Assoc J 1982; 127:990.

    7.       Dickson, B.C. (2004a) Venous thrombosis: on the history of Virchow’s triad. University of Toronto Medical Journal; 81, 166–171.

    8.       Goldhaber SZ. Risk factors for venous thromboembolism. J Am Coll Cardiol 2010; 56:1.

    9.       Anderson FA, Spencer FA. Risk factors for venous thromboembolism. Circulation 2003; 107: 19-116

    10.   Martinelli I, Cattaneo M, Taioli E, et al. Genetic risk factors for superficial vein thrombosis. Thromb Haemost 1999; 82:1215.

    11.   Barbar S, Noventa F, Rossetto V, et al. A risk assessment model for the identification of hospitalized medical patients at risk for venous thromboembolism: the Padua Prediction Score. J Thromb Haemost 2010; 8:2450.

    12.   Falck-Ytter Y, Francis CW, Johanson NA et al (2012) Prevention of VTE in orthopedic surgery patients: antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 141(2 Suppl):e278S–e325S.

    13.   Samama MM, Cohen AT, Darmon JY, Desjardins L, Eldor A, Janbon C, Leizorovicz A, Nguyen H, Olsson CG, Turpie AG, Weisslinger N (1999) A comparison of enoxaparin with placebo for the prevention of venous thromboembolism in acutely ill medical patient. N Engl J Med 341:793–800.

    14.   Amin AN, Varker H, Princic N, Lin J, Thompson S, Johnston S. Duration of venous thromboembolism risk across a continuum in medically ill hospitalized patients. J Hosp Med. 2012;7(3):231-8.

    15.   Hull RD, et al. Extended-duration venous thromboembolism prophylaxis in acutely ill medical patients with recently reduced mobility: a randomized trial. Ann Intern Med. 2010 Jul 6;153(1):8-18.

    16.   Goldhaber SZ, Leizorovicz A, Kakkar AK, et al. Apixaban versus enoxaparin for thromboprophylaxis in medically ill patients. N Engl J Med; 365: 2167-77.

    17.   Cohen AT, et al. Rivaroxaban for thromboprophylaxis in acutely ill medical patients. N Engl J Med. 2013. 368(6): 513-523.

    18.   Cohen AT, Harrington RA, Goldhaber SZ, et al. Extended Thromboprophylaxis with Betrixaban in Acutely Ill Medical Patients. N Engl J Med 2016; 375:534.

    19.   Bevyxxa(betrixaban) [package insert]. San Francisco, CA: Portola Pharmaceuticals, Inc.; June 2017.

    20.   Micromedex Solutions. Ann Arbor (MI): Truven Health Analytics; publication year [5 January 2018]. Available from: www.micromedexsolutions.com

    21.   Lovenox® (enoxaparin) [package insert]. Bridgewater, NJ. Sanofi-Aventis; October 2017.

    22.   Xarleto® (rivaroxaban) [package insert]. Titusville, NJ. Janssen Pharmaceuticals, Inc. October 2017.

    23.   Eliquis® (apixaban) [package insert]. Princeton, NJ. Bristol-Myers Squibb. November 2017.

    24.   Pradaxa® (dabigatran) [package insert]. Ridgefield, CT. Boehringer Ingelheim Pharmaceuticals, Inc. July 2017.

    Additional supporting tables are below and as a PDF file.




  • 16 Sep 2018 10:57 PM | Anonymous

    At the MSHP/KCHP Spring Meeting, the pharmacy staff at St. Luke’s Hospital in Kansas City, MO were recognized with the Best Practice Award for their innovative antimicrobial stewardship activities surrounding utilization of rapid diagnostic tests.  Shelby Shemanski, PharmD, BCCCP (Critical Care Pharmacist) and Nick Bennett, PharmD, BCPS (Antimicrobial Stewardship Pharmacist) have graciously shared details of their program with the MSHP membership for those who may be interested in instituting similar practices.

    1.  Please describe the program you started at your institution?
    Bloodstream infections (BSI) represent a significant burden to health care systems and are associated with increased morbidity and mortality. Emergence of rapid diagnostics tests (RDT) have allowed for earlier optimization of therapies for various infections. In 2015, Saint Luke’s Health System (SLHS) launched our centralized Antimicrobial Stewardship Program (ASP) which covers all system hospitals utilizing an electronic medical record (EMR). Concurrently, our microbiology department acquired a new diagnostic technology called MALDI-TOF, which is mass spectrometry microbial identification.  In 2014, the lab had implemented Filmarray PCR for blood cultures, which identifies a large percentage of organisms. In order to maximize the rapidity and understanding of test results, in 2016 microbiology staff began communicating positive blood culture results directly to an ASP pharmacist Monday through Friday, 0700 to 1530, or system pharmacists/residents at Saint Luke’s Hospital all other hours of the week. The goal of our project was to determine if integrating ASP and pharmacy personnel with RDTs would improve outcomes for patients with BSIs.

    2.  How do you (pharmacists) in your program provide care to patients and ensure safe and effective medication therapy?
    Upon receiving a positive blood culture result, pharmacists are expected to review patient-specific data provided in the EMR. This is followed by contacting the appropriate provider with the culture results and suggestions for therapy changes if needed. Pharmacists then place a progress note in the medical record including physician contacted, date and time of communication, and blood culture results. This data is recorded in a database and includes if recommendations were accepted or rejected. All cultures and communications are reviewed by ASP staff the following day or Monday following a weekend to ensure appropriate treatment selections were made or to address issues pharmacists noted in the communication log.

    Prior to 2016, microbiology staff communicated positive blood culture results to nursing staff, who then had to relay the information to the physician. Our process change allowed pharmacists to have a more proactive role in optimizing therapy, but also minimizes nursing interruptions to allow for better patient care.  Additionally, the change supports provider decision making regarding critical patient information. 

    3.  What services have you determined to be essential to support your programs?
    Because our ASP program is not a 24/7 service, we utilize our pharmacy residents and pharmacists at Saint Luke’s Hospital on evening, overnight, and weekend shifts. In addition, the SLHS Innovation Center, a program launched in 2015 to promote innovative care ideas from staff, was an essential resource for this project. Funding from the center allowed us to implement a PGY2-Critical Care Pharmacy Residency.  The intent of funding the PGY-2 position was to support the research and other staffing needs to help get this new process up and running.

    4.  How did you gain support of hospital administrators, physicians, and nursing to implement your program?
    The project was one of two funded projects out of a pool of 53 submissions in 2015.  The Innovation Center is supported on a system level with input from a multidisciplinary group of physicians, pharmacists, administrators and nurses who have ideas to improve efficiency and quality of patient care.  All employees can submit ideas for consideration.  The Innovation center not only provided funding to support the project, but also allocated a project manager and research mentor which were essential to the success of the project.

    5.  What are key barriers that needed to be overcame to start your program?
    The biggest issue we faced was education on the process change, as providers were not accustomed to pharmacists directly communicating critical test results.  Over time, providers understood the value of pharmacist knowledge in microbiology and therapy selection as it relates to blood culture results.  Likewise, nursing staff became less involved with the communication, so we had to devise a method to make the information transparent.  Thus, we developed a progress note titled “critical notification” which is inputted into the progress notes section of the chart after communication with the provider.

    6.  What are some key considerations to gain employee acceptance and buy-in for your program? 
    Make sure you have support from multiple levels ranging from senior leadership, physicians, nursing staff, and your internal staff.  The more people that buy into the value of the service, the less external (or internal) pressure you will receive when making practice changes.  Senior leadership support tends to make process changes happen at a quicker pace and remove barriers that might otherwise slow down progress.

    7.  What benefits have you been able to show with your program?
    We collected and compared pre- (2014, pre-ASP and MALDI-TOF) and post-intervention data (2016) for patients with legitimate positive blood culture results. We found that time to optimal therapy was reduced by 9.2 hours in the 2016 group (p=0.004). There was a trend in reduced inpatient and antimicrobial costs in 2016, with an estimated $110,000 in savings attributed to drug optimization alone. Documented discussions between providers and pharmacists found a high rate of agreement for antimicrobial therapies based on culture results. All recommendations for no change or escalation/dose modification were accepted. Of the 39 proposed de-escalation attempts, only 31 (79.5%) were accepted. Additionally, a physician survey was completed prior to and after our process change. Survey results indicated the new process improved communication amongst clinicians and facilitated a shared-decision making process with a perceived improvement in patient care.

    8.  What are lessons learned while implementing your program that you would like to share with other pharmacists?
    Understand the significant value you bring to the health care team.  Always be looking for ways we can integrate ourselves into current workflows or redesign one to minimize inefficiencies and maximize results.  The health care landscape is constantly shifting.  We as a profession either have to push along with the shift or ahead of it to ensure the value we provide remains visible and desired.  In infectious diseases, RDTs are a perfect example of merging our knowledge of microbiology with therapy optimization for the betterment of patient care.  The technology will continue to advance and it’s our job to help patients get the most from this new technology and support the health care team along the way.

    The MSHP Newsletter Committee would like to thank Shelby and Nick for sharing their practice with the membership!  If you have questions about this practice, or want to share a best practice of your own, please contact Sarah Cook at sarah.cook@ssmhealth.com!

  • 16 Sep 2018 10:50 PM | Anonymous

    Pharmacist Continuing Education: Stress ulcer prophylaxis: Is it still necessary?

    Author: Michael Serlin, PharmD; PGY1 Pharmacy Practice Resident, SSM Health St. Clare Hospital

    Preceptor: Christopher Carter, PharmD, BCCCP; Clinical Pharmacy Specialist - Critical Care, SSM Health St. Clare Hospital

    Program Number: 2018-07-18
    Approval Dates: October 1, 2018 to December 31, 2018
    Approved Contact Hours: One (1) CE(s) per LIVE session.

    Objectives

    1. Demonstrate foundational background knowledge of stress ulcer prophylaxis, particularly in regards to the indications for use and classifications of bleeding.
    2. Analyze and interpret the results of stress ulcer prophylaxis trials.

    Acid-reducing medications like proton pump inhibitors (PPIs) and histamine receptor 2 antagonists (H2RAs) are used commonly for stress ulcer prophylaxis in the inpatient setting. Stress ulcer prophylaxis is indicated for certain subgroups within the critically ill population but up to 71% of general medicine patients receive stress ulcer prophylaxis.1 Though it may reduce bleeding due to stress ulcer formation, stress ulcer prophylaxis may also expose patients to an increased risk of Clostridium difficile infections and ventilator-associated pneumonia due to the creation of a higher-pH environment within the stomach and proximal, small bowel.2

    The goal of this article is to provide information to assist clinicians in exercising stress ulcer prophylaxis stewardship in the inpatient setting by providing adequate background on the risks for stress ulcer formation and a review of the pertinent literature assessing the safety and efficacy of stress ulcer prophylaxis. By practicing good stewardship, clinicians can optimize the benefit of stress ulcer prophylaxis against the risk of adverse events in the appropriate patient populations.

    Stress Ulcer Formation and Enteral Nutrition
    As previously stated, stress ulcer prophylaxis is only indicated in certain critically ill patients. Critically ill patients have a variety of physiologic changes that can increase risk for ulceration. Compared to non-critically ill patients, critically ill patients have an increased gastric acid secretion and impaired blood flow to the gastric mucosa.3 Impaired blood flow to the mucosa can be caused by hemodynamic changes (i.e. hypotension), an imbalance of endothelin-1 and nitric oxide, as well as positive end-expiratory pressure from mechanical ventilation.3 This impaired blood flow can ultimately decrease production of bicarbonate and mucus that would normally provide a protective barrier in the stomach and increase ulceration risk. 

    Although the above physiologic changes can increase the risk of ulceration, it is important to note that altered gastric mucosa does not necessarily cause bleeding. Generally, in order for bleeding to occur, there must be a change in the gastric mucosa and an increased gastric acid secretion.3

    While medications can be used to modify acid secretion, enteral nutrition has been shown to increase gastric mucosal blood flow, as well as modify the imbalance between endothelin-1 and nitric oxide.3

    Types of Upper Gastrointestinal Bleeding
    There are three types of upper gastrointestinal bleeds: occult, overt, and clinically important. An occult bleed is a type of bleed that isn’t symptomatic or visibly seen. An example of occult bleeding is a positive fecal bleeding test. Overt bleeding is a type of bleed that can be visibly seen, such as hematemesis, bloody nasogastric aspirate, or melena. Clinically important bleeding is defined as overt bleeding plus: a spontaneous decrease of greater than 20 mmHg in systolic or diastolic blood pressure, an orthostatic increase in heart rate by 20 beats per minute and a decrease in systolic blood pressure by 10 mmHg, or a decrease in hemoglobin by at least two grams per deciliter or the need to transfuse at least two units of blood within 24 hours of a bleed.4 Clinically important bleeding is associated with increased mortality and increased intensive care unit (ICU) length of stay and is the main target of stress ulcer prophylaxis.4 The incidence of clinically important bleeding in ICU patients without prophylaxis has historically been from 0.1-4%.4

    1999 ASHP Stress Ulcer Prophylaxis Guidelines
    The American Society of Health-System Pharmacists’ stress ulcer prophylaxis guidelines, published in 1999, recommended that stress ulcer prophylaxis be utilized in certain critically ill populations including those that are mechanically ventilated for at least 48 hours and those that have a coagulopathy, including platelet counts less than 50,000 cells/mL3, international normalized ratios (INRs) greater than 1.5, and activated partial thromboplastin time (aPTT) greater than twice the upper limit of normal. These recommendations were based on evidence from cohort studies. Of note, there are two other indications for stress ulcer prophylaxis in the ASHP guidelines that were founded upon expert opinion only. These indications include patients that have had a gastrointestinal bleed within the past year and patients that have at least two of the following characteristics:  Diagnosis of sepsis, ICU stay longer than six days, and those with occult bleeds lasting longer than five days.5

    The ASHP guidelines also provided recommendations for special populations. Based on randomized control trials, stress ulcer prophylaxis is recommended for patients with Glasgow Coma Scale scores less than or equal to 10 and patients with thermal injuries that were greater than 35% of the patient’s body surface area (BSA). Certain populations, including head traumas and spinal cord injuries, had not been well studied when the guidelines were published. Thus, the guidelines stated that prophylaxis might be indicated on the basis of expert opinion.5

    Recently Published Stress Ulcer Prophylaxis Literature
    Selvanderan, et al.- 2016 exploratory trial7
    The article entitled “Pantoprazole or Placebo for Stress Ulcer Prophylaxis (POP-UP): Randomized Double-Blind Exploratory Study” by Selvanderan et al. was a prospective, randomized, parallel-group trial. This exploratory study aimed to establish rates of clinically important bleeding, Clostridium difficile infections, and ventilator-associated pneumonia in critically ill patients with and without prophylaxis of intravenous pantoprazole 40 mg daily.  Patients were eligible for the study if their expected time on mechanical ventilation was at least 24 hours and if they were expected to receive enteral nutrition within at least 48 hours of admission. Patients were ineligible for enrollment if they had used acid-altering medication before admission, were admitted with a gastrointestinal bleed, were using at least 100 mg of prednisolone or an equivalent dose of another corticosteroid, were admitted for gastrointestinal or cardiovascular surgery, were pregnant, were Jehovah’s witnesses, were receiving palliative care, or were an ICU readmission. Categorical data were appropriately analyzed via chi-squared or Fisher’s exact test. Parametric continuous data were analyzed via unpaired t-test and nonparametric continuous data were analyzed via Mann-Whitney U.

    There were no significant differences in baseline characteristics or processes of care, including inotrope usage or coagulopathies, in the 108 patients that received placebo and the 106 patients that received pantoprazole.  There was also no significant difference in the number of patients using enteral nutrition in each group. All of the endpoint studied, including clinically important bleeding, ventilator-associated pneumonia, Clostridium difficile infection, overt bleeding incidence, ICU length of stay, and hospital length of stay were found to be nonsignificant between the groups. There were no incidences of clinically important bleeds observed. The incidence of ventilator-associated pneumonia was 1.9% in the pantoprazole group and 0.9% in the placebo group. The incidence of Clostridium difficile infection was 0.9% in the pantoprazole group and 0% in the placebo group.

    These results show that in this population, pantoprazole provided no extra benefit and no harm. These nonsignificant results should be taken in context of the exploratory nature of the trial in that since power was not assessed in the study design, it is possible that the trial was not designed to find a difference if one truly exists.

    Alhazzani, et al.- 2017 pilot trial and meta-analysis2
    The article entitled Withholding pantoprazole for stress ulcer prophylaxis in critically ill patients: a pilot randomized clinical trial and meta-analysis” by Alhazzani et al. was an international, multicenter, randomized, double-blind, placebo-controlled, parallel-group trial that compared intravenous pantoprazole 40 mg daily to placebo. The study treatment was stopped after death, incidence of gastrointestinal bleeding, or after extubation at the discretion of the treating physician. Patients were included if they were at least 18 years old and were expected to be mechanically ventilated for at least 48 hours. Patients were excluded if they were ventilated before randomization, used PPIs due to an active bleed or for an increased bleeding risk, used dual antiplatelet therapy, were on palliative care, were pregnant, or used PPIs or H2RAs twice daily or more. The primary endpoint was incidence of clinically important gastrointestinal bleeding. The secondary endpoints were similar to those in the trial by Selvanderan et al., including length of stay, incidence of ventilator-associated pneumonia, incidence of Clostridium difficile infection, and morality rates. The trial data was analyzed via Fisher’s exact test and the meta-analysis data was analyzed via DerSimonian and Laird random-effect models.

    There were no significant differences noted in baseline characteristics including H2RA or PPI use before the study, median Acute Physiology and Chronic Health Evaluation II (APACHE II) score, and type of anticoagulants used. The only statistically significant difference noted between the 49 patients in the pantoprazole group compared to the 42 patients in the placebo group was the difference in median hospital length of stay, favoring the placebo group (placebo 25 days (interquartile range, IQR 10-42 days) vs. pantoprazole 27 days (IQR 16-38 days), p=0.049). All other differences in pilot trial results, including differences in mortality, clinically important bleeding incidences, and any bleeding incidences were not found to be statistically significant.

    The meta-analysis performed by Alhazzani et al. reviewed data on incidence of clinically important bleeding and ventilator-associated pneumonia. For the incidence of clinically important bleeding, the authors found no overall significance in the differences between PPIs vs. placebo in the pooled data from five studies (overall OR 0.96; 95% CI 0.24-3.82). The authors also found no statistically significant difference in the pooled data from four studies for ventilator-associated pneumonia (overall OR 1.32; 95% CI 0.68-2.55).

    The results from the pilot trial and the meta-analysis both show no statistically significant differences between PPIs and placebo for clinically important bleeding and infection rates.  Due to the pilot nature of the trial aspect of this article, these nonsignificant results should be interpreted with caution, as power was not assessed or calculated.

    El-Kersh, et al.- 2017 exploratory trial8
    The article entitled “Enteral nutrition as stress ulcer prophylaxis in critically ill patients: A randomized controlled exploratory study” by El-Kersh et al. was a prospective, randomized controlled trial that aimed to determine if stress ulcer prophylaxis is needed in combination with enteral feeding. Enteral nutrition, defined as 25-30 kcal per kilogram per day, was given with intravenous pantoprazole 40 mg daily or placebo. To provide appropriate feeding, gastric residual volumes were checked every four hours. If the residual volume was greater than 400 milliliters or if the patient was hypotensive or hypoxic, feeding was paused to decrease the risk of bowel ischemia. Feeding was resumed once the residual volume was less than 400 milliliters or when deemed appropriate by the treating medical teams. The feeding strategy used in the study aligns with the recommendations provided by the Society of Critical Care Medicine and the American Society for Parenteral and Enteral Nutrition.9 Patients were eligible for enrollment if they were at least 18 years old, expected to be ventilated for at least 48 hours, and had no contraindications for enteral nutrition within 24 hours of ICU admission. Patients were ineligible if they had a gastrointestinal bleed or burn injury upon admission, had head trauma or increased intracranial pressure, had a history of gastrectomy, or were pregnant or lactating.  As with the previous articles, the primary endpoint was incidence of clinically important bleeding. Secondary endpoints included incidence of Clostridium difficile infection, ICU length of stay, and hospital length of stay.

    There were no significant differences found in baseline characteristics, including median Sequential Organ Failure Assessment (SOFA) and Simplified Acute Physiology Score II scores. No differences were found as well in regards to enteral feeding characteristics, including average kcal per kilogram per day given and total enteral nutrition given. Additionally, there were no statistically significant differences in any of the endpoints studied, including the primary endpoint of clinically important bleeding (one incidence in each group; p=0.99) for the 55 patients treated with pantoprazole compared to the 47 patients treated with placebo.

    These results show no extra benefit of administering pantoprazole in mechanically ventilated patients receiving enteral nutrition in regards to clinically important bleeding incidence, incidence of Clostridium difficile infection, and length of stay. As with the other newer trials, the exploratory nature of this study should be considered when interpreting these results.

    Conclusions and recommendations for practitioners
    As mentioned previously, the exploratory and pilot designs of the newly published trials are factors that should not be overlooked when interpreting these results. It is possible that these studies were not powered to find the difference between PPIs and placebo that truly existed. With that said, these new trials offer hope that there may evidence to show a reduced need for stress ulcer prophylaxis. All three studies found no statistical difference when examining stress ulcer prophylaxis in a population in which prophylaxis was originally recommended for in the ASHP guidelines. Until larger, powered studies provide evidence suggesting that stress ulcer prophylaxis is not needed, it is reasonable to still utilize it in critically ill patients that have coagulopathies or that have been ventilated for at least 48 hours. Despite these populations not being a focus of recently published literature, it may be reasonable to utilize prophylaxis in patients with low Glasgow Coma Scale scores and with significant thermal injury. It is difficult to recommend prophylaxis be utilized in the populations that were previously recommended solely based on expert opinion due to the limited evidence for such recommendations. For reasons stated previously, it is also unlikely that stress ulcer prophylaxis is beneficial in many other populations than the critically ill, particularly those admitted to a general unit. Therefore, it is also reasonable that stress ulcer prophylaxis should generally be discontinued in non-critically ill patients.


    References:

    1. Grube RR, May DB. Stress ulcer prophylaxis in hospitalized patients not in intensive care units. Am J Health Syst Pharm. 2007 Jul 1;64(13):1396-400.
    2. Alhazzani W, Guyatt G, Alshahrani M, et al. Withholding pantoprazole for stress ulcer prophylaxis in critically ill patients: a pilot randomized clinical trial and meta-analysis. Crit Care Med 2017;45(7):1121–9.
    3. Buendgens L, Koch A, Tacke T. Prevention of stress-related ulcer bleeding at the intensive care unit: Risks and benefits of stress ulcer prophylaxis. World J Crit Care Med. 2016 Feb 4; 5(1): 57–64.
    4. Alhazzani W, Alshahrani M, Moayyedi P, et al. Stress ulcer prophylaxis in critically ill patients: review of the evidence. Pol Arch Med Wewn. 2012;122(3):107-14.
    5. ASHP Therapeutic Guidelines on Stress Ulcer Prophylaxis. ASHP Commission on Therapeutics and approved by the ASHP Board of Directors on November 14, 1998. Am J Health Syst Pharm. 1999 Feb 15;56(4):347-79.
    6. Cook DJ, Fuller HD, Guyatt GH, et al. Risk factors for gastrointestinal bleeding in critically ill patients. Canadian Critical Care Trials Group. N Engl J Med. 1994 Feb 10;330(6):377-81.
    7. Selvanderan SP, Summers MJ, Finnis ME et al. Pantoprazole or placebo for stress ulcer prophylaxis (POP-UP): Randomized double-blind exploratory study. Crit Care Med. 2016 Oct;44(10):1842-50
    8. El-Kersh K, Jalil B, McClave SA et al. Enteral nutrition as stress ulcer prophylaxis in critically ill patients: A randomized controlled exploratory study. J Crit Care. 2018 Feb;43:108-113.
    9. McClave SA, Taylor BE, Martindale RG, et al. Guidelines for the Provision and Assessment of Nutrition Support Therapy in the Adult Critically Ill Patient: Society of Critical Care Medicine (SCCM) and American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.). JPEN J Parenter Enteral Nutr. 2016 Feb;40(2):159-211.


  • 16 Sep 2018 10:42 PM | Anonymous

    Authors:  Nicholas Kovarik, PharmD and Samuel Mikovich, PharmD, PGY-1 Pharmacy Residents, SSM Health St. Mary’s Hospital – St. Louis

    Preceptor:  Davina Dell-Steinbeck, PharmD, BCPS, PGY-1 Pharmacy Practice Residency Director, SSM Health St. Mary’s Hospital – St. Louis

    Program Number: 2018-07-18
    Approval Dates: October 1, 2018 to December 31, 2018
    Approved Contact Hours: One (1) CE(s) per LIVE session.

    Learning Objectives

    1. Recall prevention and treatment recommendations made in the 2017 update to the IDSA/SHEA Clostridium difficile guidelines
    2. Identify the appropriate place in therapy for Fecal Microbiota Transplant in the treatment of recurrent infection
    3. Explain the mechanism and different modalities of Fecal Microbiota Transplant in treating recurrent infection
    4. Recall the methods of patient preparation strategies prior to delivery of Fecal Microbiota Transplant
    5. Evaluate the current evidence for using Fecal Microbiota Transplant


    Introduction
    Clostridium difficile infection (CDI) represents a major burden for hospitals in the United States, annually responsible for 500,000 infections1, 30,000 deaths2, and excess inpatients costs of over 4.8 billion dollars3. Clostridium difficile is a Gram positive, spore-forming anaerobe that mediates infection through enterotoxin production (toxins A and B) within the human gut. This organism is the most commonly identified cause of healthcare-associated infection in our country, surpassing infections caused by methicillin-resistant Staphylococcus aureus (MRSA)4. Diagnosis of CDI is based on a combination of clinical and laboratory evidence: the presence of diarrhea defined as ≥ 3 unformed stools within 24 hours and a stool test result positive for the presence Clostridium difficile toxins or DNA.

    The Clostridium difficile guidelines published by the Infectious Diseases Society of America (IDSA) and the Society for Healthcare Epidemiology of America (SHEA) were recently updated at the end of 20175. The previous update to these guidelines was performed in 2010, and only focused on adult recommendations6. The new update includes recommendations for children and brings significant changes to the treatment recommendations for adults. This article will highlight some of the major changes made to these guidelines and present the evidence that supports them. A particular focus will be placed on using fecal microbiota transplant, or FMT, to treat CDI. This article will also cover the different administration techniques for FMT. Because CDI significantly affects morbidity and mortality among hospitalized patients, there is a growing effort to find new treatment modalities as well as optimize the old ones. It is therefore essential that pharmacists stay up-to-date on the best practice methods for this disease.

    Recurrence
    A major contributing factor to CDI’s large healthcare burden is the high rate of recurrence. Rates of CDI recurrence have steadily increased over the years, and around 25% of patients treated with metronidazole or vancomycin for an initial episode will develop a recurrent infection7. Once a patient has one recurrence, the risk for a second recurrence skyrockets up to 65%8. Risk factors for recurrence include older age (≥ 65), continued antibiotic use, use of acid-suppressing medications, previous exposure to fluoroquinolones, and strain type5. Historically, metronidazole has been the mainstay of treatment for patients hospitalized with CDI, but high rates of recurrence prompted the changes to the IDSA guidelines that will be discussed later on.

    NAP-1 strain
    One reason for high recurrence rates and increasing disease severity is the emergence of the North American pulsed-field Type 1 strain (NAP-1/BI/027). The NAP-1 strain is a hypervirulent strain of Clostridium difficile that is associated with more severe symptoms, higher recurrence rates, and increased mortality. The emergence of this strain is hypothesized to be due to the overuse of fluoroquinolone antibiotics. In an epidemiologic study performed in the U.S. including over 2,000 CDI cases, investigators found that 28.4% of cases were due to this hypervirulent strain9.


    2017 Update to IDSA/SHEA Guidelines

    Prevention
    The updated IDSA guidelines make many recommendations related to prevention methods for CDI. Some of the more relevant recommendations encompass hand hygiene methods, antimicrobial stewardship efforts, and the use of probiotics and proton pump inhibitors. The latest evidence suggests that although washing your hands with soap and water is preferred in times of CDI outbreaks or direct contact with a stool specimen, using alcohol-based products is just as effective to prevent transmission of disease. Adding to the evidence in favor of antimicrobial stewardship in healthcare organizations, the guidelines strongly recommend implementation of a stewardship program. This section of the guideline details that restriction of high-risk antibiotics such as fluoroquinolones, clindamycin, and cephalosporins should be considered. Although there has been evidence to show an association between PPI use and CDI, the panel noted there is insufficient evidence for discontinuation of PPIs as a measure for preventing CDI. This recommendation stems from the lack of causal data, as only observational studies have been performed. However, they do note that unnecessary PPIs should always be discontinued. Similarly, the guidelines do not recommend using probiotics to prevent CDI due to the lack of high quality evidence.

    Treatment: Adult Recommendations5 (Table 1)
    The biggest change in the treatment of CDI in the guideline update is the deletion of metronidazole as a first-line recommended agent. This change comes with the addition of fidaxomicin as a first-line agent in its place. Metronidazole is now only recommended if vancomycin or fidaxomicin are contraindicated or unavailable. Initial data comparing metronidazole and vancomycin performed in the 1980s and 1990s showed similar efficacy10. However, randomized controlled trials more recently have shown that vancomycin use is associated with significantly higher clinical cure rates and lower recurrence rates compared to metronidazole11. Additionally, guidelines mention to avoid repeated or prolonged courses of metronidazole due to the risk of irreversible neurotoxicity.

    Fidaxomicin, marketed as Dificid®, was FDA approved in 2011. As shown in Table 1, it is now recommended first-line as an alternative to vancomycin for initial non-severe and severe infections. Fidaxomicin has mechanistic advantages over vancomycin. It has been found to be more potent in vitro than vancomycin, has high fecal concentrations, long post-antibiotic effect, and restricted activity against normal gut flora12. There are two major trials that have directly compared vancomycin to fidaxomicin (Table 2)13,14. Both of these randomized controlled trials compared vancomycin 125 mg PO QID for 10 days vs. fidaxomicin 200 mg PO BID for 10 days. Results of these two trials show no difference in clinical cure rates, but do show a statistically significant decrease in recurrent rates in the fidaxomicin group (25% vs. 15%, 27% vs. 13%). One major consideration when using fidaxomicin is the price, as it is significantly more expensive than vancomycin.

    Another change from the 2010 update is the management of recurrent infections (Table 3). The previous update recommended treating the first recurrent episode with the same agent as the initial episode. For the first recurrence, the 2017 update recommends using a tapered and pulsed dosing strategy (if standard dosing vancomycin was used initially) or switching agents. For the second and subsequent recurrences, the 2017 update does have the recommendation of using fecal microbiota transplant.

    Fecal Microbiota Transplant Mechanism
    The human gastrointestinal tract contains over 1,100 different bacterial species and over 1014 individual bacteria15. Although there are many roles of these bacteria, one that applies specifically to CDI is the ability to kill pathogens through competitive exclusion. When antibiotics interfere with this diverse group of bacteria, foreign pathogens such as Clostridium difficile can take residence. Although the exact mechanism for recurrent CDI is not fully understood, it is thought that a large part is due to a decreased microbial diversity within the gut. A study performed in 2008 evaluating the microbial diversity of feces in patients with recurrent CDI found a drastic decrease in diversity16. The concept of FMT works on this exact principle, that instillation of bacteria from a healthy individual via stool will restore the diversity of a patient with a damaged gut microbiota.

    Regulation
    FMT is defined by the FDA as a biological agent which is not FDA-approved. When treating recurrent CDI, an Investigation New Drug (IND) permit is encouraged but not required for physicians. However, the FDA is looking to regulate FMT and may eventually require an IND permit for use. Under current regulation, a licensed physician must comply with the following rules if they are to use FMT without an IND permit:

    1. The licensed health care provider treating the patient obtains adequate consent from the patient or his or her legally authorized representative for the use of FMT products. The consent should include, at a minimum, a statement that the use of FMT products to treat C. difficile is investigational and a discussion of its reasonably foreseeable risks
    2. The FMT product is not obtained from a stool bank
    3. The stool donor and stool are qualified by screening and testing performed under the direction of the licensed health care provider for the purpose of providing the FMT product for treatment of the patient.

    Guideline Recommendation
    FMT is now recommended by the 2017 update as an option for second and subsequent recurrence of CDI (strong recommendation, moderate quality of evidence). It is included in the treatment algorithm along with three antibiotic options (weak recommendations, low quality of evidence). The opinion of the panel is that appropriate antibiotic treatments for at least two recurrences should be tried before performing FMT, meaning it would have to be at least the patient’s fourth episode. However, the authors note that there is no evidence to support the number of failed antibiotic therapies.

    FMT Protocol
    There are a few different delivery modalities in which FMT can be performed. To begin, a donor must provide fecal material for preparation. In 2013, several medical societies including IDSA and American College of Gastroenterology (ACG) jointly released a consensus statement for guidance on donor screening and stool testing for FMT.17 It is preferred that a donor is an intimate, long-time partner of adult patient, first-degree relative, close friend, or well-screened donor. Donor exclusion consists of the following:

    • History of antibiotic treatment during the preceding three months of donation
    • History of intrinsic gastrointestinal illness such as inflammatory bowel disease
    • History of autoimmune illness or ongoing immune modulating therapy
    • History of chronic pain syndromes such as fibromyalgia
    • Metabolic syndrome, obesity, or malnutrition
    • History of malignant illness of ongoing oncologic therapy

    Patients should also be screened for hepatitis A, B, C, HIV, and syphilis within 4 weeks of donation as well as Clostridium difficile toxin B and culture for enteric pathogens.

    Options to deliver FMT include nasogastric tube administration, nasoduodenal delivery, nasojejunal delivery, colonoscopy, retention enema, or oral capsules. Each delivery method carries a risk such as aspiration with nasogastric tube delivery or colon perforation with colonoscopy delivery. Overall, physicians should use their clinical judgment to determine the best method of administration for FMT.

    Patients must undergo preparation before FMT. While there is heterogeneity within practices, there are a few common practices in FMT protocols. The preparation considerations from OpenBiome will be discussed.18 First, it is commonly practiced to discontinue anti-CDI antibiotics 48 hours before FMT. This is to ensure the antibiotics do not impact the transferred microbiota. Next, a standard large volume bowel preparation is suggested for both upper and lower gastrointestinal delivery. There is anecdotal evidence to suggest limited bowel preparation or no preparation yields equally effective results, but evidence is lacking to support this. If a patient is receiving FMT via lower gastrointestinal delivery, loperamide is an option for prolonging fecal retention. Again, there is limited evidence to suggest superiority over no loperamide use. Finally, some clinicians will administer a proton pump inhibitor for upper gastrointestinal delivery the evening before FMT and the morning of the procedure to lessen the impact of gastric acid on the donor microbiota during FMT.

    Summary of Evidence
    Given the nature of the process, randomized controlled trials with FMT are difficult to perform. Anecdotal reporting of FMT has touted high success rates with a benign safety profile. However, most of this literature stems from case studies and retrospective reviews. There are several randomized controlled trials published regarding FMT for treatment of CDI. The first prospective trial investigating FMT was published in 2013 by van Nood et al. In this study, FMT and vancomycin were directly compared for treatment of recurrent CDI in 43 patients.19 Patients either received 14 days of oral vancomycin, vancomycin with bowel lavage, or 4 days of oral vancomycin followed by bowel lavage and subsequent FMT delivery via nasodudodenal tube. 81% of patients in the FMT group had sustained resolution of diarrhea after the first fecal infusion while 27% of patients treated with vancomycin had symptom resolution. Other trials have also been performed comparing FMT to other CDI treatment options or evaluating different FMT delivery modalities.20-23 A summary of select trials are available in Table 4 of the appendix.

    A few meta-analysis and systematic reviews have been performed to evaluate the efficacy of FMT. One was performed by Quraishi et al. finding FMT to be more effective than vancomycin in treating recurrent and refractory CDI (RR: 0.23 95%CI 0.07-0.80).24 There also was a significant difference in efficacy observed between lower gastrointestinal delivery of FMT vs upper gastrointestinal delivery 95% (95%CI 92%-97%) vs 88% (95%CI 82%-94%) respectively (P=.02). Lastly, across studies, administering consecutive courses of FMT after a failure of the first FMT was found to have an incremental effect. 

    Conclusion
    Overall, FMT has proven to be a highly effective, low risk treatment option for a serious infection. Patient acceptance of FMT has generally been well received throughout the literature. Currently, FMT is recommended to be used after antibiotics have failed to resolve CDI. The utilization of FMT is increasing in the U.S. and with this use, there are more questions that arise. Is there a place for FMT earlier in therapy? Would this therapy potentially replace the use of antibiotics to treat CDI? Which delivery method is truly most efficacious to administer FMT? With time and more studies, the use of FMT can become more optimized to improve patient care.

    References:
    1. Lessa FC, Mu Y, Bamberg WM, et al. Burden of Clostridium difficile infection in the United States. N Engl J Med. 2015; 372:825-834.
    2. Hall AJ, Curns AT, McDonald LC, et al. The roles of Clostridium difficile and norovirus among gastroenteritis-associated deaths in the United States, 1999-2007. Clin Infect Dis. 2012; 55:216-223.
    3. Dubberke ER, Olsen MA. Burden of Clostridium difficile infection on the healthcare system. Clin Infect Dis. 2012; 55(2):S88-S92.
    4. Centers for Disease Control and Prevention. Emerging Infections Program-healthcare-associated infectious projects. 2015. Available at: http://www.cdc.gov/hai/eip/index.html.
    5. McDonald LC, Gerding DN, Johnson S, et al. Clinical Practice Guidelines for Clostridium difficile Infection in Adults and Children: 2017 Update by the Infectious Diseases Society for America (IDSA) and Society of Healthcare Epidemiology of America (SHEA). Clin Microbiol Infect. 2018; XX (00): 1–48.
    6. 6. Cohen SH, Gerding DN, Johnson S, et al. Clinical Practice Guidelines for Clostridium difficile Infection in Adults and Children: 2010 Update by the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA). Infect Control Hosp Epidemiol. 2010; 31(5):431-455.
    7. Aguado JM, Anttila VJ, Galperine T, et al. Highlighting clinical needs in Clostridium difficile infection: the views of European healthcare professionals at the front line. J Hosp Infect. 2015; 90:117-125.
    8. McFarland LV, Elmer GW, Surawicz CM. Breaking the cycle: treatment strategies for 163 cases of recurrent Clostridium difficile disease. Am J Gastroenterol. 2002; 97:1769–1775.
    9. See I, Mu Y, Cohen J, et al. NAP1 strain type predicts outcomes from Clostridium difficile infection. Clin Infect Dis. 2014; 58(10):1394-1400.
    10. Wenisch C, Parschalk B, Hasenhündl M, et al. Comparison of vancomycin, teicoplanin, metronidazole, and fusidic acid for the treatment of Clostridium difficile-associated diarrhea. Clin Infect Dis. 1996; 22:813–818.
    11. Johnson S, Louie TJ, Gerding DN, et al. Vancomycin, metronidazole, or tolevamer for Clostridium difficile infection: results from two multinational, randomized, controlled trials. Clin Infect Dis 2014; 59:345–54
    12. Mullane, K. Fidaxomicin in Clostridium difficile infection: latest evidence and clinical guidance. Ther Adv Chronic Dis. 2014; 5(2):69-84.
    13. Louie TJ, Miller MA, Mullane KM, et al. Fidaxomicin versus vancomycin for Clostridium difficile infection. N Enlg J Med. 2011; 364:422-431.
    14. Cornely OA, Crook DW, Esposito R, et al. Fidaxomicin versus vancomycin for infection with Clostridium difficile in Europe, Canada, and the USA: a double-blind, non-inferiority, randomised controlled trial. Lancet Infect Dis. 2012; 12:281-289.
    15. Qin J, Li R, Raes J, et al. A human gut microbial gene catalogue established by metagenomics sequencing. Nature. 2010; 464(7285):59.
    16. Chang JY, Antonopoulos DA, Kalra A, et al. Decreased diversity of the fecal Microbiome in recurrent Clostridium difficile-associated diarrhea. J Infect Dis. 2008; 197(3):435.
    17. Relman D, Vender RJ, Rustgi AK, Wang KK, Bousvaros A. 2013. Current consensus guidance on donor screening and stool testing for FMT. American Gastroenterological Association, Bethesda, MD. https://www.gastro.org/research/Joint_Society_FMT_Guidance.pdf.
    18. Kassam Z. OpenBiome. Clinical primer: position statement for fecal microbiota transplantation administration for recurrent clostridium difficile infection. Available at https://static1.squarespace.com/static/50e0c29ae4b0a05702af7e6a/t/5807a4cd1b631b90a05c911f/1476895949876/Clinical+Primer.pdf
    19. Van Nood E, Vrieze A, Nieuwdorp M, et al. Duodenal infusion of donor feces for recurrent Clostridium difficile. N Engl J Med. 2013; 368:407–415.
    20. Cammarota G, Masucci L, Ianiro G, et al. Randomised clinical trial: faecal microbiota transplantation by colonoscopy vs. vancomycin for the treatment of recurrent Clostridium difficile infection. Aliment Pharmacol Ther. 2015; 41:835–843.
    21. Youngster I, Sauk J, Pindar C, et al. Fecal microbiota transplant for relapsing Clostridium difficile infection using a frozen inoculum from unrelated donors: a randomized, open-label, controlled pilot study. Clin Infect Dis. 2014; 58:1515–1522.
    22. Lee CH, Steiner T, Petrof EO, et al. Frozen vs fresh fecal microbiota transplantation and clinical resolution of diarrhea in patients with recurrent Clostridium difficile infection: a randomized clinical trial. JAMA. 2016; 315:142–149.
    23. Kelly CR, Khoruts A, Staley C, et al. Effect of fecal microbiota transplantation on recurrence in multiply recurrent Clostridium difficile infection: a randomized trial. Ann Intern Med. 2016; 165:609–16.
    24. Quraishi MN, Widlak M, Bhala N, et al. Systematic review with meta-analysis: the efficacy of faecal microbiota transplantation for the treatment of recurrent and refractory clostridium difficile infection. Aliment Pharmacol Ther. 2017;46(5):479 – 493.

    Appendix

    Table 1. IDSA/SHEA Treatment Recommendations for Initial Episode of CDI in Adultsa

    Table 2. Comparison of Fidaxomicin versus Vancomycin for Treatment of CDI

    Table 3. IDSA/SHEA Treatment Recommendations for Recurrent Episode of CDI in Adultsb

    Table 4. Studies Evaluating Efficacy of FMT for CDI




  • 16 Sep 2018 9:54 PM | Anonymous

    Marijuana in Missouri-What Missouri Pharmacists Should Know
    Authors: Sierra Richard, PharmD Candidate, Sarah Cox, PharmD, MS and Mary Durham, PharmD, MS, BCPS

    Epidiolex
    On June 25, 2018, the Food and Drug Administration (FDA) approved the first drug containing a “purified drug substance derived from marijuana”, Epidiolex. This new medication differs from medications such as dronabinol and nabilone that are synthetic derivatives of marijuana based on how the medication is manufactured.1 Epidiolex is a cannabidiol oral solution approved for the treatment of two forms of epilepsy, Lennox-Gastaut syndrome and Dravet syndrome, in patients two year of age and older. Both syndromes occur early in childhood and pediatric pharmacists and community pharmacists may start seeing prescriptions for Epidiolex in this population soon. At the time of approval, Epidiolex is the only FDA approved medication for Dravet syndrome giving this population a proven treatment option for the first time.2 However, another medication for the treatment of Dravet Syndrome, Diacomit (stiripentol) was approved by the FDA on August 20, 2018 which may influence the use of Epidiolex in practice.3

    Legal Challenges
    Dispensing this medication may come with legal questions. First, cannabidiol (CBD) is a schedule I substance under the Controlled Substances Act. Since Epidiolex was approved, the Drug Enforcement Agency (DEA) has ninety days from the time of FDA approval to reconsider the schedule of CBD to legally allow Epidolex to be administered.2 The ninety-day deadline is September 23, 2018. At the time of writing, no statements regarding the marijuana rescheduling process have been published. Additionally, Missouri state law restricts the use of CBD oil. Under current state regulations, patients who have an intractable epilepsy may be approved for a Missouri Hemp Extract Registration Card after receiving a signed statement from a licensed Missouri neurologist indicating that the patient may benefit from the hemp extract treatment. This waver allows patients who are 18 year or older, or the parent or legal guardian of a minor to legally possess more than twenty ounces of CBD oil containing less than 0.3% tetrahydrocannabinol [THC] (the psychoactive component of cannabis). There are two licensed facilities in Missouri that can dispense CBD oil. The Missouri Hemp Extract Registration card is valid for one year and may be renewed by the neurologist annually. Since the program’s inauguration in 2014, 331 cards have been issued and 148 remain active. Of the currently active cards, 125 are for the treatment of minors.4

    In December of 2016 the DEA established a new drug code for marijuana extract which would improve tracking of these products. However, in their statement, they reinforced that extracts of marijuana were still classified as a schedule I controlled substance.5 Prior to this, the part of the marijuana plant that hemp was extracted from (the stalk) was excluded from the Controlled Substance Act definition of marijuana.6 Despite these regulations, many stores in Missouri cities, including Columbia, have started selling cannabis extract without a Missouri Hemp Extract Registration Card or any medical oversight.7

    Legal challenges surrounding possession of Epidiolex2 or other CBD4 oil products may bring new complexities in the care of institutionalized patients. Current regulatory status should be considered when assessing the addition of a CBD oil product to the pharmacy formulary, or developing a protocol to accommodate dispensation of a patient’s home therapy. Every step in the medication use process should be assessed, taking into account high risk points for diversion including procurement and storage, unit dose dispensation of an oral liquid controlled substance, administration, documentation, and waste. Understanding the legality of CBD possession by specific patients4 is paramount to maintaining compliance with current state and federal regulations; this may dictate the fine line between whether a patient has a product lawfully or illicitly, and the role of the pharmacist to facilitate access to safe and appropriate therapy.

    Pros and Cons of Medical Marijuana
    Research conducted regarding medical marijuana has shown that it can help reduce pain and nausea for patients suffering from cancer and other illnesses in addition to reducing the number of seizures in patients who are refractory to other treatment options.8 Additionally, a study published in the August 2014 edition of JAMA Internal Medicine found that states with legalized medical marijuana had decreased opioid related deaths compared to states where it was not legal between 1999 and 2010.9

    However, concerns arise on the long-term effects of marijuana. Reduced regulations likely would lead to increased access to minors. Current research has shown that chronic marijuana use by pre-adolescents and those in their early 20s can lead to a diminished IQ, increased risk of dropping out of school, and increased risk of respiratory problems. Furthermore, there is mixed evidence on the safety of operating a motor vehicle after using marijuana. This becomes increasingly difficult to determine as the metabolites of marijuana remain in the body for days to weeks after use. 8


    What does this mean for Missouri pharmacists?
    Currently, Missouri pharmacies can legally dispense synthetic THC derivatives such as dronabinol and nabilone given that they are classified as schedule III and schedule II medications, respectively. However, with the FDA approval of Epidiolex it is possible that the DEA schedule of marijuana could change. In addition, there are will be three initiatives supporting medical marijuana legalization on the Missouri ballots in November10. If legislative changes occur, institutions may need to consider updating policies regarding the handling of CBD oil.


    Resources:

    1. marinol.com [Internet]. North Chicago (IL): AbbVie Inc.; c2017 [cited 2018 Sep 2]. Available from: http://www.marinol.com/hcp/differences-from-medical-marijuana

    2. fda.gov [Internet]. Silver Spring (MD): U.S. Food and Drug Administration; c2018 [cited 2018 Sep 2]. Available from: https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm611046.htm

    3. fda.gov [Internet]. Silver Spring (MD): U.S. Food and Drug Administration; c2018 [cited 2018 Sep 2]. Available from: https://www.fda.gov/Drugs/InformationOnDrugs/ucm618455.htm

    4. health.mo.gov [Internet]. Jefferson City (MO): Missouri Department of Health & Senior Services; c2014 [updated 2018 June 30; cited 2018 Sep 2]. Available from: https://health.mo.gov/about/proposedrules/hempextract.php

    5. gpo.gov [Internet]. Springfield (VA): U.S. Department of Justice Drug Enforcement Administration; c2016 [cited 2018 Sep 2]. Available from: https://www.gpo.gov/fdsys/pkg/FR-2016-12-14/pdf/2016-29941.pdf?utm_campaign=subscription%20mailing%20list&utm_source=federalregister.gov&utm_medium=email

    6. deadivision.usdoj.gov [Internet]. Springfield (VA): U.S. Department of Justice Drug Enforcement Administration; c1990 [cited 2018 Sep 2]. Available from: https://www.deadiversion.usdoj.gov/21cfr/21usc/802.htm

    7. columbiatribune.com [Internet]. Columbia (MO): Columbia Tribune; c2017 [cited 2018 Sep 2]. Available from: http://www.columbiatribune.com/news/20171223/stores-sell-cannabis-extract-despite-state-regulations

    8. health.usnews.com [Internet]. Washington, D.C.: U.S. News & World Report; [cited 2018 Sep 2]. Available from: https://health.usnews.com/health-news/patient-advice/articles/2016-10-12/marijuanas-public-health-pros-and-cons

    9. Bachhuber M. Medical Cannabis Laws and Opioid Analgesic Overdose Mortality in the United States, 1999-2010. JAMA Intern Med [Internet]. 2014 [cited 2018 Sep 2]; 174(10): 1668-1673. Available from: https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/1898878

    10. www.sos.mo.gov [internet]. Jefferson City (MO): Missouri Secretary of State; [cited 2018 Sep 9]. Available from: https://www.sos.mo.gov/default.aspx?PageId=9456


  • 08 Aug 2018 11:06 AM | Anonymous

    UMKC School of Pharmacy

    As usual, we have been very busy at the UMKC School of Pharmacy!  While it would be impossible here to describe all that has been going on, I would like provide a brief update on recent activities at the school.

    UMKC School of Pharmacy at MSU:  After six years of hard work by UMKC and MSU faculty and staff, as well as support from the state of Missouri and many hard-working legislators, we have come through on our promise to provide pharmacy education in Southwest Missouri.  Our first cohort of 31 students graduated from our Springfield location in May.  Prior to graduation, most of the students had secured jobs in and around Southwest Missouri.  This group of outstanding students included many who would not have been able to pack up and move to our sites in Kansas City or Columbia in order to attend pharmacy school.  Special thanks go to all who made this happen, but especially our friends and colleagues at Missouri State University.  President Clif Smart and Provost Frank Einhellig and all of the folks there who worked with us to make dreams come true.

    “APhA-ASP National Champions”.  If ESPN would cover pharmacy student competitions, then the entire country, even those outside the pharmacy world, would know the dominance of the UMKC chapter of the American Pharmacists Association-Academy of Student Pharmacists (APhA-ASP)!  This year, our chapter was once again recognized as the number one chapter in the country!  This is the second time since 2012 that our chapter has been recognized by APhA as the number one chapter, and every year in between they have been among the top seven or four chapters in the nation.  Our students are clearly having a huge impact on the health and wellness of people in our country, and especially throughout central and southwestern Missouri as well as the Kansas City area.  We are proud that they continue to bring such positive national attention to UMKC.  We also had national APhA awards provided to individual UMKC student pharmacists including:  Sara Massey (Class of 2018) received the John A. Gans Scholarship from the APhA Foundation; Sierra Woods (Class of 2019) received the APhA Good Government Student Pharmacist of the Year.

    Outstanding Faculty Advisors.  I often get asked by other deans of pharmacy around the country about the keys to the success of our student chapter of APhA-ASP, and the answer is simple:  it’s clearly the outstanding faculty advisors they have.  Special thanks go to the mentorship provided by Drs. Kelly Cochran, Kathryn Holt, Lisa Cillessen, Angela Brownfield, Sarah Cox, Heather Taylor, Andrew Bzowyckyj, and Cameron Lindsey.  All of these faculty are well-known nationally for leading our students, but we are particularly pleased that Dr. Valerie Ruehter received the APhA-ASP Outstanding Chapter Advisor Award—the top advisor in the country!

    Other National Student Awards.  Our students received many other national awards.  Marian Lyford (Class of 2018) was recognized by the United States Public Health Service with the 2018 Excellence in Public Health Pharmacy Award.  Also, Dion Tyler (Class of 2018) and his interprofessional team of health care student finished 3rd at the annual CLARION National Competition at the University of Minnesota.

    Faculty and Staff Focus on Student Success!  While we are absolutely elated that our students rake in all the national awards, the truth is their greatest accomplishment is graduation.  For that ultimate measure of student success, we are forever grateful for the hard work and dedication of our staff and faculty.  We are also proud of our student success numbers where 94.4 % of the students who entered our program in 2014 graduated on time in 2018.  While we do not yet have NAPLEX pass rates from them, we do know that for 2017 graduates—97.5 % of whom graduated on time—92% passed the NAPLEX on first sitting.

    Faculty Accolades.  Many of our faculty have received substantial accolades in the last year, far too many to list all here.  Among our clinical faculty, some of the accomplishments included:  Dr. Andy Smith was named a Fellow of the American College of Clinical Pharmacy; Dr. Heather Taylor became a Board-Certified Pharmacotherapy Specialist; Dr. Heather Lyons-Burney was named MPA Faculty Member of the Year and received the Jefferson Award, a national program started by Jacqueline Kennedy in 1972 that honors everyday heroes in our community; Dr. Paul Gubbins published a book as Editor entitled Drug Interactions in Infectious Disease: Mechanisms and Models of Drug Interactions, 4th Ed.; Dr. Maureen Knell co-authored a publication in Pain Medicine this year that is receiving significant attention locally and nationally for understanding opioid prescribing patterns; Drs. Angela Brownfield, Paul Gubbins, and Valerie Ruehter received the Award for Excellence in Scholarship in Experiential Education from the American Association of Colleges of Pharmacy; and Dr. Kendall Guthrie was elected to serve on the Board of Directors of the MPA.

    There are many other great accomplishments of our students faculty in the past year.  If you can make time to come by and see us, we’d be happy to tell you all about it.  You are all welcome to visit the school anytime at our sites in Kansas City, Columbia, and/or Springfield.  We also appreciate your assistance in identifying any students who might be interested in pursuing pharmacy careers.  Just let us know, we love to talk to anyone about our great profession! 

    Best wishes to everyone in MSHP!

    Russell B. Melchert, Ph.D.
    Dean of Pharmacy and Professor


  • 23 Jul 2018 10:39 AM | Anonymous

    UMKC School of Pharmacy - SSHP

    Authors:  Anna Parker and Jordyn Williams, UMKC SSHP Chapter Presidents

    The spring and summer semesters at the UMKC School of Pharmacy are a little more relaxed than our fall semester. In February, our Columbia campus teamed up with MMSHP and the Ronald McDonald House to prepare meals for patients and families receiving care at the Women and Children's Hospital. It was a great time serving the local community through the event.  The Columbia campus also participated in a pull tab collection competition with local hospitals to raise money for the Ronald McDonald House.  All together, they were able to collect over 30 pounds of pull tabs.  Aside from that, we held our monthly general meetings during the spring semester with visiting speakers to share their experiences working as health-system pharmacists. Dr. Rachel Howland from Truman Medical Center visited during one of our last meetings and presented a very unique patient case. All of the attendees enjoyed hearing how Dr. Howland handled the case with her healthcare team and was able to provide appropriate pharmacological care.  The meeting and case presentation helped show students the vital role a clinical pharmacist can play in patient care.

    This summer the SSHP executive team is busy gearing up for our main events that happen in the fall semester. Residency program directors should be on the lookout for their invitation to attend Residency Roundtable, which will take place on September 29th at each UMKC campus. Our Clinical Skills Competition and membership drive will also be taking place this coming fall.

    The Kansas City campus would like to extend a warm welcome to Dr. Jeremy Hampton, who will be serving as our new advisor this year. We would also like to thank Dr. Tatum Mead and Dr. Stephanie Schauner for their time serving as advisors in Kansas City. We are thankful for your involvement with SSHP and wish you the best! All three campuses are excited to start the new school year in August and are ready to see our chapter grow, serve, and learn.


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