North Carolina Pharmacist Volume 101 Number 2 Spring 2020
Advancing Pharmacy. Improving Health.
NCAP Virtual Legislative Week July 20th-24th See inside for details!
Official Journal of the North Carolina Association of Pharmacists ncpharmacists.org
Official Journal of the North Carolina Association of Pharmacists 1101 Slater Road, Suite 110 Durham, NC 27703 Phone: (984) 439-1646 Fax: (984) 439-1649
www.ncpharmacists.org EDITOR-IN-CHIEF Tina Thornhill LAYOUT/DESIGN Rhonda Horner-Davis EDITORIAL BOARD MEMBERS Anna Armstrong Jamie Brown Lisa Dinkins Jean Douglas Brock Harris Amy Holmes John Kessler Angela Livingood Bill Taylor
BOARD OF DIRECTORS EXECUTIVE DIRECTOR Penny Shelton PRESIDENT Dave Phillips PRESIDENT-ELECT Beth Mills PAST PRESIDENT Debra Kemp TREASURER Thomas D’Andrea
North Carolina Pharmacist Volume 101 Number 2
Spring 2020
Inside • From the President .....................................................................................3 • Important Legislative Week Information............................................................4 • North Carolina Pharmacists Weigh-in On the Pandemic..........................................6 • Migraine Headaches...........................................................................................11 • Pharmacy Guided Procalcitonin Ordering.............................................................21 • Ambulatory Care Academy Member Spotlight.....................................................28
Check us out. Click here! North Carolina Pharmacist is supported in part by:
SECRETARY Matthew Kelm
• Pharmacists Mutual Companies ...........................................................5
BOARD MEMBERS
• EPIC Pharmacies Inc ...........................................................................7
Brianna Berish Courtney Bradley Shannon Brown Ouita Gatton Ryan Mills Holly Nunn Ann Marie Nye Vinay Patel Jennifer Wilson North Carolina Pharmacist (ISSN 0528-1725) is the official journal of the North Carolina Association of Pharmacists. An electronic version is published quarterly. The journal is provided to NCAP members through allocation of annual dues. Opinions expressed in North Carolina Pharmacist are not necessarily official positions or policies of the Association. Publication of an advertisement does not represent an endorsement. Nothing in this publication may be reproduced in any manner, either whole or in part, without specific written permission of the publisher.
• Pharmacy Technician Certification Board ..........................................10 • NCAP Career Center ..........................................................................20 • Pharmacy Quality Commitment ........................................................30
ADVERTISING For rates and deadline information, please contact Rhonda Horner-Davis at rhonda@ncpharmacists.org
•From the President • David C. Phillips, PharmD, BCPS
As we reflect on the first half of the year, we realize our attention has largely been divided. On the 2020 – A Year for CHANGE one hand, COVID feels like part of a new normal. We continue to feel humbled by all the unknown and the rising numbers of cases Leslie Dwight, an aspiring writer, and hospitalizations in our state. penned the following poem and On the other hand, we are largely shared it on social media on June focused on issues raised by recent 3rd: killings, the Black Lives Matter movement, and the implications “What if 2020 isn’t cancelled? for us as individuals and as a profession. NCAP stands united with What if 2020 is the year we’ve national pharmacy organizations, been waiting for? and the pharmacy profession as a whole, to fight against the inA year so uncomfortable, so painequities and racism plaguing our ful, so scary, so raw — that it finalcountry! To learn more about ly forces us to grow. what NCAP and pharmacy organizations across the country are A year that screams so loud, finaldoing and the actions they are ly awakening us from our ignotaking to fight racism, click here to rant slumber. read the full statement. A year we finally accept the need for change. Declare change. Work for change. Become the change. A year we finally band together, instead of pushing each other further apart.
2020 isn’t cancelled, but rather the most important year of them all.” So, what if 2020 is not cancelled? What if 2020 is a year for significant change?
kit click here. NCAP has launched a new legislative and government affairs homepage to organize all our advocacy work in one place. Click here to check out the new homepage.
Do not forget to save the date for the 2020 NCAP Annual Convention that will be held at the Benton Convention Center in Winston-Salem on October 29th and 30th. The theme for this year’s convention is public health and NCAP will be celebrating its 20th anniversary. Stay tuned for more details!
Finally, I would like to take a moment to recognize the Class of 2020. Congratulations on successfully graduating from your respective pharmacy school or residency program. You put in numerous hours of hard work and your final year of education was unlike any other. You should be very proud of your achievements. Good luck on all your future endeavors! Please know that NCAP is here to support you, and we would be honored to have you join us in strengthening our voice. Make 2020 your year and “be the change you want to see in the world.” (Mahatma Gandhi)
In a continued effort to keep you informed and up-to-date, NCAP has been hard at work to develop and provide numerous resources and tools for our members. On June 12th, a COVID-19 Testing Toolkit was released. This toolkit, developed by the NCAP COVID-19 work group in partnership with Campbell University College of Pharmacy & Health Sciences, serves as a resource for NC phar- David C. Phillips, PharmD, BCPS macists to get the latest updates on COVID-19. To access the toolPage 3
Join us for the 2020 NCAP Virtual Legislative Week July 20th-24th Please take advantage of this opportunity to meet virtually with key members of our General Assembly to educate policymakers about issues affecting our profession. With the unprecedented response from our legislators, we cannot emphasize enough how important your voice and engagement are to this week-long event’s success. To show your support, register at ncpharmacists.org or click here. You will find a list of General Assembly members with confirmed meeting dates and times as well as valuable information, including talking points to navigate an efficient and successful discussion with your chosen representative(s). In preparation for our discussion with legislators, Tony Solari, our NCAP Lobbyist, will host a virtual meeting on July 16th, 2020, at 7 pm. Click here to join the meeting or return to the registration page for a link to the recorded session after the meeting.
Page 4
North Carolina Pharmacists Weigh-in On the Pandemic By: Dr. Kecia Missos
nicians found themselves on the frontlines helping patients navigate new virtual complexities of health care imposed by stayat-home orders, while continuing to provide safe and effective medicines, as well as serving as a source of reliable information, and a degree of calm in the wake of much uncertainty. Hospital pharmacists and technicians were challenged to provide new and creative ways for providing patient care in the face of both personal protective equipment and critical drug shortages. Suddenly pharmacy personnel found themselves amid the pandemic working harder than ever on behalf of their patients. For many, it was a frantic pace with new workPharmacists have always been es- flows and numerous additional sential healthcare providers, but stressors. NCAP wanted to gain during the COVID-19 pandemic, insight from those serving on the pharmacists and pharmacy tech- frontlines in order to improve our The North Carolina Association of Pharmacists (NCAP) created an online COVID-19 Resource to provide pharmacists with up-to-date state and federal guidance, as well as general practice information. In addition to the COVID-19 Resource, NCAP also created an online portal for pharmacies to request volunteer help during the pandemic. Then in mid-April 2020, at the height of the pandemic upswing in our state, NCAP asked pharmacists to participate in a short survey to assess their unique perspectives on the challenges faced, as well as the impact of the virus on their practice, personal well-being, and their patients.
Page 6
services and to better advocate for the profession.
Survey respondents were asked to share the first three COVID-19 mitigation strategies employed in their practice as well as the greatest challenge and lessons learned. Respondents were also asked to reflect on how the pandemic had impacted them personally. Participants were asked to state where they obtained pandemic information and what they believed the role of NCAP should be in times like these. Finally, respondents were asked to share their perspective on the role of pharmacists in COVID testing and vaccine administration. (See Figure 1: Survey Questions).
The questionnaire was shared with NCAP members and as of the end of April 2020, 79 individuals
the authority to: (Multiple choice, yes-no-unsure) o Collect patient test samples (antigen) for COVID-19 to be sent to state-approved labs o Conduct rapid point-ofcare testing (antigen) for COVID-19 o Collect patient samples (antibodies) for COVID-19 to be sent to state-approved labs o Conduct rapid point-ofcare testing (antibodies) for COVID-19 o Administer COVID-19 immunization for adults o Administer COVID-19 immunization for children
practice? (Open-ended, text) had completed the survey. Respondents’ answers for open-end- 2. What has been the greatest challenge for your practice ed questions were categorized by during this state of emergency? subject. Common responses are (Open-ended, text) summarized in infographic in3. How has this pandemic affected formation, entitled “Pharmacists’ you personally? (Open-ended, COVID-19 Perspective” found on text) page 8. 4. What is one lesson learned Author: At the time of this project, Dr. Missos was a P4-student at Campbell University College of Pharmacy & Health Sciences and was conducting an Advanced Pharmacy Practice Experience with the North Carolina Association of Pharmacists. kmkosins0315@email.campbell.edu Figure 1: Survey Questions 1. What were the first three COVID-19 mitigating strategies that were implemented in your
5.
6. 7.
8.
during this pandemic that will impact how you prepare for future states of emergency? (Open-ended, text) Have you used the NCAP COVID-19 Information Resource Webpage? (Multiple choice, yesno-unsure) How have you stayed informed and up to date during this pandemic? (Open-ended, text) What roles do you believe NCAP should serve that would be most helpful during declared states of emergency? (Open-ended, text) Once available, do you believe pharmacists should be granted
We Deliver Solutions for a Healthier Bottom Line EPIC Pharmacies, Inc. provides more than 1,500 independent member pharmacies across the U.S. with the group buying power and managed care solutions essential to delivering quality patient care. Membership offers: • Group volume purchasing power • Aggressive wholesaler pricing programs • Profits distributed to members at year-end • EPIC Pharmacy Network, Inc. (EPN) membership fee included at no cost – access to third-party contracts • Clinical services tools, including expert assistance from our in-house pharmacist and access to custom PrescribeWellness offerings and EQuIPP •
PUT THE POWER OF A NETWORK BEHIND YOU
– free third-party claims reconciliation program and automated reimbursements below cost system
•
800-965-EPIC | EPICRX.COM Page 7
– Web-based solution for pharmacy regulatory and compliance management
TM
Pharmacists' COVID-19 Perspective Information 7.3%
Other 13%
Management/Workflow 17.9%
Social Distancing 9.8%
Greatest Challenges
Remote Work/Telehealth 13%
Morale 13%
Shortages 16.3% Patient-Related Issues 9.8%
5
Social distance requires numerous changes to the physical layout of the pharmacy and the services provided. Pharmacists also reported feeling isolated from friends at family.
2
Medication & PPE shortages were also cited as a major challenge. Many pharmacists reported purchasing inventory early on to mitigate the projected drug and PPE shortages.
6
Patient interactions are not only limited by a physical distance and difficulties with telehealth, but misinformation or lack of understanding can lead to unsafe interactions with patients.
3
Working remotely, virtual learning environments, and transitioning to telehealth platforms is a challenge across the field. Engagement with providers, patiemts, and students is reported as more difficult.
7
Information credibility and dissemination remains a major concern, and pharmacists reported struggling to keep up with uncertainty, constantly changing policies, and investigating new innovations.
4
As the leader in the pharmacy, many active pharmacists have felt the burden of maintaining workforce morale and managing increased anxiety of not only themselves, but their coworkers as well.
8
Pharmacists also face many other challenges that have not been mentioned, including financial strain and lack of billing protocols for the new services they are required to provide.
1
Time management & workflow management were among the most commonly reported challenges that North Carolina pharmacists are facing during the COVID-19 Pandemic.
Pharmacists are looking for ways to get involved
67%
Believe pharmacists should collect patient specimens to be sent to state-approved COVID19 labs
77%
Believe pharmacists should conduct rapid point-of-care testing for COVID-19 antigen or antibodies
99%
Believe pharmacists should be authorized to administer the COVID-19 immunization to adults (78% also believe pharmacists should administer to children)
All active pharmacists have experienced numerous changes and unique challenges due to the current coronavirus pandemic. This information was gathered by NCAP to provide insight into the pharmacists' perspective. Page 8
COMMON INTERVENTIONS IMPLEMENTED
Use of PPE & additional sanitizing measures
Daily employee screening of temperature & symptoms
Drive-thru, curbside pick-up, & delivery offered instead of walk-in services
Telehealth, virtual visits and working remotely when feasible
SURVEY RESPONDENTS' AREA OF PRACTICE Community Hospital Clinic Long-Term Care Academia Other 0
10
20
30
Pharmacy student classwork has transitions to remote learning & APPE rotations have been modified to reduce exposure and eliminate risk when possible.
PERSONAL IMPACT OF COVID-19 ON PHARMACISTS
Work-related stress from increased hours and overall workload
Social isolation due to quarantine and stayat-home orders
Financial stress of cut hours, reduced income, retirement losses, or other costs
Anxiety and other mental health-related issues
Your safety and the safety of your patients is our highest priority! NCAP will continue working to further the profession of pharmacy and provide the best possible information. Page 9
Migraine Headaches:
A Pharmacotherapy Update By: Dr. Kaitlyn Gibson Introduction
Migraine is a neurological disorder that results in headache attacks characterized by moderate to severe pain. These headaches have a complex pathophysiology with involvement of various neural networks. The pain from an attack is thought to be caused by activation of trigeminal sensory pathways which innervate various intracranial structures, such as the eyes. 1 The typical course of a migraine attack consists of a premonitory phase (in which some individuals may experience aura, which are reversible neurological symptoms), the headache, and a headache resolution phase. Attacks may last anywhere from 4 to 72 hours, during which time many individuals experience disabling symptoms. Among the most common symptoms are
photophobia, phonophobia, and gastrointestinal symptoms such as nausea and vomiting; however, individuals can experience a wide variety of other symptoms unique to their migraine attacks.1 In the 2012 National Health Interview Survey, 14.2% of adults in the United States reported a migraine in the previous 3 months.2 Migraines are most prevalent in the those who are 18- to 44-years, with females being more affected than males (19.1% vs 9.0% over a 3-month period).2 Individuals that experience migraine are significantly impacted both physically and financially. Most patients experience some level of functional disability during an attack due to extreme light, sound, touch, or smell sensitivity, visual disturbances, nausea or vomiting, Page 11
or tingling or numbness in the face or extremities.3 In the International Burden of Migraine Study (IBMS), 79.8% of patients reported severe to very severe disability due to their migraines. The estimated cost over a 3-month period for the treatment of migraine (not including indirect costs) is around $1,000.4 This is a huge financial burden to patients and can include visits to providers or emergency departments, diagnostic testing, and medications.4 In a study published in 2017, 7,671 patients of 857,073 required 2 or more emergency department visits for their migraine and 185,911 saw a neurologist.5 Treatment recommendations vary depending if an individual is being treated for an acute migraine attack or is taking pre-
ventative medications. The 2000 US Headache Consortium guidelines for acute treatment of migraine list triptans as a first-line treatment, with other options with proven clinical benefit being ergotamine derivatives, aspirin, NSAIDs such as ibuprofen and naproxen, and combination products such as acetaminophen/aspirin/caffeine.6 In the 2012 guideline update for episodic migraine prevention, preferred agents are antiepileptics such as divalproex and topiramate, beta-blockers such as metoprolol and propranolol, and frovatriptan. Other options that can be considered are antidepressants such as amitriptyline and venlafaxine, other beta-blockers such as atenolol and nadolol, and other triptans such as naratriptan and zolmitriptan.7 Treatment options for both acute management and prevention should be tailored based on patient-specific factors. Since the most recent guideline update, there have been several new classes of medications that have been approved for both acute treatment and prevention. The objective of this review is to evaluate new drug classes for acute treatment or prevention of migraine, examine the evidence supporting their use, and discuss potential future roles in therapy.
New Therapies in Acute Management
Triptans exert their effects via serotonin (5-HT) receptors with a high affinity for 5-HT1B and 5-HT1D. 5-HT1B receptors located on the blood vessels of smooth muscle cells cause
cranial vasoconstriction, while 5-HT1D receptors are in trigeminal nerve terminals and dorsal horn. 5 It is believed that stimulation of these receptors block release of vasoactive peptides and neurotransmitters that convey information to the thalamus leading to a decrease in pain sensation. Due to vasoconstriction, triptans are contraindicated in patients with previous stroke or myocardial infarction, uncontrolled hypertension or ischemic heart disease.5,8 New therapies target two other receptors, 5-HT1F and calcitonin gene-related peptide. Patients with a contraindication to a triptan with a higher affinity for 5-HT1B and 5-HT1D, may be able to try one of the novel agents since neither of these newer agents cause vasoconstriction.9-11 Serotonin 5-HT1F Receptor Agonist
Lasmiditan (Reyvow) was approved by the FDA in October 2019 for the acute treatment of migraine with or without aura as a Class V controlled substance. It is the first of a new group of headache medicines called the “ditans.�9
Lasmiditan is available in 50 mg and 100 mg tablets. Recommended dosing is 50, 100, or 200 mg orally as needed with no more than one dose taken within a 24-hour period. Unlike triptans, a second dose has not been shown to be effective for the same migraine attack. Dose adjustment in the presence of rePage 12
nal or hepatic impairment is not required. Dizziness is the most common adverse event and appears to be dose-related (9% in 50 mg, 15% in 100 mg, 17% in 200 mg).9 Lasmiditan may also cause driving impairment and CNS depression; therefore, patients should be counseled not to drive until they determine how the medication may affect them. 9 In a phase 3, randomized, double-blinded, placebo-controlled study, lasmiditan was evaluated for efficacy and safety. This research involved 1,856 adults with a diagnosis of migraine for at least 1 year prior to study initiation. Patients were randomized 1:1:1 to receive a first dose of either lasmiditan 200 mg, lasmiditan 100 mg, or placebo. 12 Patients were also randomized to a second dose for rescue treatment for migraine recurrence. Patients in the 200 mg first dose group were randomized 2:1 to lasmiditan 200 mg or placebo. Patients in the 100 mg first dose group were randomized 2:1 to lasmiditan 100 mg or placebo. All patients in the placebo first dose group received placebo as a second dose. The primary efficacy endpoint was a comparison of the proportion of patients in the lasmiditan 200 mg and placebo groups who were headache pain free at 2 hours after the first dose.12 Key secondary efficacy endpoints included: a comparison in the lasmiditan 200 mg and placebo groups for absence of their most bothersome migraine symptom (either nausea, phonophobia, or photophobia) at 2 hours after the first dose; a comparison in
the lasmiditan 100 mg and placebo groups for freedom from headache pain at 2 hours after the first dose; and a comparison in the lasmiditan 100 mg and placebo groups for absence of their most bothersome migraine symptom. Results showed statistically significantly more patients in the lasmiditan 200 mg group (32.2%, p<0.001) were free from headache pain at 2 hours following the dose compared to placebo (15.3%).12 Patients in the lasmiditan 100 mg group also showed statistically significance for freedom from headache at 2 hours after the dose compared to placebo (28.2%, p<0.001). 12 Similar results were seen for absence of the most bothersome symptom, with 40.7% (p<0.001) of patients in the lasmiditan 200 mg group having freedom from their most bothersome symptom 2 hours after the dose compared to 29.5% in the placebo group. 12 40.9% (p<0.001) of patients in the lasmiditan 100 mg group showed absence of their most bothersome symptom 2 hours after the dose. The most common adverse event related to the study treatment was dizziness, with 16.3% in the lasmiditan 200 mg group, 12.5% in the lasmiditan 100 mg group, and 3.4% in the placebo group.12 In a post hoc analysis of pooled data from two phase 3 studies, SAMURAI and SPARTAN, lasmiditan was evaluated for efficacy versus placebo in treating migraine-related headache pain and most bothersome symptom.13 The use of migraine preventive treatment was allowed if the patient had been on a sta-
ble dose at least 3 months prior to screening. Between the two trials, a total of 3,891 adult patients with a diagnosis of episodic migraine with or without aura for at least 1 year were enrolled. In both trials, patients were randomized evenly into the following groups: lasmiditan 100 mg, lasmiditan 200 mg, or placebo. The SPARTAN trial added a fourth group, lasmiditan 50 mg. Patients took their assigned dose during their next migraine attack within 4 hours of pain onset. The primary efficacy outcome for both trials was the proportion of patients that were headache pain-free at 2 hours after the dose. The key secondary efficacy endpoint was the absence of the patientâ&#x20AC;&#x2122;s most bothersome symptom at 2 hours after the dose. 13 Results were similar to the previous trial; all doses of lasmiditan showed statistically significant (all p-values < 0.05) increases in the percentage of patients who were free from headache pain and had absence of their most bothersome symptom at 2 hours after the dose versus placebo. These two trials also analyzed the efficacy of lasmiditan in patients taking topiramate and propranolol for migraine prevention. Outcomes for the primary and key secondary efficacy endpoint were similar amongst patients using topiramate or propranolol versus patients not taking one of those medications (interaction p-values >0.1). 13 Rates of adverse events were also similar amongst patients using migraine preventive medication versus patients not using migraine preventive medication (14.9% vs 14.6% for dizziness, Page 13
respectively).13
Oral Calcitonin Gene-Related Peptide Receptor Antagonists
Calcitonin gene-related peptide (CGRP) is a neurotransmitter that is released during a migraine attack and promotes pain transmission in the trigeminovascular system. Oral CGRP receptor antagonists (gepants) antagonize the CGRP receptor to block the action of the neurotransmitter and thus reduce migraine-associated pain during an attack.10,14 There are currently two medications approved by the FDA in this class: ubrogepant and rimegepant. Ubrogepant
Ubrogepant (Ubrelvy) was approved in December 2019 for acute treatment of migraine with or without aura in adults. It is available in 50 mg or 100 mg oral tablets, with a recommended dose of 50 or 100 mg as needed for migraine-related headache pain. Patients may take a second dose of ubrogepant at least 2 hours after the initial dose if needed; however, patients should not exceed a total of 200 mg in a 24-hour time period. The recommended dose in severe hepatic impairment (Child-Pugh Class C) is 50 mg for the initial and second doses. Patients with severe renal impairment (CrCl 15-29 mL/min) should also take 50 mg for the initial and second dose. Patients with a CrCl < 15 mL/min should avoid the use of ubrogepant. There is also a dose adjustment for the concomitant use with some medications. Ubrogepant
should be avoided with use of a strong CYP3A4 inhibitor. With the use of moderate CYP3A4 inhibitors, the initial dose of ubrogepant should be 50 mg and a second dose should be avoided within 24 hours. The dose of ubrogepant should be reduced to 50 mg for both the initial and second dose in the presence of weak CYP3A4 inhibitors and BCRP/P-gp inhibitors. The most common adverse events seen in clinical trials, with occurrence >2% and greater than placebo, are nausea and somnolence.10
In one of the two phase 3 trials conducted for the approval of ubrogepant, a total of 1,672 adults with at least a 1-year history of migraine with or without aura were enrolled. This was a randomized, double-blind, placebo-controlled, parallel-group trial. Patients were randomized 1:1:1 to receive placebo (two tablets of placebo), ubrogepant 50 mg (one tablet of ubrogepant 50 mg and one tablet of placebo), or ubrogepant 100 mg (two tablets of ubrogepant 50 mg). Patients were also randomized for an optional second dose to either the same dose as their initial assignment or placebo. Patients initially in the placebo group also received placebo for the second dose. The coprimary efficacy endpoints were freedom from headache pain and absence of the most bothersome symptom (photophobia, phonophobia, or nausea) at 2 hours after the initial dose. Secondary efficacy endpoints included pain relief at 2 hours after the initial dose, sustained pain relief 2 to 24 hours after the initial dose, freedom from pain 2 to 24
hours after the initial dose, and absence of photophobia, phonophobia, and nausea at 2 hours after the initial dose. Results showed a statistically significant difference versus placebo for the coprimary endpoints for both ubrogepant groups. 11.8% of patients in the placebo group experienced freedom from pain 2 hours after the first dose, compared to 19.2% (P=0.002) in the ubrogepant 50 mg group and 21.2% (P<0.001) in the ubrogepant 100 mg group. Absence of the most bothersome symptom 2 hours after the first dose occurred in 27.8% of patients in the placebo group, compared to 38.6% (P=0.002) in the ubrogepant 50 mg group and 37.7% (P=0.002) in the ubrogepant 100 mg group. Rates of adverse events seem to be dose-related and no patients discontinued the study due to adverse events. Nausea occurred in 1.6% of patients in the placebo group, 1.7% in the ubrogepant 50 mg group, and 4.1% in the ubrogepant 100 mg group. Somnolence occurred in 0.8% of patients in the placebo group, 0.6% in the ubrogepant 50 mg group, and 2.5% in the ubrogepant 100 mg group (no P-values provided).14 Rimegepant
Rimegepant (Nurtec ODT) was approved in February 2020 for the acute treatment of migraine with or without aura in adults.11 It is available as a 75 mg orally disintegrating tablet (ODT), with a recommended dose of 75 mg as needed for migraine-related headache. The maximum dose in a 24-hour period is 75 mg.11 Patients with severe hepatic impairPage 14
ment (Child-Pugh Class C) should not take rimegepant. Concomitant administration with strong CYP3A4 inhibitors, moderate to strong CYP3A inducers, and P-gp or BCRP inhibitors should be avoided. If a patient is also taking a moderate CYP3A4 inhibitor, no more than 1 dose of rimegepant should be administered in a 48-hour period. Severe hypersensitivity reactions, including dyspnea and rash have occurred up to days after administration of rimegepant. Nausea was the most common adverse event reported in clinical trials (â&#x2030;Ľ 1%).11
In the trial conducted for FDA approval of the ODT formulation of rimegepant, a total of 1,466 adults with at least a 1-year history of migraine with or without aura were randomized.15 This was a randomized, double-blind, multicenter, placebo-controlled phase 3 trial. Patients were randomized in a 1:1 fashion to receive either rimegepant 75 mg ODT or placebo. Randomization was stratified based on the patientâ&#x20AC;&#x2122;s usage of a migraine preventive medication. Coprimary efficacy endpoints were freedom from pain and freedom from the patientâ&#x20AC;&#x2122;s most bothersome symptom (phonophobia, photophobia, or nausea) at 2 hours after the dose.15 Twenty-one secondary endpoints were tested, and some include: pain relief, freedom from photophobia, phonophobia, or nausea, and ability to function at 2 hours after the dose; freedom from pain, freedom from the most bothersome symptom, pain relief, and ability to function normally at 90 minutes after the dose; as well as similar endpoints at 24 to 48 hours after the dose. Results showed statis-
tically superior results for coprimary endpoints. 21% of patients in the rimegepant group reported freedom from pain at 2 hours after the dose, compared to 11% in the placebo group (p<0.0001; risk difference 10, 95% CI 6-14). 35% of patients in the rimegepant group experienced freedom from their most bothersome symptom, while 27% in the placebo group reported the same result (p=0.0009; risk difference 8, 95% CI 3-13). Rimegepant was also shown to be superior to placebo for all secondary endpoints besides freedom from nausea and pain relapse. The most common adverse events seen were nausea (2% in the rimegepant group vs <1% in the placebo group) and urinary tract infection (1% in both groups).15 New Therapies in Preventive Management
Most preventive agents listed in the guidelines are not migraine-specific therapies. Common options include some beta-blockers, antiepileptics, and antidepressants, most of which the mechanism of migraine prevention is not well understood. Each of these classes have their own list of undesirable effects; thus, current preventive migraine management is extremely patient-specific.7 The new class of medications for migraine prevention, injectable CGRP receptor antagonists, specifically targets a ligand or receptor that is believed to contribute to migraine formation. In addition to a more specific mechanism of action, the medications in this new class are dosed on a monthly basis or longer.16 Most of the preventive options
mentioned in the guidelines must be taken daily to maintain efficacy.7 Injectable CGRP Receptor Antagonists
This medication class consists of monoclonal antibodies that target and bind to circulating CGRP ligand or its receptor leading to prevention of migraine headaches.16,17 There are currently four medications approved in this class: galcanezumab, fremanezumab, erenumab, and eptinezumab. Galcanezumab
Galcanezumab (Emgality) was approved in September 2018 for the preventive treatment of migraine. In June 2019, the FDA approved another indication, treatment of episodic cluster headache. It is a humanized IgG4 monoclonal antibody that targets the CGRP ligand. Galcanezumab is available as a 120 mg/mL single-dose prefilled pen and 100 mg/mL or 120 mg/mL single-dose prefilled syringe. Recommended dosing for migraine prevention is 240 mg (supplied as two consecutive subcutaneous injections of 120 mg each) once as a loading dose, then 120 mg injected subcutaneously once monthly.17 There are no dosage adjustments recommended by the manufacturer for renal or hepatic impairment. 17 Hypersensitivity reactions have been reported up to days after administration. The most common adverse event reported during clinical trials was injection site reactions. 17 Galcanezumab should be stored in the Page 15
refrigerator and allowed to sit at room temperature for 30 minutes prior to administration.17
In the EVOLVE-1 trial, galcanezumab was evaluated for the prevention of episodic migraine. It was a randomized, double-blind, placebo-controlled, multicenter phase 3 study. 18 A total of 862 adults with at least a 1-year history of migraine were randomized 2:1:1 to receive placebo, galcanezumab 120 mg, or galcanezumab 240 mg, all once monthly. The primary endpoint was to determine the superiority of at least 1 dose of galcanezumab versus placebo for mean change from baseline in the number of monthly migraine headache days (MHDs). 18 Secondary outcomes included proportion of patients with reduction in monthly MHDs, MHDs with acute medication use, Patient Global Impression of Severity scores (a 7-point scale that ranks severity of illness from normal to severely ill), and Migraine Disability Assessment scores (ranks days missed in school, work, activities, et cetera to provide a score range of little or no disability to severe disability due to migraine).18 Both the 120 mg dose and 240 mg dose of galcanezumab achieved the primary endpoint, with a reduction in 1.9 MHDs in the 120 mg group and a reduction of 1.8 MHDs in the 240 mg group (both P-values < 0.001). 18 Galcanezumab 120 mg and 240 mg both also achieved a statistically significantly greater improvement from baseline versus placebo in scores for both Patient Global Impression of Severity and Migraine Disability Assessment. 18 The most frequently reported adverse event in all groups was injection site pain,
with rates similar between all groups. Adverse events that had higher rates of occurrence in the galcanezumab groups compared to placebo were injection site erythema, injection site pruritis, and injection site reaction (all >2% in both galcanezumab groups).18
After the publication of the EVOLVE-1 trial, a study was conducted to evaluate the long-term safety of galcanezumab. This was a randomized, multicenter, open-label phase 3 trial that randomized a total of 270 adults with at least a 1-year history of migraine headaches. 19 Patients were randomized 1:1 to receive either galcanezumab 120 mg or galcanezumab 240 mg. To achieve the primary objective of long-term safety evaluation of galcanezumab, the study assessed serious adverse events, treatment-emergent adverse events, discontinuation rates, vital signs and weight, electrocardiograms, laboratory measurements, suicidal ideation and behavior using the Columbia Suicide Severity Rating Scale, and incidence of treatment-emergent anti-drug antibodies.19 Secondary objectives included the evaluation of efficacy measures to fully assess the long-term effectiveness of galcanezumab.19 77.8% of patients completed the study over a total of 12 months of treatment. Less than 5% of patients discontinued the trial due to adverse events. The most common adverse events reported were similar to those of previous trials; injection site pain, reaction, or erythema frequency between the two dosage groups were not statistically different. Overall mean reduction in MHDs over the 12-month treatment period was 2.2 days in the 120 mg
group and 2.1 days in the 240 mg group.19 Fremanezumab
Fremanezumab (Ajovy) was FDA approved in September 2018 for the preventive treatment of migraine. It is a fully humanized IgG2Î&#x201D;a/kappa monoclonal antibody that targets the CGRP ligand.20 Fremanezumab is available in a single-dose prefilled syringe as 225 mg/1.5 mL solution. Recommended dosing is 225 mg injected subcutaneously once monthly or 675 mg every 3 months (three consecutive 225 mg subcutaneous injections).20 There are no dosage adjustments recommended by the manufacturer for renal or hepatic impairment. Fremanezumab should be stored in the refrigerator and allowed to sit at room temperature 30 minutes prior to administration. Hypersensitivity reactions, including rash, pruritis, drug hypersensitivity, and urticaria have been reported from within hours to one month after administration.20 The most common adverse event reported in clinical trials was injection site reactions (incidence >5% and greater than placebo).20 In a phase 3 trial that evaluated the efficacy, safety, and side effect profile of two doses of fremanezumab, a total of 1,130 adults with a history of migraine for at least 12 months were enrolled. This was a randomized, double-blind, placebo-controlled, parallel-group trial. Patients were randomized 1:1:1 to receive either placebo, fremanezumab monthly injections, or fremanezumab quarterly injections. All patients received Page 16
three injections at baseline and one injection at weeks 4 and 8 with doses varying depending on group assignments. The primary endpoint was the mean change in average number of headache days. Secondary endpoints included the mean change from baseline in the average number of migraine days per month, the percentage of patients with a reduction of at least 50% in the average number of headache days per month, and the mean change from baseline in the average number of days per month in which acute headache medication was used in the 12week period after the first day.21 Results showed a significant decrease in the number of headache days per month for both fremanezumab groups. The number of headache days per month was reduced by a mean of 4.3 days in the quarterly group, 4.6 days in the monthly group, and 2.5 days in the placebo group (P<0.001 for both groups compared to placebo). There was also a significant reduction in the number of days per month in which acute headache medication was used for both fremanezumab groups compared to placebo (mean of 3.7 days in the quarterly group, 4.2 in the monthly group, and 1.9 in the placebo group, P<0.001 for both groups compared to placebo). One of the most commonly reported adverse events was injection site reactions, with a frequency of 40% the placebo group, 47% in the quarterly group (P=0.08), and 47% in the monthly group (P=0.03).21 Erenumab
Erenumab (Aimovig) was approved in May 2018 for preventive treatment of migraine. It is a
human IgG2 monoclonal antibody that binds to the CGRP receptor with high affinity. Erenumab is available in a 70 mg/mL single-dose prefilled autoinjector and syringe. 22 The needle shield and needle cap of the prefilled syringe dosage form contain a derivative of latex and may cause allergic reaction in patients with latex sensitivities. 22 Recommended dosing is 70 mg injected subcutaneously once a month; however, some patients may benefit from 140 mg injected subcutaneously once a month (two consecutive injections of 70 mg each). No dose adjustments for renal or hepatic impairment are recommended by the manufacturer. Erenumab should be stored in the refrigerator and allowed to sit at room temperature for 30 minutes prior to administration. The most common adverse events seen in clinical trials were injection site reactions and constipation (frequency at least 3% and more often than placebo).22
In the ARISE study, erenumab was evaluated for efficacy and safety in migraine prevention. It was a randomized, double-blind, placebo-controlled, parallel-group, multicenter phase 3 trial. A total of 547 adults with at least a 12-month history of episodic migraine with or without aura were enrolled. Patients were randomized 1:1 to receive erenumab 70 mg monthly subcutaneous injections or placebo for 12 weeks. 23 The primary endpoint was change from baseline in monthly migraine days in month 3 of the treatment phase. Secondary endpoints included achievement of more than 50% reduction from baseline in monthly migraine
days, change from baseline in monthly acute migraine-specific medication treatment days, achievement of at least a 5-point reduction in monthly average Migraine Physical Function Impact Diary score, and achievement of at least a 5-point reduction in monthly average Impact on Everyday Activities score.23 At week 12, patients in the erenumab group reported a mean reduction of 2.9 monthly migraine days, compared to a mean reduction of 1.8 days in the placebo group (p<0.001). 23 Erenumab was also statistically superior to placebo for most secondary endpoints with the exception of the change in scores for the Migraine Physical Function Impact Diary and Impact on Everyday Activities. Adverse events reported that had a frequency >2% and higher than placebo were upper respiratory tract infection, injection site pain, and fatigue (no p-values reported).23 Eptinezumab
The newest addition to this drug class, eptinezumab (Vyepti), was approved in February 2020 for the prevention of migraine. It is a humanized IgG1 monoclonal antibody that binds to the CGRP ligand. Administration for eptinezumab is intravenous infusion only, rather than a subcutaneous injection like the other injectable CGRP receptor antagonists. It requires dilution with 100 mL 0.9% Sodium Chloride Injection, USP prior to administration. Single-dose vials are 100 mg/mL, and recommended administration is 100 mg intravenous infusion over 30 minutes every 3 months. Some patients may benefit from 300 Page 17
mg IV infusion every 3 month. There are no preservatives in the vials and any unused portion remaining in the vial should be discarded. 24 There are no dose adjustments recommended by the manufacturer for renal or hepatic impairment. 24 Hypersensitivity reactions such as angioedema, urticaria, facial flushing, and rash have occurred mainly during infusion. The most common adverse events reported in clinical trials (frequency greater than 2%, and 2% or greater than placebo) were nasopharyngitis and hypersensitivity.24
In the PROMISE-1 trial, eptinezumab was evaluated for efficacy, safety, and pharmacokinetics for prevention of episodic migraine. 25 Chronic migraine patients were included in the PROMISE-2 study. PROMISE-1 was a parallel-group, double-blind, randomized, placebo-controlled, multicenter phase 3 study. A total of 898 adults with at least a 12-month history of migraine with at least 4 migraine days per month in the 3 months prior to screening were enrolled in the trial. 25 Patients were randomized 1:1:1:1 to receive either eptinezumab 30 mg, 100 mg, 300 mg, or placebo for 4 treatments (primary efficacy analysis was completed through the second treatment). The primary efficacy endpoint was the change from baseline in monthly migraine days over weeks 1-12, assessed by eDiary data. 25 Key secondary efficacy endpoints included a 75% migraine responder rate over weeks 1-4 and weeks 1-12, a 50% migraine responder rate over weeks 1-12, and percentage of patients with a migraine on the day after dosing.25 Results
revealed a statistically significant reduction from baseline in the frequency of migraine days during weeks 1-12 versus placebo for the eptinezumab 100 mg and 300 mg groups. 25 Patients in the placebo group had a reduction of 3.2 monthly migraine days, in the eptinezumab 30 mg group patients experienced a reduction of 4.0 monthly migraine days (unadjusted p=0.0046; not statistically significant per the testing hierarchy). Patients in the eptinezumab 100 mg group reported a reduction of 3.9 monthly migraine days (unadjusted p=0.0182) and patients in the 300 mg group experienced a reduction of 4.3 monthly migraine days (unadjusted p=0.0001), both of which were considered statistically significant per the testing hierarchy. 25 Adverse events that had a frequency higher than placebo included upper respiratory tract infection, nasopharyngitis, and fatigue.25
those with contraindications or failure to traditional migraine treatments. A potential barrier to novel agents for many patients is cost (see Table 1). Many manufacturers are offering coupon cards to reduce the cost to patients, but not everyone is eligible, and they are typically valid only for a set amount of time. Despite the lack of longterm data and cost, these newly approved drugs with different mechanisms of action for acute or preventive treatment of migraine are a much-needed addition to the arsenal of treatment options for patients suffering from migraine headaches.
With no updated guidelines yet to reflect the addition of novel therapies or head-to-head trials comparing new therapies to the gold standards, it is difficult to determine the place in therapy for lasmiditan and the CGRP receptor antagonists. Current published phase 3 trials demonstrate short-term efficacy and safety of these novel agents; however, there are very few long-term studies available yet since most of the drugs were approved within the previous two years. Despite a wide array of data that accompanies more traditional therapies, such as triptans, many patients may benefit from these novel agents, such as
1.Dodick DW. Migraine. Lancet. 2018;391(10127):1315-30. 2. Burch RC, Loder S, Loder E, Smitherman TA. The Prevalence and Burden of Migraine and Severe Headache in the United States: Updated Statistics from Government Health Surveillance Studies. Headache. 2015;55(1):21-34. 3. Migraine Research Foundation. About Migraine. Available at: https:// migraineresearchfoundation.org/ about-migraine/migraine-facts/. Accessed 4/28/2020. 4. Stokes M, Becker WJ, Lipton RB, et al. Cost of Health Care Among Patients with Chronic and Episodic Migraine in Canada and the USA: Results From the International Burden of Migraine Study (IBMS). Headache. 2011;51(7):1058-77. 5. Bonafede M, Cai Q, Cappell K, et al.
Conclusion
Author: Dr. Kaitlyn Gibson is a recent graduate of the Campbell University College of Pharmacy & Health Sciences. kagibson0830@ email.campbell.edu> References
Page 18
Factors Associated with Direct Health Care Costs Among Patients with Migraine. JMCP. 2017;23(11):1169-76. 6. Silberstein SD. Practice Parameter: Evidence-Based Guidelines for Migraine Headache (An Evidence-Based Review). Neurology. 2000;55(6):754-62. 7. Silberstein SD, Holland S, Freitag F, Dodick DW, Argoff C, Ashman E. Evidence-based guideline update: Pharmacologic treatment for episodic migraine prevention in adults. Neurology. 2012;78:1337-45. 8. The role of triptans in the treatment of migraine in adults. BMJ. 2014;62:28-36. 9. Reyvow (lasmiditan) [prescribing information]. Indianapolis, IN: Lilly USA, LLC; October 2019. 10. Ubrelvy (ubrogepant) [prescribing information]. Madison, NJ: Allergan USA, Inc; December 2019. 11. Nurtec ODT (rimegepant) [prescribing information]. New Haven, CT: Biohaven Pharmaceuticals, Inc; February 2020. 12. Kuca B, Silberstein SD, Wietecha L, Berg PH, Dozier G, Lipton RB. Lasmiditan is an effective acute treatment for migraine. Neurology. 2018;91:e2222-32. 13. Loo LS, Ailani J, Schim J, Baygani S, Hundemer H, Port M, Krege JH. Efficacy and safety of lasmiditan in patients using concomitant migraine preventive medications: findings from SAMURAI and SPARTAN, two randomized phase 3 trials. The Journal of Headache and Pain. 2019;20(84). 14. Dodick D, Lipton R, Ailani J, Lu K, Finnegan M, Trugman J, Szegedi A. Ubrogepant for the Treatment of Migraine. N Engl J Med. 2019;381(23):2230-41. 15. Croop R, Goadsby PJ, Stock DA, et al. Efficacy, safety, and tolerability of rimegepant orally disintegrating tablet for the acute treatment of migraine: a randomized, phase 3, double-blind, placebo-controlled trial. Lancet. 2019;394(10200):737-45. 16. Scuteri D, Adornetto A, Rom-
bolĂ L, et al. New Trends in Migraine Pharmacology: Targeting Calcitonin Gene-Related Peptide (CGRP) With Monoclonal Antibodies. Front Pharmacol. 2019;10(363). 17. Emgality (galcanezumab) [prescribing information]. Indianapolis, IN: Eli Lilly and Company; September 2018. 18. Stauffer VL, Dodick DW, Zhang Q, Carter JN, Ailani J, Conley RR. Evaluation of Galcanezumab for the Prevention of Episodic Migraine: The EVOLVE-1 Randomized Clinical Trial. JAMA Neurol. 2018;75(9):1080-88. 19. Camporeale A, Kudrow D, Sides R, Wang S, Van Dycke A, Selzler KJ, Stauffer VL. A phase 3, long-term,
open-label safety study of Galcanezumab in patients with migraine. BMC Neurol. 2018;18(188). 20. Ajovy (fremanezumab) [prescribing information]. North Wales, PA: Teva Pharmaceuticals USA, Inc; September 2018. 21. Silberstein SD, Dodick DW, Bigal ME, et al. Fremanezumab for the Preventive Treatment of Chronic Migraine. N Engl J Med. 2017;377(22):2113-22. 22. Aimovig (erenumab) [prescribing information]. Thousand Oaks, CA: Amgen Inc; May 2018. 23. Dodick DW, Ashina M, Brandes JL, et al. ARISE: A Phase 3 randomized trial of erenumab for episodic migraine.
Cephalagia. 2018;38(6):1026-37. 24. Vyepti (eptinezumab) [prescribing information]. Bothell, WA: Lundbeck Seattle BioPharmaceuticals, Inc; February 2020. 25. Ashina M, Saper J, Cady R, et al. Eptinezumab in episodic migraine: A randomized, double-blind, placebo-controlled study (PROMISE-1). Cephalagia. 2020;40(3):241-54. 26. GoodRx.com; Pricing information. Accessed 4/30/2020.
Table 1: Summary of monthly costs for novel drugs for migraine acute or preventive treatment26 Drug
Average Monthly Cost*
Lasmiditan
$640
(#8 100-mg tablets)
Ubrogepant
$850
(#10 50-mg tablets)
Rimegepant
$850
(1 dose pack of 8 ODT)
Galcanezumab
$560
(1 single-dose pen)
Fremanezumab
$600
(1 single-dose syringe)
Erenumab
Eptinezumab
$600
(1 single-use vial is $1,500 and is a 3-month supply)
(1 single-dose pen)
$500
*Prices do not reflect any available manufacturer coupons or insurance prices that could provide additional savings to patients
Page 19
Pharmacy Guided Procalcitonin Ordering in Adult Inpatients with Lower Respiratory Tract Infections
By: Dr. Katie Dircksen, Dr. Riley Bowers, Dr. Dustin Bryan, Ms. Emily Woodfield, and Dr. Serina Tart
Introduction
Lower respiratory tract infections are among the most common diagnoses for antibiotic prescriptions; however, a study by the Center for Disease Control (CDC) found that 86% of patients presenting with pneumonia had either a viral infection or lacked an identifiable pathogen.1,2 Lower respiratory tract infections (LRTI) can be diagnosed via microbiologic testing, but culture results can take days and often do not identify the causative organism(s). Consequently, the diagnosis of LRTI in the emergency department (ED) is based on symptoms and clinical history. Symptoms of LRTI include cough, sputum production, dyspnea, tachypnea, pleuritic pain, rales, crepitation, and signs of infection (core body temperature >38.0°C, leukocyte count >10,000/µL or <4000/µL).3 With these symp-
PCT concentration elevations secondary to bacterial infections typically rise within 2-4 hours of an inflammatory trigger and reach their peak at approximately 2448 hours. Peak concentrations may be higher depending on the severity of the infection and deProcalcitonin (PCT) is an inflam- cline quickly at a predictable rate matory marker that can indicate with the resolution of inflammathe presence of a bacterial infec- tion.1 tion.5 In patients without an acute bacterial infection, this lab value Due to the specificity for bacteriis typically undetectable (<0.07 al infection, a high PCT level has mcg/L). Triggers that cause in- a positive predictive value indiflammation specific to bacterial cating that antibiotics are necinfections include microbial tox- essary. If the PCT level is low, a ins (i.e., endotoxins) and cyto- non-bacterial cause for the pakines (tumor necrosis factor (TF- tient’s symptoms should be conN)-alpha, interleukin-1 beta, and sidered.6 In 2012 a Cochrane interleukin-6). In contrast, viral review showed that an initial infections lack PCT synthesis due assessment of PCT levels resultto cytokines released by the virus ed in the reduction in antibiotic that inhibit TNF-alpha production use by 60-70% in patients with and thus prevent inflammation.5 low-severity respiratory tract infections.7 The same Cochrane
toms being of low specificity, it is easy to misdiagnose a patient with LRTI when they truly have another diagnosis, such as an exacerbation of chronic obstructive lung disease (COPD), heart failure (HF), or asthma.4
Page 21
review found that trending PCT values in patients with community-acquired pneumonia resulted in a 40% reduction in the duration of the antibiotic treatment without increasing morbidity or mortality.7 In the ProREAL study, the authors showed that the duration of antibiotic therapy was significantly shorter if a PCT algorithm was followed compared with when it was overruled (5.9 days vs 7.4 days; 95% CI -2.04 to -0.98; p<0.001).8
duration of all antibiotic therapy (DOT) prescribed during the inpatient stay and at discharge for adult inpatients with LRTI before and after the intervention of pharmacy guided PCT ordering. The secondary objectives were to compare time, in days, to antibiotic de-escalation from IV to PO antibiotics in adult inpatients with LRTI who did and did not have pharmacist ordered PCT levels to guide therapy, to assess prescriber acceptance of pharmacist recommendations after protocol When patients present with LRTI introduction, and to compare the at our institution, PCT levels are number of PCT levels ordered becurrently obtained at the discre- fore and after protocol introduction of the provider and there is tion. no established protocol for PCT monitoring or follow-up. The pur- Patients were included if they pose of this quality-initiative pilot were Âł 18 years old and admitted sought to determine if a pharma- to the institution between Novemcist-guided PCT ordering protocol ber 1, 2018, to January 31, 2019 and algorithm for patients pre- (control group) or November 1, senting with a primary diagnosis 2019, to January 31, 2020 (interof LRTI reduced the duration of vention group). Patients were reantibiotic therapy. quired to have a suspected or diagnosed bacterial LRTI defined as Methods a principal diagnosis upon admission, which was identified from a This study was a single-center, generated list of diagnosis codes. quasi-experimental, quality-im- Diagnosis codes were generated provement initiative conducted through Midas, which is an intefrom November 1, 2019, to Janu- grated, care management, data, ary 31, 2020, in compliance with workflow, and reporting tool. the pharmacist guided PCT pi- Patients had to be reviewed by lot protocol (Appendix I), which either the antimicrobial stewardwas approved by the institutionâ&#x20AC;&#x2122;s ship (AMS) pharmacist, internal Pharmacy and Therapeutics Com- medicine (IM) pharmacist, or a mittee. The retrospective control pharmacy resident to be included group consisted of patients ad- in the study. mitted with LRTI from November 1, 2018, to January 31, 2019. The Patients were excluded if they study protocol was granted ex- had CKD stage 4 or 5 (eGFR <30 empt status by the Institutional mL/min) on hemodialysis (HD) Review Board of the study site. or were susceptible to increased inflammation (Table 1). Patients The primary objective of this were also excluded if they had study was to compare the total chronic infection or concurrent Page 22
infection necessitating antibiotic treatment. Pregnant patients were excluded, as well as patients who were directly admitted (transfers) from other facilities, had antibiotics present at the admission medication reconciliation, or had been admitted for >24 hours without an initial PCT level drawn. An AMS or IM pharmacist reviewed each patient admitted with LRTI and determined if the patient met inclusion criteria. If the patient was included in the study, the pharmacist would follow the pilot protocol for ordering and monitoring PCT levels (Appendix I). Documentation of the pharmacistâ&#x20AC;&#x2122;s recommendations after protocol introduction was completed in Epic via iVents by the reviewing pharmacist.
Using a preset alpha of 0.05 and two-sided 95% confidence interval with an anticipated decrease of 20% in total antibiotic duration, we estimated a required sample size of 129 patients per group to reach 80% power; therefore, we targeted approximately 160 patients per group for inclusion in the study. For the primary objective, we conducted an unpaired student t-test with 95% confidence intervals to compare means of antibiotic duration in DOT. The secondary analysis of time to antibiotic de-escalation in DOT was also compared using an unpaired student t-test with 95% confidence intervals. The remaining secondary objectives were analyzed using descriptive statistics. Results
There were 208 patients iden-
tified for the control group, and 319 patients identified for the intervention group using LRTI diagnosis codes. Of the 208 patients in the control group, 75 patients met inclusion criteria (36.1%) compared to only 41 patients meeting inclusion criteria in the intervention group (12.9%) (Figure 1). The baseline characteristics of the two groups also varied (Table 2). The average age for patients in the control group was 66.6 years old, compared to 58.1 years in the intervention group. Most patients in the control group were women (57%), whereas men were the majority of patients in the intervention group (54%). There were 45 patients in the control group (60%) that had at least one or more co-existing illnesses, compared to 19 patients in the intervention group (46.3%). Lastly, the intervention group had more signs of infection at presentation, with a higher mean temperature (37.3°C vs 36.8°C) and a higher WBC count (12.4 vs 11.8). Both groups had relatively low numbers of positive sputum cultures.
The primary objective of total antibiotic duration in DOT was not found to be statistically significant when comparing the control group to the intervention group, 10.8 days vs 10.0 days, respectively (95% CI -2.49-0.86; p=0.34). Our secondary objective of time to antibiotic de-escalation in DOT was also not statistically significant when comparing the control group to the intervention group, 4.8 vs 4.8 days, respectively (95% CI -1.09-1.26; p=0.89). When assessing prescriber acceptance to pharmacist-guided PCT monitoring, prescribers were
more likely to accept recommendations to de-escalate antibiotics than they were to accept recommendations to discontinue antibiotics (Table 3). The number of PCTs ordered during the intervention group time frame (88) was more than the number of those ordered during the control group time frame (29).
mendations was higher at 86%. The willingness to accept de-escalation recommendations compared to discontinuation recommendations supports the idea of prescriber reluctance to discontinue antibiotics despite guideline recommendations. While our time to antibiotic de-escalation in the control group compared to the intervention group was not Discussion statistically significant, the prescriber acceptance rate of recomImplementing a pharmacist guid- mendations points to a potential ed PCT algorithm failed to pro- place in practice where pharmacy duce a statistically significant could have an impact. reduction in total antibiotic duration. Even though there was no Under the pilot PCT protocol, 88 statistical difference seen in DOT, PCT levels were ordered. Each test there was a trend towards de- is $25, totaling $2,200. Comparacreased DOT in the intervention tively, 29 PCT levels were ordered group; however, the study did not during the control group time meet the calculated power need- period, which totaled $725. Our ed to show significance. pharmacists found that unnecessary PCT levels had to be ordered The difference in time to antibi- per our protocol. Considering the otic de-escalation in DOT was not lack of statistical significance for statistically significant between our objectives and the difference the control group and the inter- in costs, future protocols should vention group. It is also import- include pharmacist’s clinical deant to note that patient length of cision whether or not additional stay (LOS) in the institution was PCT levels are justified. approximately five days in both groups. The lack of statistical The major strength of our study significance for time to antibiot- was that we decreased confoundic de-escalation could be due to ing variables as much as possible de-escalating antibiotics at dis- by having an extensive set of excharge. clusion criteria. While this limits our patient population size, it alPrescriber acceptance of recom- lows us to confidently assess that mendations was low when phar- the study was not influenced by macists recommended discontin- confounding variables. uing antibiotics, with only 33% accepted. This could be due to the There were limitations to the pilack of prescriber understanding lot protocol. The first one idenof PCT values, the patient’s infec- tified was the heavy workload tion worsening, or the prescrib- that the protocol placed on select er’s reluctance to discontinue pharmacists. The AMS and IM antibiotics. Prescriber acceptance pharmacists only reviewed paof antibiotic de-escalation recom- tients during the first shift hours Page 23
Monday through Friday. This hindered our ability to include all patients with LRTI in the intervention group due to some meeting exclusion criteria by being admitted on the weekend. Another limitation would be the short LOS that we noticed retrospectively. While decreasing hospitalization for these patients is ideal, it impeded our ability to collect follow up PCT levels, and thus decreased our chances to make recommendations. The baseline characteristics varied between the control group and the intervention group. We hypothesize that this is due to changing electronic health record (EHR) systems between the control group time frame and the intervention group time frame. The control group EHR was more difficult to navigate and find pertinent patient information, while the intervention group EHR was more user friendly and easily accessible. Lastly, our patient population was small, and the study did not meet the calculated power needed to show significance. Conclusion
Pharmacist guided PCT ordering and monitoring did not result in a decrease in total days of antibiotic therapy at our institution. Due to this and the increased workload it placed on our pharmacists, we determined this protocol could not be implemented to the entire department in its current state. Nevertheless, with the trend towards shorter antibiotic duration and high acceptance rates of pharmacist’s recommendations for antibiotic de-escalation, there may be a place in practice for pharmacist guided PCT ordering and monitoring in the future. An increase
in prescriber awareness and additional pharmacist involvement will aid in making a standing protocol successful. References
1. Rhee C, Mansour M. (2019). Procalcitonin use in lower respiratory tract infections. Bond S (Ed), UpToDate. Retrieved August 20, 2019, from https://www. uptodate.com/contents/procalcitonin-use-in-lower-respiratory-tract-infections. 2. Jain S, Self WH, Wunderink RG, Fakhran S, Balk R, Bramley AM, et al. Community acquired pneumonia requiring hospitalization among U.S. adults. N Engl J Med 2015; 373:415–27. 3. Schuetz P, Christ-Crain M, Thomann R, et al. Effect of procalcitonin-based guidelines vs standard guidelines on antibiotic use in lower respiratory tract infections: the ProHOSP randomized controlled trial. JAMA 2009;302(10):1059–66. 4. Schuetz P, Briel M, Christ-Crain M, Stolz D, Bouadma L, Wolff M, Luyt CE, Chastre J, Tubach F, Kristoffersen KB, et al. Procalcitonin to guide initiation and duration of antibiotic treatment in acute respiratory infections: an individual patient data meta-analysis. Clin Infect Dis 2012;55(5):651– 662. doi: 10.1093/cid/cis464. 5. Lee H. Procalcitonin as a biomarker of infectious diseases. Korean J Intern Med 2013; 28(3):285-291. 6. Sagar R, Kutz A, Mueller B, Scheutz P. Procalcitonin-guided diagnosis and antibiotic stewardship revisited. BMC Med 2017;15:15 7. Schuetz P, Muller B, Christ-Crain M, Stolz D, Tamm M, Bouadma L, Luyt CE, Wolff M, Chastre J, Tubach F, et al. Procalcitonin to initiate or discontinue antibiotics in acute respiratory tract inPage 24
fections. Cochrane Database Syst Rev 2012; 9(9). 8. Dusemund F, Bucher B, Meyer S, et al. Influence of procalcitonin on decision to start antibiotic treatment in patients with lower respiratory tract infection: insight from the observational multicentric ProREAL surveillance. Eur J Clin Microbiol Infect Dis 2013; 32(1):51-60. 9. Schuetz P, Beishuizen A, Broyles M, et al. Procalcitonin-guided antibiotic stewardship: an international experts consensus on optimized clinical use. Clin Chem Lab Med 2019; 57(9): 1308-1318.
The authors have no disclosures to report.
Authors: Katie Dircksen, PharmD (Corresponding Author) is a PGY1 Pharmacy Resident, Acute Care Track at Cape Fear Valley Medical Center (CFVMC), kdirckse@gmail. com; Riley Bowers, PharmD, BCCP, BCPS, is the Associate Director of Graduate Pharmacy Education at CFVMC and Clinical Assistant Professor at Campbell University College of Pharmacy & Health Sciences (CPHS); Dustin Bryan, PharmD, BCPS is the PGY1 Pharmacy Residency Director at CFVMC; Ms. Emily Woodfield is a 2021 PharmD Candidate at CPHS; Serina Tart, PharmD is an Antimicrobial Stewardship Clinical Pharmacist at CFVMC.
Table 1: Additional Exclusion Criteria Patients Susceptible to Increased Inflammation Admitted to intensive care unit Immediate postnatal period
Receiving immunomodulatory agents (e.g., T-cell antibodies, alemtuzumab, interleukin-2, and granulocyte transfusions) Neuroendocrine tumors (medullary thyroid cancer) Pre-existing lung disease/lung cancer Severe immunosuppression Cystic fibrosis
Active tuberculosis
Severe physical trauma
Recent surgery during current admission
Cardiac arrest or circulatory shock during current admission Pancreatitis during current admission
Intracranial hemorrhage during current admission
Severe burns being treated during current admission
Table 2: Baseline Characteristics Age (yrs) ± SD
Male – n (%)
Co-existing illness – n (%)
Control Group (n=75)
Intervention Group (n=41)
66.6 ± 16.8
58.1 ± 16.6
29 (39)
9 (22)
32 (43)
COPD HF
Asthma
21 (28)
10 (24)
36.8 ± 0.8
37.3 ± 0.9
8 (11)
Infectious Signs on Admission Temperature (°C) ± SD WBC Count ± SD
Positive Sputum Culture – n (%)
22 (54)
6 (15)
11.8 ± 5.2
12.4 ± 5.9
5 (6.7)
1 (2.4)
Table 3: Prescriber Acceptance of Recommendations Intervention Group (n=41) Prescriber acceptance of antibiotic discontinuation Prescriber acceptance of antibiotic de-escalation
5/15 (33%)
12/14 (86%)
Page 25
Figure 1: Patient Population Intervention Group
Control Group
319 patients reviewed
208 patients reviewed
133 (64%) patients were excluded from final analysis 55 (41%) had CKD III/IV or ESRD 34 (25%) susceptible to increased inflammation 22 (17%) required antibiotics for concurrent infection 14 (11%) were transfers 8 (6%) did not have LRTI as primary diagnosis
278 (87%) patients were excluded from final analysis 59 (21%) susceptible to increased inflammation 58 (21%) required antibiotics for concurrent infection 54 (20%) had CKD III/IV or ESRD 34 (12%) >24 hr admit w/o PCT 31 (11%) not followed 26 (9%) were transfers 16 (6%) discharged before any PCT levels returned 41 patients met inclusion criteria during November 1, 2019-January 31,2020
75 patients met inclusion criteria during November 1, 2018-January 31,2019
Page 26
Appendix I:
PROCALCITONIN ALGORITHM Immunocompetent patients only
Patient with admission diagnosis of LRTI, pharmacist will: Order PCT level within 24 hours of admission, if not already completed, and per algorithm below INITIAL PROCALCITONIN LEVEL BACTERIAL INFECTION UNLIKELY
BACTERIAL INFECTION LIKELY
Appendix I:
PROCALCITONIN ALGORITHM
0.26-0.5 0.1-0.25 > 0.5 mcg/L Immunocompetent patients only mcg/L mcg/L Patient with admission diagnosis of LRTI, pharmacist will: Order PCT level within 24 hours of admission, if not already completed, and per algorithm below
< 0.1 mcg/L
ANTIBIOTIC USE
Strongly Discouraged DiscouragedINFECTION UNLIKELY BACTERIAL < 0.1 mcg/L
-
INITIAL PROCALCITONIN LEVEL
0.1-0.25 mcg/L
Strongly Encouraged BACTERIAL INFECTION LIKELY
Encouraged
0.26-0.5
RECOMMENDATION mcg/L
Repeat measurement within 24 hours if antibioticANTIBIOTIC USE started Consider alternative diagnosis if PCT remains low Strongly Discouraged Pharmacist documents recommendation in Discouraged progress note from iVent
> 0.5 mcg/L
- Continue empiric antibiotics - De-escalate as cultures indicate - Draw PCT levels every 48 hrs (72 hours if Encouraged weekend overlaps) toStrongly assess duration of antibiotic Encouraged therapy
FOLLOWRECOMMENDATION UP PROCALCITONIN LEVEL Clinical judgment should supersede lab values
-
- Continue empiric antibiotics De-escalate as cultures indicate ≥ 0.5- mcg/L AND decreased by less than 80% - Draw PCT levels every 48 hrs (72 hours if overlaps) to assess Continueweekend Antibiotics and follow PCTduration for maxof antibiotic therapyof 4 levels total
Repeat measurement within 24 hours if antibiotic started< 0.25 mcg/L OR 80% decrease from initial Consider alternative diagnosis if PCT remains low Pharmacist documents recommendation Recommend to Stop Antibiotics in progress note from iVent Document recommendation as progress note
FOLLOWRECOMMENDATION UP PROCALCITONIN LEVEL Clinical judgment should supersede lab values
If PCT is increasing or not adequately decreasing, consider treatment failure. ≥ 0.5 mcg/L AND decreased by less than 80% Evaluate for expanding coverage or further diagnostic evaluation. Continue Antibiotics and follow PCT for max of 4 levels total
Cessations of antibiotics encouraged if signs/symptoms have resolved. < 0.25 mcg/L OR 80% decrease from initial Consider continuation if clinically unstable to or Stop disease progress present Recommend Antibiotics Document recommendation as progress note
RECOMMENDATION
If PCT is increasing or not adequately decreasing, consider treatment failure. Evaluate for expanding coverage or further diagnostic evaluation.
Cessations of antibiotics encouraged if signs/symptoms have resolved. Consider continuation if clinically unstable or disease progress present
Page 27
Ambulatory Care Academy Update and Executive Committee Member Spotlight Dr. Jenn Wilson The newly created Ambulatory Care Academy officially launched in January 2020 and at this time, we are focusing our efforts on spreading the word by letting members and nonmembers know there is a new academy home for individuals who identify as ambulatory care practitioners. With the change in bylaws, members can choose to identify with more than one academy (though only may serve in an elected position in one at any given time). We feel this will be important for those who maybe have a diverse practice background and may feel ties to additional practice areas.
The Ambulatory Care Academy is interested in trying to connect with ambulatory care pharmacists across the state. We hope to network with currently existing groups to build positive working relationships and promote the advancement of ambulatory care practice.
As an executive committee, plan to provide a means for sharing of ideas through the use of the Higher Logic platform over the remainder of the year. There will be various discussion posts and questions related to relevant practice topics. We encourage all members who are interested in learning more to login and update their member profile to reflect membership in the Ambulatory Care Academy, as well as to update preferences in Higher Logic to receive alerts regarding discussion posts. We also encourage anyone who has a question or idea related to ambulatory care practice to post to Higher Logic.
We will be recruiting a chair-elect and one member-at-large for the 2021 year. If you are interested in getting more involved in a leadership capacity or even just learning more about the Academy, please reach out to Chair, Jenn Wilson, Chair-Elect, Irene Ulrich, or any of the executive committee members listed below. Jenn Wilson, PharmD, BCACP is an Associate Professor with Wingate University School of Pharmacy. She is transitioning into the role of Director of Introductory Pharmacy Practice Experience. Until May of this year, she was a clinical pharmacist with Community Health Services of Union County, a free medical clinic in Monroe, NC. She is currently Chair for the Ambulatory Care Academy Executive Committee. She previously has served on the Board, Community Care Forum, Education Committee, and New Practitioner Network. j.wilson@wingate.edu Irene Park Ulrich, PharmD, BCACP, CPP is an ambulatory care clinical pharmacist at the MAHEC Family Health Centers in Asheville, NC, and assistant professor of clinical education at the UNC
Eshelman School of Pharmacy. She has served on several NCAP committees over the past 5 years, and in addition to the Ambulatory Care Academy Executive Committee, she currently serves on the Convention Planning and eLearning Project Teams. She is currently the Chair-elect for the Ambulatory Care Academy and is an active member of the Western North Carolina Outpatient Pharmacy Partners (WNCOPP) group under NCAP. Irene.Ulrich@ mahec.net Holly Causey Canupp, PharmD, BCACP, CPP, CDCES is an ambulatory care clinical pharmacist at Duke University Hospital specifically practicing in internal medicine at the Duke Outpatient Clinic. She currently serves as a member at-large on the
Page 28
Ambulatory Care Academy Executive Committee and Chair of the Residency Conference Planning Committee and previously served on the New Practitioner Network. holly.causey@duke.edu Megan Coleman, PharmD, BCPS, CPP is a practice faculty member at Wingate University School of Pharmacy. Her ambulatory care practice site is at Matthews Free Medical Clinic where works as a Clinical Pharmacist Practitioner. She is currently serving as a member-at-large on the Ambulatory Care Academy Executive Committee and she previously served on the Health-Systems Forum Executive Committee. m.coleman@wingate.edu
Jen Kim, PharmD, BCPS, BCACP, BC-ADM, CPP is based out of Greensboro (Clinical Pharmacist with Cone Health Internal Medicine). She has been a member of NCAP for 7 years and was previously on the Chronic Care Forum and Student Committee. She is currently serving as a member-at-large for the Ambulatory Care Academy Executive Committee. jen.kim@conehealth.com
Kim Nealy, PharmD, BCPS, CDCES, CPP is an Associate Professor with Wingate University School of Pharmacy and Clinical Pharmacy Specialist with Novant Senior Care in Matthews. She is currently
serving as a member-at-large for the Ambulatory Care Academy Executive Committee and previously served on the Health-Systems Forum Executive Committee and New Practitioner Network. k.nealy@wingate.edu
Donnie Nuzum, PharmD, BCACP, BC-ADM, CDCES, CPP is an Associate Professor with Wingate University School of Pharmacy and Clinical Pharmacy Specialist at Atrium Health Union Family Practice in Monroe. He is a member-at-large for the Ambulatory Care Academy Executive Committee and on the planning committee for the Ambulatory Care Pharmacy Forum of North Carolina. dnuzum@ wingate.edu Michelle Rager, PharmD, BCPS, CDCES, CPP works as a Clinical Pharmacist Practitioner with New Hanover Regional Medical Center (NHRMC) in Wilmington, NC. Michelle joined NHRMC in June 2017 after previously working as an ambulatory care faculty member at Shenandoah University. She practices in chronic care and population health management. Michelle also serves as the RPD for the PGY1 Community-Based Pharmacy Residency Program at NHRMC. She currently serves as a member-at-large for the Ambulatory Care Academy Executive Committee. michelle.rager@nhrmc.org
Call for Articles North Carolina Pharmacist (NCP) is currently accepting articles for publication consideration. We accept a diverse scope of articles, including but not limited to: original research, quality improvement, medication safety, case reports/case series, reviews, clinical pearls, unique business models, technology, and opinions. NCP is a peer-reviewed publication intended to inform, educate, and motivate pharmacists, from students to seasoned practitioners, and pharmacy technicians in all areas of pharmacy. Articles written by students, residents, and new practitioners are welcome. Mentors and preceptors – please consider advising your mentees and students to submit their appropriate written work to NCP for publication. Don’t miss this opportunity to share your knowledge and experience with the North Carolina pharmacy community by publishing an article in NCP. Click on Guidelines for Authors for information on formatting and article types accepted for review. For questions, please contact Tina Thornhill, PharmD, FASCP, BCGP, Editor, at tina.h.thornhill@gmail.com. Page 29
