• 09 Jun 2022 2:01 PM | Anonymous

    Authors: Kelly Knauer, PharmD; Ulyana Kucherepa, PharmD 

                PGY-1 Pharmacy Practice Residents 
    Mentor: Davina Dell-Steinbeck, PharmD, BCPS 

     

    Program Number:  2022-05-04 
    Approved Dates:   June 1, 2022-December 1, 2022 
    Approved Contact Hours:  One Hour(s) (1) CE(s) per session
     

    Learning Objectives 

    1. Review current guideline recommendations on DAPT duration in patients undergoing percutaneous coronary intervention.  
    2. Differentiate unique features of P2Y12 inhibitors  
    3. Describe the results of existing evidence investigating DAPT duration after percutaneous coronary revascularization. 
    4. Identify possible confounders to recent trials that may impact the external validity of the results 
    5. Apply knowledge of patient considerations for P2Y12 inhibitors to results of recent literature to select an appropriate DAPT therapy for a patient after percutaneous coronary revascularization 
     
    Background  
     
    Dual antiplatelet therapy (DAPT) is the foundation of secondary prevention of cardiac or cerebrovascular thrombotic complications in patients undergoing coronary revascularization. P2Y12 inhibitors (Table 1) have been extensively studied in combination with aspirin showing that DAPT decreases ischemic risks but increases the risk of major bleeding compared to aspirin alone10. Clopidogrel, one of the first P2Y12 inhibitors, has some pharmacological limitations including variations in metabolism given genetic polymorphisms, slow onset of action, and relatively mild platelet reactivity inhibition. Thus, newer P2Y12 inhibitors such as prasugrel, ticagrelor and cangrelor were developed.1 

     

    2016 ACC/AHA guidelines recommend a minimum one month of DAPT in patients with stable ischemic heart disease (SIHD) receiving a bare metal stent (BMS) since the risk of BMS thrombosis is highest during the initial time after the stent placement. Bare metal stents can be considered for patients who cannot tolerate DAPT (i.e. high bleeding risk, planned major surgery, medication non-adherence).2 However, in most patients with SIHD, drug-eluting stents (DES) are used for the purposes of coronary stenosis prevention. Patients receiving first generation DES (paclitaxel or tacrolimus) should receive at least 12 months of DAPT [2,3]. Newer generation DES (everolimus-, zotarolimus-, ridaforolimus-eluting stents and bioresorbable polymer) showed lower restenosis and thrombosis risk.2,3 With respect to such evidence, 2016 ACC/AHA and 2017 ESC guidelines recommendations on DAPT in SIHD post-percutaneous coronary intervention (PCI) have been shortened from 12 to 6 months (or 3 months if high bleeding risk).2,4  Suggested duration of DAPT in patient with acute coronary syndrome (ACS) post-PCI is at least 12 months (or 6 months if high bleeding risk) per 2016 AHA/ACC and 2017 ESC guidelines2,4 

     

    P2Y12 Inhibitors 

     

    P2Y12 inhibitors are an integral part of antithrombosis due to their role in interruption of platelet aggregation. In typical physiology, platelets patch vessel wall injuries by attaching to an exposed extracellular matrix in the subendothelium through a series of actions. First, platelets interact with the adhesive protein von Willebrand factor by using the glycoprotein (GP) Ib-IX-V receptor complex located on its membrane, and also attach to collagen using GP Ia/IIa and GP VI receptors. Once the platelet is bound, it activates, alters shape, and stimulates degranulation to release soluble platelet agonists including thromboxane and adenosine diphosphate (ADP). These platelet agonists amplify platelet response and aggregation. ADP binds to P2Y1 and P2Y12 G-protein coupled receptors on platelets to activate the GP IIb/IIIa receptor, which results in further platelet degranulation, thromboxane production, and platelet aggregation. P2Y12 inhibitors prevent the activation of GP IIb/IIIa receptor and resulting platelet aggregation by interfering with the binding of ADP to the P2Y12 receptor. 5,6 

     

    Several P2Y12 inhibitors are available on the market with each having their own considerations. Clopidogrel is a prodrug, and requires metabolism to its active form carboxylesterase-1 through CYP2C19. Poor and intermediate metabolizers of this enzyme may not have the same efficacy as a result, and an alternate P2Y12 inhibitor might be a better choice. Poor metabolizers include genotypes *2/*2, *2/*3, *3/*3, which are more commonly found in patients of Asian descent, and intermediate genotypes include *1/*2, *1/*3, and *2/*17. Prasugrel is also a prodrug, however it is converted to its active metabolite by several pathways and is less affected by variations in metabolism. Notably, it should be avoided in patients who have a history of stroke or transient ischemic attack. Prasugrel is found on the Beers list and is generally not recommended for use in patients over the age of 75 due to bleeding risks. Additionally, dose reductions are recommended for patients with a body weight of less than 60 kg. Ticagrelor is a reversible P2Y12 inhibitor, and is the only one that requires twice daily dosing. It is recommended to avoid aspirin doses of more than 100 mg daily while using ticagrelor due to reduced efficacy. Cangrelor is an intravenous option for patients who are unable to take oral agents. It is a reversible inhibitor with a rapid onset of action and a short half-life. As a result, normal platelet function returns within an hour of treatment discontinuation. Table 1 provides a guide for recommended dosing of the different P2Y12 options. 5,6 


    Clinical Trial Review   

    There has been increased recent interest in the question of DAPT duration of therapy for patients following PCI, with many studies having been published in this area. Table 2 gives a summary of some of the more current individual studies that have been completed on this topic including the studied population and the conclusions that were drawn. Additionally, there have been several meta-analyses and systematic reviews conducted to investigate the most optimal duration of DAPT in patients undergoing PCI that are discussed further. Cumulatively, the results of these studies demonstrate the complexity of the topic and the need for patient specific considerations in therapy recommendations. 

    A recent systematic review and individual level meta-analysis of randomized controlled trials by Valgimili et al. assessed the risks and benefits of P2Y12 inhibitor monotherapy compared with DAPT and whether these associations were modified by patient characteristics [12]. Trials including patients with concomitant indications for anticoagulation were excluded. The investigators censored ischemic and bleeding events in the initial phase of treatment (1 month after coronary revascularization) as the rates of stent thrombosis are known to be highest approximately 1 month after coronary revascularization . The findings showed that aspirin withdrawal 1-3 months after PCI and continuation with monotherapy conserved ischemic protection compared with DAPT with effects irrespective of the choice of P2Y12 inhibitor. [12] 

    Another recent meta analysis by Xu et al. assessed randomized controlled trials that included adults with coronary artery disease who received DAPT after PCI with implantation of drug eluting stents. Any studies utilizing bare metal stents were excluded, as well as studies with a crossover design. In total, 24 trials with a total of 81,339 participants overall were reviewed. Five trials compared DAPT for 12 months to durations longer than a year, seven trials compared DAPT for 12 months to 6 months, three trials compared DAPT 12 months to DAPT for 3 months followed by aspirin monotherapy, three trials compared DAPT for 12 months to DAPT for 3 months followed by P2Y12 monotherapy, four trials compared DAPT for 6 months to DAPT for longer than a year, and two trials compared DAPT for 12 months to DAPT for one month followed by P2Y12 monotherapy.  [13]  

    The findings demonstrated no statistical differences in mortality and cardiac death risk between DAPT for 3 months followed by P2Y12 monotherapy when compared to the other DAPT durations. Unsurprisingly, DAPT for longer than one year was associated with more risks for major bleeding. Studies with shorter durations of DAPT of 3 months or less were associated with reduced risks of bleeding. Interestingly, when assessing ischemic endpoints it was found that DAPT for 3 months followed by P2Y12 monotherapy, DAPT for 3 months followed by aspirin monotherapy, and DAPT for 1 month followed by P2Y12 monotherapy were not significantly different from DAPT for longer than one year, however DAPT for 6 months and DAPT for 12 months were shown to have an increased risk of myocardial infarction compared to DAPT for longer than 12 months. Ultimately, the conclusion was drawn that DAPT for 3 months followed by either P2Y12 or aspirin monotherapy, or DAPT for 1 month followed by P2Y12 monotherapy have a balanced risk of hemorrhage and ischemia, with no clear higher benefit of one strategy out of the three.  [13]  

     

    Takeaways and Recommendations  

    When reviewing that data from the recent literature, there are a few points that are important to consider. First of all, most of the studies were conducted in Asia. This may be a confounding factor, especially in considering the trials that included clopidogrel due to the increased likelihood of genetic differences in metabolism. Secondly, there was an overrepresentation of ticagrelor compared to prasugrel in the studies utilizing newer P2Y12 inhibitors, which may limit the generalizability of the results to prasugrel. Overall, there are several important aspects that are worth investigating to further define the most optimal DAPT duration including the choice of P2Y12 inhibitor, patient demographics (ethnicity), and degree of vessel occlusion. 

     

    In the current practice guidelines, short-term DAPT duration has not been clearly outlined.  

    Nevertheless, a paradigm shift in DAPT duration in patients post-PCI is obviously emerging. A short-term DAPT in patients post-PCI may be an attractive option to mitigate the bleeding risks associated with antiplatelet agents. Long-term duration of DAPT was correlated with increased incidence of bleeding events in comparison to one to three months of P2Y12 monotherapy in patients undergoing percutaneous coronary revascularization with drug-eluting stents [5-9]. Recent meta-analyses have not shown significant differences in major ischemic events in 1-3 months of DAPT in comparison to standard 12-month therapy in patients with CAD after DES implantation [10-11]. This emerging evidence offers a short-term duration of DAPT followed by P2Y12 inhibitor monotherapy as a reasonable choice, particularly in high-bleeding risk patients.  

     

    References  

    1. Laine M, Paganelli F, Bonello L. P2Y12-ADP receptor antagonists: Days of future and past. World J Cardiol. 2016;8(5):327-332.  
    2. Levine GN, Bates ER, Bittl JA, et al. 2016 ACC/AHA Guideline Focused Update on Duration of Dual Antiplatelet Therapy in Patients With Coronary Artery Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines: An Update of the 2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention, 2011 ACCF/AHA Guideline for Coronary Artery Bypass Graft Surgery, 2012 ACC/AHA/ACP/AATS/PCNA/SCAI/STS Guideline for the Diagnosis and Management of Patients With Stable Ischemic Heart Disease, 2013 ACCF/AHA Guideline for the Management of ST-Elevation Myocardial Infarction, 2014 AHA/ACC Guideline for the Management of Patients With Non-ST-Elevation Acute Coronary Syndromes, and 2014 ACC/AHA Guideline on Perioperative Cardiovascular Evaluation and Management of Patients Undergoing Noncardiac Surgery [published correction appears in Circulation. 2016 Sep 6;134(10):e192-4]. Circulation. 2016;134(10):e123-e155.  
    3. Colombo A, Chieffo A, Frasheri A, et al. Second-generation drug-eluting stent implantation followed by 6- versus 12-month dual antiplatelet therapy: the SECURITY randomized clinical trial. J Am Coll Cardiol. 2014; 64:2086–97. 
    4. Valgimigli M, Bueno H, Byrne RA, et al. 2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS: The Task Force for dual antiplatelet therapy in coronary artery disease of the European Society of Cardiology (ESC) and of the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J. 2018;39(3):213-260.  
    5. Wallentin L. P2Y(12) inhibitors: differences in properties and mechanisms of action and potential consequences for clinical use. Eur Heart J. 2009;30(16):1964-1977. 
    6. Quick Answers. IBM Micromedex [database online]. Truven Health Analytics/IBM Watson Health; 2022. Accessed March 19, 2022. https://www.micromedexsolutions.com 
    7. Kim BK, Hong SJ, Cho YH, et al. Effect of Ticagrelor Monotherapy vs Ticagrelor With Aspirin on Major Bleeding and Cardiovascular Events in Patients With Acute Coronary Syndrome: The TICO Randomized Clinical Trial. JAMA. 2020;323(23):2407-2416.  
    8. Watanabe H, Domei T, Morimoto T, et al. Effect of 1-Month Dual Antiplatelet Therapy Followed by Clopidogrel vs 12-Month Dual Antiplatelet Therapy on Cardiovascular and Bleeding Events in Patients Receiving PCI: The STOPDAPT-2 Randomized Clinical Trial. JAMA. 2019;321(24):2414-2427. doi:10.1001/jama.2019.8145 
    9. Mehran R, Baber U, Sharma SK, et al. Ticagrelor with or without Aspirin in High-Risk Patients after PCI. N Engl J Med. 2019;381(21):2032-2042.  
    10. Hahn JY, Song YB, Oh JH, et al. Effect of P2Y12 Inhibitor Monotherapy vs Dual Antiplatelet Therapy on Cardiovascular Events in Patients Undergoing Percutaneous Coronary Intervention: The SMART-CHOICE Randomized Clinical Trial [published correction appears in JAMA. 2019 Oct 1;322(13):1316]. JAMA. 2019;321(24):2428-2437.  
    11. Vranckx P, Valgimigli M, Jüni P, et al. Ticagrelor plus aspirin for 1 month, followed by ticagrelor monotherapy for 23 months vs aspirin plus clopidogrel or ticagrelor for 12 months, followed by aspirin monotherapy for 12 months after implantation of a drug-eluting stent: a multicentre, open-label, randomised superiority trial. Lancet. 2018;392(10151):940-949.  
    12. Xu Y, Shen Y, Chen D, Zhao P, Jiang J. Efficacy and Safety of Dual Antiplatelet Therapy in Patients Undergoing Coronary Stent Implantation: A Systematic Review and Network Meta-Analysis. J IntervCardiol. 2021;2021:9934535. Published 2021 May 5.  
    13. Valgimigli M, Gragnano F, Branca M, et al. P2Y12 inhibitor monotherapy or dual antiplatelet therapy after coronary revascularisation: individual patient level meta-analysis of randomised controlled trials [published correction appears in BMJ. 2022 Jan 27;376:o239]. BMJ. 2021;373:n1332. Published 2021 Jun 16. doi:10.1136/bmj.n1332 

  • 09 Jun 2022 11:40 AM | Anonymous

    I want to start with a huge congratulations to all our R&E poster and award winners!  Their contributions to our society and their research achievements are at the heart of the purpose of the R&E Foundation. 

    Poster Winners: 

    First Place Original Research

    Kaci Mack, PharmD. Candidate at UMKC (Project completed at St. Luke’s Hospital) 

    Comparison of latency antibiotic regimens and dosing in the setting of Preterm Prelabor

     

    2nd place Original Research 

    Avery Tolliver, PharmD, PGY1 Pharmacy Practice Resident Mercy Hospital, Springfield, MO

    Efficacy of Ketamine Sedation Regimens Compared to Non-Ketamine Sedation Regimens in COVID-19 Patients  

     

    Best Encore Presentation 

    Jamie Sullivan, PharmD, PGY1 Pharmacy Resident (Children’s Mercy Hospital, KC)

    Evaluation of amoxicillin/clavulanate suspension formulation selected for inpatient orders at a pediatric hospital 

     

    Best Resident Presentation 

    Alison Croft, PharmD, Southeast Hospital 

    Evaluation of Opioid Prescribing at Postoperative Discharge at a Community Hospital  

     

    Best Student Presentation 

    Kaylee Nichols from UMKC 

    Optimization of Pharmacist-Led Heart Failure Consults 

     

    Research and Education Award Winners 

    The MSHP R&E Foundation is pleased to honor a health system pharmacist for outstanding service to the profession as a preceptor to pharmacy students and/or residents through the Tonnies Preceptor of the Year Award.   

    The 2022 Tonnies Preceptor of the Year Awardee is: 

    Cassie Heffern, Pharm.D., BCACP from Cox Health 

     

    The Garrison Award is presented each year in which a deserving candidate has been nominated in recognition of sustained contributions in multiple areas: 

    • Outstanding accomplishment in practice in health-system pharmacy; 

    • Outstanding poster or spoken presentation at a state or national meeting; 

    • Publication in a nationally recognized pharmacy or medical journal; 

    • Demonstrated activity with pharmacy students from St. Louis or the UMKC Schools of Pharmacy; 

    • Development of an innovative service in a health-system pharmacy in either education, administration, clinical service, or distribution; 

    • Contributions to the profession through service to ASHP, MSHP and/or local affiliates. 

    The 2022 Garrison Award winner is: 

    Tony Huke, Pharm.D., BCPS from Vizient Inc. 

     

    Please join me in once again congratulating these authors and awards winners in their successful research and recognition by MSHP R&E Foundation! 

     

    Educational Sessions 

    The MSHP R&E Foundation continues to offer our new Resident Ground Rounds series and our Preceptor Development Series.   

    Information for the Resident Ground Rounds Series can be found here:  

    https://www.moshp.org/event-4540419  

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

    The Preceptor Development Series continues with quarterly programming for preceptors of all levels throughout our state.  Please check the Upcoming Events section of the MSHP website for the full schedule of events. 

    Due to our inability to have in person events, fund raising for the R&E foundation has been a challenge over the last few years.  If you are able, please donate to the R&E here: https://www.moshp.org/donate  

    Additionally, please visit the recently updated R&E Website at https://www.moshp.org/foundation which includes the R&E Board, updated award winners, and award archives! 

    Have a wonderful late spring and early summer! 

    Respectfully submitted,  

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

     


  • 25 May 2022 8:09 AM | Anonymous

    By: Annie Kliewer, PharmD, BCPS

    Hundreds of community and health-system based pharmacists came together in Jefferson City. On April 6th, we flooded the capitol with white coats, talking to our legislators about a variety of issues that greatly impact the practice of pharmacy and the care which we can provide our patients. Here is where each of the pharmacy/healthcare related bills of MSHP, MHA and MPA’s ended up by the conclusion of the 2022 MO Legislative session on May 13, 2022:

    HB 2305

    Creates provisions relating to insurance coverage of pharmacy servicesSponsored by:

    • Representative Dale Wright, represents portions of St. Francois, Ste. Genevieve, and Perry counties
    Summary:
    • Whitebagging - Requires coverage from insurance plans for certain services including pharmacist-administered services, and coverage for products even if not obtained from covered entity   
    • 340B - Health carriers/PBMs may not discriminate against reimbursement of 340B drugs.
    • Biosimilars - Requires coverage for biosimilars in which the reference product is covered.

    Updated Status:

    • Referred to the House’s Insurance Committee
    • A public hearing was completed on 4/5/2022 in which MSHP and MPA members spoke in support of the bill
    • The bill did not reach the floor for a vote prior to the close of session 


    HB 1677 (SB 921)Enacts provisions relating to payments for prescription drugs

    Sponsored by:

    • Senator Bill White, represents Jasper, Dade, and Newton counties
    • Representative Dale Wright, represents portions of St. Francois, Ste. Genevieve, and Perry counties
    Summary:
    • Requires increased reporting from PBMs on rebates received from manufacturers and amount that was not passed on to Missouri Consolidated Health Care Plan
    • PBMs cannot discriminate against 340B drug pricing, and must reimburse fairly
    • Penalties can be imposed on a PBM for each violation
    Updated Status:  
    • Referred to the House’s Health and Mental Health Policy Committee
    • Passed in the House and sent to the Senate on 3/28/2022
    • Referred to Senate’s Insurance and Banking Committee on 3/31/2022
    • Public Hearing was held on 4/12/2022
    • The bill did not reach the Senate floor for a vote prior to the close of session 


    HB 2452 (SB 1126)

    Modifies provisions relating to the administration of medications by pharmacists

    Sponsored by:

    • Senator Holly Thompson Rehder, represents Bollinger, Cape Girardeau, Madison, Perry, Scott, and Wayne counties
    • Representative Bennie Cook, represents Texas, Phelps, Pulaski, and Howell Counties.

    Summary:

    • Repeals former legislation that limited pharmacists to administering only certain vaccines
    • Allows pharmacists with Medication Therapy Services (MTS) certificate to administer ANY vaccine approved by the FDA to persons 7 years and older using statewide collaborative practice agreement

    Updated Status: 

    • Referred to the House’s Emerging Issues Committee
    • Perfected with Amendments HA 1, HA 2 as amended, HA 3 adopted on 4/14/2022
    • Placed on the informal third reading calendar on 4/25/2022
    • Dropped from Calendar, pursuant to House rules on 5/10/2022
  • 14 Apr 2022 8:33 AM | Anonymous

    By: Nicole Evans-Turk, Pharm.D Candidate 2022

    Mentor: Amy Tiemeier, Pharm.D., BCPS

    With the growing medicalization of marijuana and legalization of recreational marijuana, information on the medicinal value of the plant as well as risks of using marijuana are needed. With any drug, there are risks and benefits to its use. Marijuana is the most used drug by adolescents.1 With strains of marijuana becoming more potent and with new inventive ways to consume it, risks may be more significant in adolescents and have impact into adulthood. This article will discuss the potential risks for adolescents who use marijuana, with marijuana being defined as the whole plant that is smoked or ingested.

    Adolescents have more access to marijuana now than they did even 10 years ago. While it is available for adults over 21 in some states, 11-23% of recreational outlets may sell to minors.2 Marijuana has also commercialized and is advertised in newspapers and on billboards. While more research is needed to determine whether the exposure to marijuana advertisements influences adolescents to start using marijuana before adulthood, at least one study has found a positive correlation between ad exposure and perceived ease of access for teens.3 Annual prevalence of marijuana usage among high school seniors increased from 22% to 36% over the decade from 2004 to 2014.1 In a 2020 survey, 19.8% of high school age people report using marijuana in the past month4. With the increased usage, there are effects on the brain that affect more and more people as they mature into adults. A review of adolescent brain development and marijuana is important given these facts.

    Adolescence is a critical period for neurodevelopment and it is characterized by dynamic changes in the mesolimbic dopamine pathway.5 The echocannabinoid (eCB) system reaches peak expression and activity during adolescence. The eCB system acts as a regulator in the reward pathway and also plays a role in determining vulnerability to drug addiction. The CB1 (cannabinoid 1) receptor and eCB ligand N-arachidonoylethanolamine (AEA) both have peaks in expression during adolescence as well. AEA is regulated by the enzyme fatty acid amide hydrolase (FAAH), which is expressed in brain regions that are implicated in the reward and addiction pathways. Activation of this system gives adolescents more intense effects from marijuana than adults usually experience due to the greater expression of AEA and CB1. With prolonged and repeated activation, adolescent brains have a higher risk of a psychological addiction through these pathways5. National surveys have found that youth who engaged in marijuana use in later teen years were less likely to develop substance use disorders compared with those who started earlier, which correlates with the changes in the eCB system in adolescents compared to adults.4

    Marijuana-related effects on white matter and grey matter can have widespread implications for brain development, such as impairments in daily functioning.1 White matter in the brain is the communication pathways between areas of the brain and grey matter is the structures where the processing is done. Grey matter changes for marijuana users during adolescence is still being studied, but a study in 2010 found users to have decreased right orbital prefrontal cortex volume compared to non-users. The prefrontal cortex controls the executive functioning skills such as planning and decision-making. The decreased volume of the prefrontal cortex correlates to lower executive reasoning skills and executive dysfunction. The volume reduction is positively correlated with the age in which the person started using marijuana, with the most changes being seen in those who started using at a younger age.1 Findings in white matter between adolescent marijuana users and non-users also differ. An increase in mean diffusivity in the prefrontal fiber bundles of the corpus callosum is also found in adults who use marijuana heavily and started as an adolescent. These fibers are what allows the prefrontal cortex to receive information and process it. The effects of these changes to the grey and white matter of the brain are theorized to negatively affect executive functioning skills but the full extent is still being studied.

    A common theory is that using THC (tetrahydrocannabinol) in adolescence can contribute to mental disorders in adulthood. In a study where they used a questionnaire to assess whether cannabis use was linked to increased psychiatric symptoms, respondents who met criteria for cannabis use disorder were more likely to report having experienced hallucinations or paranoia. Participants who also met criteria for depression were also more likely to experience hallucinations or paranoia with use of cannabis.6 Adolescents who use marijuana are more likely to misattribute meaning to life events, which can implicate symptoms of psychological disorders. Cannabis use is considered an environmental risk factor in the development of cognitive dysfunction and psychotic disorders.5 While psychological disorders correlate with adolescent marijuana use, there is not enough data to link the two as cause and effect. There could be another conclusion that adolescents with psychological disorders may be self-medicating with marijuana.

    The conclusions of a meta-analysis show that executive functioning seems to be more impaired in frequent users who are adolescents than in frequent users who are adults. Most age related effects seem to be prominent among heavy and dependent users compared to those who may use sporadically.  In addition, adolescents may also have more cravings after marijuana intoxication compared to adults.6 Marijuana use was associated with declines in neural connectivity over time, which correlate to adverse effects on IQ and executive function.4 Executive function refers to decision-making, planning, self-control and organization. This confirms that there are physical changes in the adolescent brain that happen with frequent marijuana usage. The full extent of how the brain and cognitive abilities are affected needs to be researched further.

    In conclusion, pharmacists should be aware of the decisions that adolescents make to use marijuana. With new data coming out that confirms there are neurodevelopmental changes that can happen with prolonged marijuana use in adolescents, children and caregivers should be educated on the potential long-term effects of using marijuana during adolescent years. A pharmacist who specializes in pediatrics or psychiatry should also continue to keep up to date on new research as it comes out about the eCB system and its mechanisms in relation to marijuana.


    References

    1. Jacobus J, Tapert SF. Effects of cannabis on the adolescent brain. Curr Pharm Des. 2014;20(13):2186-2193. doi:10.2174/13816128113199990426
    2. Lipperman-Kreda S, Grube JW. Impacts of Marijuana Commercialization on Adolescents' Marijuana Beliefs, Use, and Co-use With Other Substances. J Adolesc Health. 2018;63(1):5-6. doi:10.1016/j.jadohealth.2018.05.003
    3. Turel O. Perceived Ease of Access and Age Attenuate the Association Between Marijuana Ad Exposure and Marijuana Use in Adolescents. Health Educ Behav. 2020;47(2):311-320. doi:10.1177/1090198119894707
    4. Dharmapuri S, Miller K, Klein JD. Marijuana and the Pediatric Population. Pediatrics. 2020;146(2):e20192629. doi:10.1542/peds.2019-2629
    5. Hurd YL, Manzoni OJ, Pletnikov MV, Lee FS, Bhattacharyya S, Melis M. Cannabis and the Developing Brain: Insights into Its Long-Lasting Effects [published correction appears in J Neurosci. 2020 Jan 8;40(2):493]. J Neurosci. 2019;39(42):8250-8258. doi:10.1523/JNEUROSCI.1165-19.2019
    6. Levy S, Weitzman ER. Acute Mental Health Symptoms in Adolescent Marijuana Users. JAMA Pediatr. 2019;173(2):185-186. doi:10.1001/jamapediatrics.2018.3811
    7. Meruelo AD, Castro N, Cota CI, Tapert SF. Cannabis and alcohol use, and the developing brain. Behav Brain Res. 2017;325(Pt A):44-50. doi:10.1016/j.bbr.2017.02.025
  • 13 Apr 2022 1:18 PM | Anonymous

    By: Avery Tolliver, PharmD; PGY1 Pharmacy Resident

    Mentor: Blake Rosenfelder, PharmD; Clinical Pharmacy Specialist
    Mercy Hospital, Springfield, MO

    Program Number:  2022-04-07
    Approved Dates:  April 1, 2022-October 1, 2022
    Pending Approval for Contact Hours:  One Hour(s) (1) CE(s) per session

    Learning Objectives:

    1. Identify similarities and differences between tenecteplase and alteplase for fibrinolysis.
    2. Identify ischemic stroke patients in which tenecteplase could be of benefit.  
    3. Discuss the most recent data surrounding the use of tenecteplase for ischemic strokes.

    Background

    Acute ischemic strokes (AIS) are one of the leading causes of death for Americans.  In the United States around 795,000 people suffer from strokes each year, leading to significant morbidity and mortality.1 The American Heart Association’s (AHA) and American Stroke Association’s (ASA) joint guidelines on the early management of AIS has for many years recommended the use of the fibrinolytic medication alteplase for select ischemic stroke patients who can be treated within 4.5 hours of symptom onset. AHA/ASA AIS guidelines prior to the 2019 revision did not recommend the use of fibrinolytics other than alteplase. In the 2019 guideline revision AHA/ASA changed their recommendations, suggesting the use of tenecteplase over alteplase could be reasonable in patients without contraindications for intravenous (IV) fibrinolysis that are also eligible to undergo mechanical thrombectomy.2 The updated recommendation was a result of newly published studies comparing tenecteplase and alteplase. Since the publication of the 2019 guidelines, additional studies have shown the efficacy of tenecteplase for ischemic strokes and have further supported its use. These studies, along with shortages of alteplase, have increased the medical community’s interest in and use of tenecteplase. The following discussion of the evidence supporting tenecteplase for AIS and comparing it to alteplase will better prepare pharmacists to treat ischemic stroke patients and answer tenecteplase related questions from their multidisciplinary teams.

    Tenecteplase vs. Alteplase

    Alteplase (brand name Activase) and tenecteplase (brand name TNKase) are thrombolytic agents that have been approved by the Food and Drug Administration (FDA) for the treatment of ST-elevation myocardial infarction (STEMI).3,4 Alteplase is also FDA approved for acute ischemic stroke and pulmonary embolism, but these are off-label uses for tenecteplase. Alteplase is one of the most used thrombolytic agents and gained FDA approval in 1989, afterwards came the approval of tenecteplase in 2000.3,4

    Tenecteplase and alteplase are in the same drug class causing them to have similarities but also to have pharmacokinetic and pharmacodynamic differences. Both agents work by binding to fibrin and converting plasminogen to plasmin initiating fibrinolysis of a thrombus.3 Alteplase, a recombinant tissue plasminogen activator (tPA), varies from tenecteplase (TNK-tPA) by modifications of three molecular sites. The three molecular modifications were engineered to give tenecteplase a longer half-life compared to alteplase.5 Tenecteplase has a biphasic initial half-life of 20 to 24 minutes and terminal half-life of 90 to 130 minutes which is longer than alteplase’s initial half-life of 5 minutes and terminal half-life of 27 to 46 minutes.3,4 Additionally, tenecteplase’s three molecular modifications allow for higher fibrinogen specificity and enhanced resistance to plasminogen activator inhibitor-1 compared to alteplase.5 Although pharmacokinetically different in some ways alteplase and tenecteplase are both hepatically metabolized.3,4

    Due to the structural and pharmacokinetic differences between tenecteplase and alteplase their dosing strategies are different from one another. For the indication of AIS, a total dose of 0.9 mg/kg of alteplase is given IV, with 10% of the dose given as a bolus over one minute followed by the remaining 90% of the dose given by continuous infusion over 60 minutes.3 The maximum dose of alteplase for AIS is 90 mg. The complex administration of bolus and continuous infusions is due to alteplase’s short half-life and is avoided with tenecteplase’s longer half-life. For tenecteplase the AHA/ASA guideline recommended AIS dosing is 0.25 mg/kg with a maximum of 25 mg given as a single IV bolus over 5 seconds.2,3 The difference in tenecteplase dosing for the FDA-approved STEMI indication and the off-label AIS indication should be noted.  The tenecteplase dosing for STEMI is based on weight ranges, and doses range from 30 to 50mg, which is approximately 0.5 mg/kg; however, the dose is still administered as a single bolus over 5 seconds. Neither tenecteplase nor alteplase require dose adjustments for renal or hepatic impairment.3

    Although these two thrombolytic agents are dosed differently, they are supplied in similar ways and are expensive. Alteplase comes in kits from the manufacturer, Genentech, with 50 mg or 100 mg vials of alteplase.3,4 The kits contain sterile water for injection and a transfer device to reconstitute the vials. Additionally, alteplase vials include a hanging loop to allow administration of the dose from the vial. The 50 mg alteplase kit costs around $5,300 and the 100 mg kits cost around $10,500 each. Tenecteplase is also supplied by Genentech, and a 50 mg kit contains a 50 mg vial of tenecteplase, sterile water for injection, and syringe for reconstituting the vial and bolus administration. The tenecteplase kit costs around $7,500. One precaution to be aware of when preparing and administering tenecteplase is that it is incompatible with dextrose solutions; lines must be flushed with saline prior to and after administration. Alteplase is compatible with 5% dextrose and 0.9% saline.3,4 Additionally, the packaging for tenecteplase kits is designed to highlight the dosing for a STEMI.  As a consequence, this could result in a substantial overdose if STEMI dosing is used when treating an AIS. 

    Along with other commonalities, tenecteplase and alteplase have similar adverse drug reactions. The major adverse drug reactions for both agents include a variety of hemorrhagic complications. Tenecteplase has high rates of hematomas (12.3%), hemorrhage (21.8%), renal artery hemorrhage (3.7%), and gastrointestinal hemorrhage (1.9%). Alteplase has high rates of intracranial hemorrhage (within 90 days 15%), gastrointestinal hemorrhage (5%), and genitourinary tract hemorrhage (4%). Neither of the agents have black box warnings or risk evaluation and mitigation strategies (REMS) programs.3,4

    Recent Tenecteplase AIS Studies

    The 2019 revision to the AHA/ASA acute ischemic stroke guidelines stated that tenecteplase could be used over alteplase for patients without contraindications for IV fibrinolysis and who are eligible to undergo mechanical thrombectomy.2 This new recommendation was a result of the EXTEND-IA TNK trial (Tenecteplase Versus Alteplase Before Endovascular Therapy for Ischemic Stroke) published in April of 2018.6 The EXTEND-IA TNK trial was a prospective, randomized, blinded outcome trial. Ischemic stroke patients included in the trial were within 4.5 hours of symptom onset and had large-vessel occlusion of the internal carotid, middle cerebral, or basilar artery. Patients also had to be eligible for IV thrombolysis and endovascular thrombectomy. Included patients were randomized to tenecteplase at a dose of 0.25 mg/kg (maximum 25 mg) or alteplase at a dose of 0.9 mg/kg (maximum 90 mg). The primary outcome investigated was substantial reperfusion, defined as the restoration of blood flow to more than 50% of the affected area or an absence of retrievable thrombus in the target vessel. The primary outcome was observed in 22 patients (22%) who received tenecteplase and 10 patients (10%) who received alteplase (P=0.002 for noninferiority). For the secondary outcome of modified Rankin scale (mRs) score at 90 days the tenecteplase group had a median score of 2 compared to the median score of 3 for the alteplase group (P=0.04). This outcome suggests a better functional outcome with tenecteplase compared to alteplase. However, there was no significant difference shown in early neurologic improvement measured by median National Institutes of Health Stroke Scale (NIHSS) scores at 24 hours. The NIHSS score at 24 hours for the tenecteplase group was 3 and NIHSS score was 6 for the alteplase group (P=0.06). The results of EXTEND-IA TNK show that tenecteplase is noninferior to alteplase in restoring perfusion for proximal cerebral artery occlusions and tenecteplase could lead to better functional outcomes for AIS patients.6

    The EXTEND-IA TNK trial showed noninferiority of the 0.25 mg/kg (25 mg maximum) dose of tenecteplase compared to alteplase for AIS. However, during the recruitment phase of the EXTEND-IA TNK trial the results of the Norwegian Tenecteplase Stroke Trial (NOR-TEST) were published and NOR-TEST used 0.4 mg/kg of tenecteplase. NOR-TEST, a phase 3, randomized, open-label, superiority trial was published in August 2017.7 Ischemic stroke patients with measurable deficits on the NIHSS, admitted within 4.5 hours of symptom onset or within 4.5 hours of awakening with symptoms, and eligible for IV thrombolysis were eligible for the NOR-TEST study. Patients were randomized to two groups, an alteplase group receiving standard dosing and a tenecteplase group receiving 0.4 mg/kg (maximum 40 mg) as a single bolus. The primary end point evaluated was excellent functional outcome at 3 months measured as a mRs score of 0 to 1. In the tenecteplase group 354 (64%) achieved the primary outcome compared to 345 (63%) in the alteplase group (P=0.52). For the secondary outcome of intracranial hemorrhage (ICH) 24 to 48 hours after thrombolytic treatment, 47 (9%) patients in the tenecteplase group suffered from ICH compared to 50 (9%) in the alteplase group (P=0.82). Death at 3 months was also reported showing 29 (5%) deaths in the tenecteplase group compared to 26 (5%) in the alteplase group (P=0.68).7 The NOR-TEST trial did not show tenecteplase to be superior to alteplase for treatment of AIS. However, the NOR-TEST trial did show that the higher tenecteplase dose of 0.4 mg/kg had a similar safety profile to alteplase.

    Following the EXTEND-IA TNK and NOR-TEST trial publications a meta-analysis of 5 randomized trials was performed to determine if evidence supported tenecteplase being noninferior to alteplase for acute ischemic stroke.8 The formal meta-analysis published in May 2019 looked at the primary efficacy end point of disability free outcome, measured as a mRs score of 0 to 1, at 3 months post stroke. All alteplase patients received the standard AIS dosing, and tenecteplase patients received one of three doses as a one-time bolus, 0.1 mg/kg (6.8%), 0.25 mg/kg (24.6%), or 0.4 mg/kg (68.6%). Data from all 5 trials contributed to the primary outcome of disability free outcomes in 57.9% of tenecteplase patients compared to 55.4% of alteplase patients. The random-effects meta-analysis showed a risk difference of 4% (95% CI, -1% to 8%) falling within the noninferiority criteria for the primary outcome. For the secondary analysis of functional independence, measured as a mRs score of 0 to 2 at 3 months, data was available from 4 of 5 trials. The data showed the rate of independence was 71.9% in the tenecteplase group compared to 70.5% in the alteplase group, with a risk difference of 8% (95% CI, -4 to 20%) showing noninferiority. For the safety outcomes of symptomatic ICH and death, data was available for all 5 trials. ICH occurred in 3% of tenecteplase patients and 3% of alteplase patients. Mortality occurred at 3 months in 7.6% of tenecteplase patients compared to 8.1% of alteplase patients. Overall, this combined clinical trial data indicates that tenecteplase given for the treatment of AIS is noninferior to alteplase when measuring disability free outcomes and poses no greater safety risk.8

    In addition, another systemic review with meta-analysis exploring the use of tenecteplase for thrombolysis in stroke patients was published in 2021.9 The meta-analysis included eight studies involving a total of 2031 patients that underwent thrombolysis for AIS. Tenecteplase showed an increase in recanalization rate (ARD =0.11, 95% CI [0.01;0.02]) and early neurological improvement (ARD=0.10, 95% CI [0.02;0.17]) compared to alteplase. Also, tenecteplase demonstrated an increase in good (mRs 0-2) and excellent (mRs 0-1) functional outcomes; however, these improvements were not statistically significant. Safety outcomes for this meta-analysis also showed no difference in ICH or mortality between tenecteplase and alteplase.9 This systemic review with meta-analysis reinforces the results of prior studies and further strengthens the AHA/ASA guideline recommendation on the use of tenecteplase.

    Earlier Tenecteplase AIS Studies

    The recent randomized controlled trials and meta-analysis are being used to support the AHA/ASA guideline changes, but they are not the only studies supporting the use of tenecteplase for AIS. There are three older randomized controlled studies that are also frequently referenced. The first being Phase IIB/III Trial of Tenecteplase in Acute Ischemic Stroke published in 2010.10 This study is a randomized, multi-center, double-blind trial comparing tenecteplase and alteplase in AIS patients within 3 hours of symptom onset. The study compared tenecteplase 0.1 mg/kg, 0.25 mg/kg, and 0.4 mg/kg to alteplase. Specifically looking into the co-primary outcomes of proportion of poor outcomes (mRs 4-6) and proportion of good outcomes (mRs 0-1). The study was terminated early, however, the results reported out showed the 0.1 mg/kg tenecteplase group to have the least poor outcomes with only 7 (22.6%) compared to 10 (32.3%) in the alteplase group. The 0.25 mg/kg tenecteplase group had the most good outcomes with 15 (48.4%), followed by the 0.1 mg/kg group with 14 (45.2%), and the alteplase group only had 13 (41.9%).10 This study continues to show the trend of tenecteplase having similar outcomes to alteplase for AIS and possibly having fewer poor outcomes.

    Another phase IIB, randomized, open-label, blinded trial that is commonly referenced is A Randomized Trial of Tenecteplase versus Alteplase for Acute Ischemic Stroke by Parsons, et al.11 The study included AIS patients within six hours of symptom onset with presence of intracranial occlusion of the anterior cerebral, middle cerebral, or posterior cerebral arteries on computed tomography (CT) angiography. Patients were randomized to one of three groups: 0.1 mg/kg (maximum 10 mg) tenecteplase, 0.25 mg/kg (maximum 25 mg) tenecteplase, or alteplase. The co-primary outcomes investigated were the percentage of the perfusion lesion that was reperfused 24 hours after treatment and clinical improvement at 24 hours measured by NIHSS scores. Reperfusion at 24 hours occurred in 79.3% ± 28.8% of the tenecteplase patients compared to 55.4% ± 38.7% of the alteplase patients (P=0.004). While the improvement in NIHSS scores between baseline and 24 hours was around 3 ± 6.3 hours in the alteplase group compared to 8.0 ± 5.5 hours in the tenecteplase group (P<0.001). This study is limited by its small enrollment of 75 patients in total, however, it shows greater reperfusion and greater clinical improvement in the tenecteplase group compared to alteplase.11

    The third trial, ATTEST (Alteplase Versus Tenecteplase for Thrombolysis After Ischemic Stroke: a phase 2, randomized, open-label, blinded endpoint study), is commonly referenced and is the foundation for a current on-going study.12 Eligible AIS patients had to have measurable deficits shown by the NIHSS score, be within 4.5 hours of symptom onset, and be eligible for IV thrombolysis. Patients were randomized to 0.25 mg/kg (maximum 25 mg) tenecteplase or standard dose alteplase. The primary outcome investigated was the percentage of hypo-perfused tissue salvaged at 24 to 48 hours post treatment. This was measured by pre and post treatment CTs. There was no significant difference in the primary outcome between tenecteplase (68%) and alteplase (68%). There were also no statistically significant secondary outcomes. However, there was a trend towards more early neurological improvement at 24 hours in the tenecteplase group with 19 (40%) compared to the alteplase group at 12 (24%), and a trend toward a higher proportion of good neurological outcomes (mRs 0-1) at 90 days in the tenecteplase group 13 (28%) compared to alteplase 10 (20%).12 The outcomes of this trial once again support previously discussed studies.

    Dosing of Tenecteplase for AIS  

    Considering the results of the NOR-TEST trial using tenecteplase doses of 0.4 mg/kg (maximum of 40mg) and the EXTEND-IA trial using 0.25 mg/kg (maximum of 25 mg), the EXTEND-IA trial researchers performed the EXTEND-IA TNK Part 2 trial to determine the optimal dosing of tenecteplase in AIS patients.13 EXTEND-IA TNK Part 2 is a randomized, open-label, blinded end point trial of AIS patients within 4.5 hours of symptom onset determined to have large vessel occlusion of the intracranial internal carotid, middle cerebral, or basilar artery. Additionally, patients had to be eligible for IV thrombolysis and endovascular thrombectomy. Eligible patients were randomized to either 0.4 mg/kg (40 mg maximum) of tenecteplase or 0.25 mg/kg (25 mg maximum) of tenecteplase. Substantial reperfusion defined as restoring blood flow to more than 50% of the involved territory or an absence of retrievable intracranial thrombus was the primary outcome investigated. The primary outcome occurred in 29 (19.3%) of the patients in the 0.4 mg/kg tenecteplase group and 29 (19.3%) of those receiving 0.25 mg/kg of tenecteplase (P=0.89). Additionally, the analysis of the secondary outcomes showed no significant differences between groups for mRs scores at 90 days and early neurological recovery. More notably the safety outcome showed no significant difference in symptomatic ICH with 7 (4.7%) of 0.4 mg/kg patients having symptomatic ICHs compared to 2(1.3%) of the 0.25 mg/kg patients (P=0.12). Also, no difference was seen in mortality with 26 deaths in the 0.4 mg/kg group and 22 deaths in the 0.25 mg/kg group (P=0.35). The EXTEND-IA TNK Part 2 trial showed no significantly improved cerebral reperfusion with 0.4 mg/kg of tenecteplase compared to 0.25 mg/kg prior to endovascular thrombectomy in patients with large vessel occlusion ischemic strokes.13 EXTEND-IA TNK Part 2 results further support the use of the 0.25 mg/kg (max 25 mg) dose recommended by the AHA/ASA guidelines.2

    In-Progress Studies

    Whether or not tenecteplase should be used in place of alteplase for AIS is still a difficult question to answer with the current data from small sample size studies. However, there are several studies currently being performed that will give more insight into this question when completed. One on-going study is the Alteplase-Tenecteplase Trial Evaluation for Stroke Thrombolysis (ATTEST2) which is looking at functional outcome at 90 days, measured by the modified Rankin Scale, to determine if tenecteplase is superior in efficacy to alteplase.14 A similar study is The Norwegian Tenecteplase Stroke Trial 2 (NOR-TEST 2) which is looking into the safety and efficacy of 0.4mg/kg of tenecteplase versus alteplase for AIS patients within 4.5 hours of symptom onset, awakening with stroke symptoms, or bridge therapy before thrombectomy. The primary endpoint is functional outcome at 90 days measured with the mRs.15 Another on-going study is the Alteplase Compared to Tenecteplase in Patients with Acute Ischemic Stroke (AcT) trial to see if 0.25 mg/kg (max 25 mg) IV tenecteplase is non-inferior to IV alteplase in patients with AIS. Like the other ongoing studies, the primary outcome is functional outcome between days 90 to 120 based on the mRs.16 These are a few of the in-progress studies looking into the efficacy and safety of tenecteplase compared to alteplase for AIS patients. These studies have the potential to further define tenecteplase’s place in therapy for AIS patients.  

    Conclusion 

    Tenecteplase has many positive attributes making it a more ideal choice than alteplase for thrombolysis in AIS patients. Its molecular modifications allow higher fibrinogen specificity, enhanced resistance to plasminogen activator inhibitor 1, and a longer half-life compared to alteplase. These qualities allow bolus administration of tenecteplase which is faster and less error prone than the bolus and infusion administration of alteplase. The bolus administration of tenecteplase also allows non-thrombectomy hospitals faster door-in to door-out times for those patients that require thrombolysis followed by thrombectomy at a qualified institution. Finally, in addition to faster administration, tenecteplase is less costly than alteplase by approximately $3,000 dollars per dose.

    Tenecteplase’s pharmacokinetic profile is ideal for AIS patients, and study results are starting to reinforce that fact. The studies reviewed show tenecteplase has comparable efficacy to alteplase in AIS patients with large vessel occlusions and could lead to better functional outcomes. Tenecteplase, compared to alteplase in one meta-analysis, also showed non-inferiority in disability free outcomes and increased functional independence. Another meta-analysis reported increased recanalization rates and early neurological improvement with tenecteplase compared to alteplase. All of these studies are showing positive results in favor of using tenecteplase for patients who are candidates for IV thrombolysis and mechanical thrombectomy. In addition to positive outcomes, the studies also indicate that tenecteplase’s safety profile is similar to alteplase’s profile in regard to adverse drug reactions. Although currently reported studies already illustrate promising results in favor of tenecteplase, the results of on-going studies will further define tenecteplase efficacy and place in therapy for AIS.

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    References

    1. Centers for Disease Control and Prevention. Stroke Facts. Centers for Disease Control and Prevention website. May 25, 2021. Accessed January 20, 2022. https://www.cdc.gov/stroke/facts.htm.
    2. Powers WJ, Rabinstein AA, Ackerson T, et al. Guidelines for the early management of patients with acute ischemic stroke: 2019 update to the 2018 guidelines for the early management of acute ischemic stroke: A guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2019;50(12):e344-e418. doi: 10.1161/STR.0000000000000211.
    3. Lexi-Drugs. Lexicomp Online. Wolters Kluwer Health, Inc. Accessed January 7, 2021. http://online.lexi.com
    4. In: IBM Micromedex® DRUGDEX® (electronic version). IBM Watson Health, Greenwood Village, Colorado, USA. Accessed January 7, 2021. https://www.micromedexsolutions.com.
    5. Tanswell P, Modi N, Combs D, Danays T. Pharmacokinetics and pharmacodynamics of tenecteplase in fibrinolytic therapy of acute myocardial infarction. Clin Pharmacokinet. 2002;41(15):1229-45. doi: 10.2165/00003088-200241150-00001.
    6. Campbell B, Mitchell P, Churilov L, et al. Tenecteplase versus alteplase before thrombectomy for ischemic stroke. N Engl J Med. 2018 Apr 26;378(17):1573-1582. doi: 10.1056/NEJMoa1716405.
    7. Logallo N, Novotny V, Assmus J, et al. Tenecteplase versus alteplase for management of acute ischaemic stroke (NOR-TEST): A phase 3, randomized, open-label, blinded endpoint trial. Lancet Neurol. 2017 Oct;16(10):781-788. doi: 10.1016/S1474-4422(17)30253-3.
    8. Burgos AM, Saver JL. Evidence that tenecteplase is noninferior to alteplase for acute ischemic stroke: Meta-analysis of 5 randomized trials. Stroke. 2019 Aug;50(8):2156-2162. doi: 10.1161/STROKEAHA.119.025080.
    9. Oliveira M, Fidalgo M, Fontao L, et al. Tenecteplase for thrombolysis in stroke patients: Systematic review with meta-analysis. Am J Emerg Med. 2021 Apr;42:31-37. doi: 10.1016/j.ajem.2020.12.026.
    10. Haley E, Thompson J, Grotta J, et al. Phase IIB/III trial of tenecteplase in acute ischemic stroke: Results of a prematurely terminated randomized clinical trial. Stroke. 2010 Apr;41(4): 707-11.doi: 10.1161/STROKEAHA.109.572040.
    11. Parsons M, Spratt N, Bivard A, et al. A randomized trial of tenecteplase versus alteplase for acute ischemic stroke. N Engl J Med. 2012 Mar 22;366(12):1099-107. doi: 10.1056/NEJMoa1109842.
    12. Huang X, Cheripelli B, Lloyd S, et al. Alteplase versus tenecteplase for thrombolysis after ischemic stroke (ATTEST): A phase 2, randomized, open-label, blinded endpoint study. Lancet Neurol. 2015 Apr;14(4):368-76. doi: 10.1016/S1474-4422(15)70017-7.
    13. Campbell B, Mitchell PJ, Churilov L, et al. Effect of intravenous tenecteplase dose on cerebral reperfusion before thrombectomy in patients with large vessel occlusion ischemic stroke: The EXTEND-IA TNK Part 2 randomized clinical trial. JAMA. 2020 Apr 7;323(13):1257-1265. doi: 10.1001/jama.2020.1511.
    14. U.S. National Library of Medicine. Alteplase-Tenecteplase Trial Evaluation for Stroke Thrombolysis (ATTEST2). ClinicalTrials.gov. June 27, 2016. Updated March 29, 2018. Accessed January 20, 2022.https://clinicaltrials.gov/ct2/show/NCT02814409.
    15. U.S. National Library of Medicine. The Norwegian Tenecteplase Stroke Trial 2 (NOR-TEST 2). ClinicalTrials.gov. February 26, 2019. Updated November 8, 2021. Accessed January 20, 2022. https://clinicaltrials.gov/ct2/show/NCT03854500.
    16. U.S. National Library of Medicine. Alteplase Compared to Tenecteplase in Patients with Acute Ischemic Stroke (AcT). ClinicalTrials.gov. March 26, 2019. Updated December 16, 2021. Accessed January 20, 2022. https://clinicaltrials.gov/ct2/show/NCT03889249 ?term=Tenecteplase&cond=Stroke&draw=2&rank=17.
  • 13 Apr 2022 12:45 PM | Anonymous

    Authors: Lauren McCulley, PharmD, Center for Behavioral Medicine - Kansas City, MO And Mary Beth Dameron, PharmD, BCACP, University Health - Kansas City, MO

    Program Number: 2022-02-02
    Approved Dates:   April 1, 2022-October 1, 2022
    Approved Contact Hours:  One Hour(s) (1) CE(s) per session

    Learning Objectives:

    • Identify the pathophysiology for migraines
    • Describe the role of CGRP inhibitors in migraine therapy
    • Differentiate dosing and mechanism of action between the different CGRP inhibitors
    • Analyze the relevant studies looking at the safety and efficacy of CGRP inhibitors in migraine treatment
    • Determine the place in therapy for CGRP inhibitors


    Background:

    Migraine is a chronic neurologic disease that affects more than 10% of the population worldwide.1 It is often associated with significant distress in a person’s life, which can lead to an inability to perform daily tasks, financial burden, and an increased risk for comorbid mental health diagnoses (such as anxiety and depression).2 The prevalence of migraine and severe headache in the US adult population is 9.7% in males and 20.7% in females.3 According to the National Institutes of Health, migraine-associated pain involves an intense pulsing or throbbing pain in one area of the head. It is often accompanied by nausea, vomiting, phonophobia, and/or photophobia. Common migraine triggers include stress, anxiety, hormonal changes, weather changes, bright or flashing lights, lack of food or sleep, and dietary substances.1 Identification and avoidance of patient-specific triggers may reduce or prevent migraine attacks.

    There are many proposed mechanisms that likely play a pivotal role in the pathophysiology of migraines. Migraine pain is thought to happen after stimulation of the trigeminal sensory nervous pain pathways from vasodilation of local intracranial blood vessels.4 As the trigeminovascular pain pathway is stimulated, vasoactive peptides such as substance P and calcitonin gene-related peptide (CGRP) are released. This leads to an exacerbation of vasodilation, which results in inflammation and pain.5 Due to knowledge regarding the role of CGRP in migraine pathophysiology, new medications specifically targeting CGRP or its receptor have been developed. CGRP antagonists are thought to alleviate migraines through the following processes6:

    • Blocking neurogenic inflammation: CGRP antagonists bind to CGRP receptors present on mast cells, which inhibits inflammation caused by the trigeminal nerve release of CGRP onto mast cells within the meninges of the brain
    • Decreasing artery dilation: CGRP antagonists inhibit dilation of intracranial arteries by blocking CGRP receptors present in smooth muscle cells
    • Inhibiting pain transmission: CGRP antagonists bind to CGRP or its receptors, which results in suppression of pain through inhibition of the central relay of pain signals

    According to the International Classification of Headache Disorders (ICHD-3), a diagnosis of migraine is based on the frequency of monthly migraine days (MMDs), monthly headache days (MHDs), duration of headache attack, and symptom presentation.7 Migraines can be categorized as episodic or chronic and can be treated with preventive and abortive therapies. There are many preventive and abortive treatments approved for migraine. Preventative treatments are used to reduce attack frequency, severity, duration, and disability. Based on patient preference, use of prophylactic therapy is indicated in patients whose migraine attacks interfere with their daily routines despite abortive treatment, have frequent attacks, and have contraindications to or fail abortive treatments.2 Before CGRP inhibitors were studied and approved for preventative treatment, people with migraines were trialed on many oral medications including beta blockers, tricyclic antidepressants, and antiepileptics.  According to the consensus statement in 2021 from the American Headache Society, CGRP inhibitors are indicated for preventative treatment in migraines when persons with migraines have an intolerance or an inadequate response to an 8-week trial of two or more oral preventative treatment options.2

    With CGRP inhibitors playing a larger role in treatment for preventative migraines, this article will discuss CGRP inhibitors and the evidence behind each agent.

    CGRP inhibitors:

    Four CGRP monoclonal antibodies (mAbs) have been approved by the U.S. Food and Drug Administration (FDA) for migraine prophylaxis: eptinezumab, erenumab, fremanezumab, and galcanezumab. Erenumab is the only CGRP mAb that targets the CGRP receptor, whereas the others target the CGRP ligand. Small molecule CGRP antagonists are oral options approved for the preventive treatment of episodic migraine and include atogepant and rimegepant. Additional details outlining medication-specific characteristics can be found in Table 1 below.


    Literature Review:

    Several efficacy and safety trials have been performed to investigate CGRP agents for episodic and chronic migraines and for abortive and preventative treatment. There are no head-to-head trials of CRGP inhibitors in patients with migraines but most of these trials had similar designs and primary endpoints. Each of these trials will be discussed below.

    Erenumab (Aimovig)

    Erenumab has been studied for preventative treatment for both episodic and chronic migraines. There were 2 trials performed for efficacy and safety in episodic migraines. Study 1, known as the STRIVE trial, included 955 patients who were randomized to a subcutaneous injection of erenumab 70mg, 140mg, or placebo once monthly for 6 months. Individuals were included in the trial if they had a history of migraine (with or without aura) for at least 12 months and had at least 4 but no more than 15 migraine days a month across the 3 months prior to screening and during baseline. The primary endpoint was to assess the change from baseline in mean monthly migraine days over months 4 to 6. Researchers found that both erenumab 70mg and 140mg significantly reduced monthly migraine days and use of acute migraine-specific medications when compared to placebo, as outlined in table 2 below.8


    Like the STRIVE trial, study 2 aimed to assess efficacy and safety in episodic migraine preventative treatment. The trial included 546 patients randomized to either erenumab 70mg or placebo subcutaneously once monthly for 3 months. The inclusion criteria was the same as the STRIVE trial. The primary endpoint was the change from baseline in monthly migraine days at month 3. Similar to the STRIVE trial discussed above, this trial found that erenumab 70mg once monthly significantly reduced monthly migraine days and use of acute migraine-specific medications when compared to placebo. Additional details regarding results of efficacy endpoints can be found in table 3.8


    The last trial assessed erenumab for prevention of chronic migraines. This was a 3 month trial with 667 patients randomized to erenumab 70mg, 140mg or placebo given as a subcutaneous injection once monthly. This trial included those with a history of at least 5 attacks of migraine without aura or migraine with visual sensory, speech, language, retinal, or brainstem aura. Participants had to have at least 15 headache days and a minimum of 8 migraine days per month as reported by the participant. The primary endpoint was similar to trials 1 and 2, change from baseline in monthly migraine days at month 3. Consistent with previous studies discussed, both erenumab 70mg and 140mg demonstrated statistically significant improvements in monthly migraine days compared to placebo. A summary of key efficacy endpoints can be found in table 4.8


    Galcanezumab (Emgality)

    Trials for galcanezumab have been performed to assess safety and efficacy in episodic and chronic migraines. Study 1 (EVOLVE-1) and Study 2 (EVOLVE-2) had similar trial designs and included adults with a history of episodic migraine (4 to 14 migraine days per month). The primary endpoint for both studies was the mean change from baseline in the number of monthly migraine headache days over a 6 month treatment period. Patients in EVOLVE-1 and EVOLVE-2 were randomized to receive once monthly injections of galcanezumab 120mg, 240mg, or placebo. Those randomized to the 120mg group received a 240mg galcanezumab loading dose as well. EVOLVE-1 had a total of 858 patients randomized and EVOLVE-2 had a total of 915 patients randomized all 18 to 65 years of age. Overall, these trials demonstrated statistically significant improvements in monthly migraine days with galcanezumab 120mg once monthly dose. The 240mg once monthly dose showed no additional benefit over the 120mg dose. Results of the primary efficacy endpoint are summarized in table 5.9


    The third trial, REGAIN, included adults ages 18 to 65 years old who had a history of chronic migraines (≥15 headache days per month with ≥8 migraine days per month). Patients were randomized to the same doses as trialed in the EVOLVE studies over a 3 month treatment period. The primary endpoint was the mean change from baseline in the number of monthly migraine headache days over the 3 month treatment period. REGAIN had a total of 1113 patients randomized and 1037 individuals completed the 3-month study. Galcanezumab 120mg demonstrated statistically significant improvement in mean change from baseline in the monthly migraine headache days, which is consistent with findings of the EVOLVE trials as discussed above. Galcanezumab 240mg once monthly showed no additional benefit compared to galcanezumab 120mg once monthly. See table 6 for additional details.9


    Fremanezumab (Ajovy)

    The efficacy of fremanezumab was demonstrated in 2 randomized, 3 month, placebo-controlled studies. Study 1 included adults with a history of episodic migraine (<15 headache days per month) who were randomized to receive subcutaneous injections of fremanezumab 675mg every 3 months, fremanezumab 225mg once monthly, or placebo once monthly. Additionally, patients had to have 85% compliance with a headache e-diary and a total body weight between 99 and 265 pounds for study inclusion. The primary endpoint was the mean change from baseline in the monthly average number of migraine days during the 3 month treatment period. A total of 791 patients completed the trial and the trial found that the quarterly (every 3 month) injection and the monthly injection demonstrated statistically significant improvements in migraine days compared to placebo. Results of the primary efficacy endpoint are summarized in table 7.10


    Much like the other trials involving CGRP inhibitors, fremanezumab was also studied in those with chronic migraines (at least 15 headache days per month). In study 2, patients were randomized to fremanezumab 675mg initially, followed by 225 mg once monthly, 675 mg every 3 month, or placebo once monthly for a 3 month treatment period. This study had the same inclusion criteria as study 1 with the exception of the number of headache days per month. A total of 1034 patients completed the trial, and the primary efficacy endpoint was the mean change from baseline in the monthly average number of headache days of at least moderate severity during the 3-month treatment period. Both the monthly and quarterly dosing provided statistically significant improvement in migraine days compared to placebo as outlined in table 8 below.10


    Eptinezumab (Vyepti)

    Eptinezumab has been evaluated for efficacy in two randomized placebo-controlled trials. Study 1 included adults with a history of episodic migraines, which was defined as 4 to 14 headache days with at least 4 migraine days per month. A total of 665 patients were randomized to receive eptinezumab 100mg, 300mg, or placebo every 3 months for 12 months. The primary endpoint was change from baseline in mean monthly migraine days over months 1 through 3. Treatment with eptinezumab 100mg and 300mg demonstrated statistically significant improvements in migraine days compared to placebo. Refer to table 9 for results of the primary efficacy endpoint.11


    The second eptinezumab study included patients with a history of chronic migraine defined as 15 to 26 headache days per month of which at least 8 were migraine days. A total of 1073 patients were randomized to receive eptinezumab 100mg, 300mg, or placebo every 3 months for 6 months total. This study also included those who had a diagnosis of chronic migraine and medication overuse headache. The primary endpoint was the same as study 1 and eptinezumab 100mg and 300mg demonstrated statistically significant improvements in monthly migraine days compared to placebo. Table 10 includes details of the primary efficacy endpoint for this trial.11


    Rimegepant (Nurtec ODT)

    The efficacy of rimegepant was evaluated for the preventive treatment of episodic migraine in adults in a randomized, double-blind, placebo-controlled trial. Individuals with at least a 1-year history of migraine (with or without aura) were randomized to receive every other day dosing of rimegepant 75mg or placebo for 12 weeks. Trial participants had a history of 4 to 18 moderate or severe monthly migraine attacks. Those who experienced ≥6 migraine days and ≤18 headache days during the observation phase were eligible for the study. The primary efficacy endpoint was change from baseline in the mean number of monthly migraine days during weeks 9-12. Results of the trial showed statistically significant improvements for the primary efficacy endpoint in those given rimegepant 75mg every other day compared to placebo, as further described in table 11.12


    Atogepant (Qulipta)

    The efficacy of atogepant was evaluated for the preventive treatment of episodic migraine in adults in two randomized, multicenter, double-blind, placebo-controlled studies. In study 1, 910 participants were randomized to atogepant 10mg, 30mg, 60mg, or placebo once daily for 12 weeks. The primary efficacy endpoint was the change from baseline in mean monthly migraine days across the 12-week treatment period. A total of 805 (88%) of individuals completed the study and atogepant showed statistically significant improvements for the primary efficacy endpoint in those receiving atogepant at any dose when compared to placebo. Key results are included in Table 12.13


    In study 2, 652 participants were randomized to receive atogepant 10mg, 30mg, 60mg, or placebo once daily for 12 weeks. The primary efficacy endpoint evaluated was the same as study 1 and as demonstrated in study 1, there was a significantly larger reduction in mean monthly migraine days across the 12-week treatment period in those receiving atogepant at any dose compared to placebo. Refer to Table 13 for additional details regarding results of the primary efficacy endpoint.13


    Conclusion:

    Migraines can be extremely disabling and may lead to significant distress regarding ability to function or complete daily activities. Preventative migraine treatment is indicated when someone experiences frequent and prolonged severe attacks. Many oral options are available for patients for preventative treatment. However, the emergence of CGRP inhibitors have allowed for yet another treatment option for people who suffer from migraines. Guidelines suggest CGRP inhibitors are indicated after failure of at least two oral preventative treatments. The choice of which CGRP inhibitor to use in a patient is dependent on several factors such as insurance status, patient preference, and tolerability.

    Take the CE Quiz

    References:

    1. Migraine Information Page. National Institute of Neurological Disorders and Stroke. U.S. Dep. Health Hum. Serv. Updated online December 31, 2019. Accessed January 9, 2021. https://www.ninds.nih.gov/Disorders/All-Disorders/Migraine-Information-Page
    2. Ailani J, Burch RC, Robbins MS; Board of Directors of the American Headache Society. The American Headache Society Consensus Statement: Update on integrating new migraine treatments into clinical practice. Headache. 2021 Jul;61(7):1021-1039. doi: 10.1111/head.14153. Epub 2021 Jun 23. PMID: 34160823.
    3. Burch R, Rizzoli P, Loder E. The Prevalence and Impact of Migraine and Severe Headache in the United States: Figures and Trends From Government Health Studies. Headache. 2018 Apr;58(4):496-505. doi: 10.1111/head.13281. Epub 2018 Mar 12. PMID: 29527677.
    4. Hargreaves RJ, Shepheard SL. Pathophysiology of migraine--new insights. Can J Neurol Sci. 1999 Nov;26 Suppl 3:S12-9. doi: 10.1017/s0317167100000147. PMID: 10563228.
    5. Durham P. Calcitonin Gene-Related Peptide (CGRP) and Migraine. Headache. 2006 June;46 Suppl 1:S3-S8.
    6. Durham PL. CGRP-receptor antagonists--a fresh approach to migraine therapy? N. Engl. J. Med. 2004;350(11):1073-1075. doi:10.1056/NEJMp048016.
    7. Headache Classification Committee of the International Headache Society (IHS). The International Classification of Headache Disorders, 3rd edition. Cephalalgia. 2018; 38(1):1-211.
    8. Aimovig [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2019.
    9. Emgality [package insert]. Indianapolis, IN: Eli Lilly and Company; 2018.
    10. Ajovy [package insert]. North Wales, PA: Teva Pharmaceuticals Inc.;2020.
    11. Vyepti [package insert]. Bothell, WA: Lundbeck Seattle BioPharmaceuticals; 2021.
    12. Nurtec [package insert]. New Haven, CT: Biohaven Pharmaceuticals, Inc.; 2020.
    13. Qulipta [package insert]. Dublin, Ireland: Forest Laboratories Ireland Ltd.;2021.
  • 13 Apr 2022 10:15 AM | Anonymous

    By: Brittany Heuay, PharmD Candidate 2022; St. Louis College of Pharmacy at University of Health Sciences and Pharmacy in St. Louis

    Mentor: Kara Berges, PharmD; Mercy Pharmacy Wentzville

    The COVID-19 pandemic has had far-reaching effects beyond the illness caused by the novel virus. The disruption and isolation brought on by the pandemic has increased the demand for mental health services as feelings of loneliness, loss, grief, and anxiety overwhelm those with and without pre-existing mental health illness1. In September of 2021, authors from The Journal of the American Medical Association (JAMA) reported a startling increase of cannabis use in pregnant women during the COVID-19 pandemic. Women report using cannabis as a way to relieve stress and anxiety brought on by both general stressors of pregnancy and those related to COVID, such as social isolation, financial and psychosocial distress, increased burden of childcare, changes in accessing prenatal care, and concerns about heightened risk of COVID-19 for both mother and baby2.

    Data from Kaiser Permanente Northern California was pulled to test the hypothesis that prenatal cannabis use was increasing during the COVID-19 pandemic. Urine samples were screened using universal toxicology from January 1, 2019 through December 21, 2020 during standard prenatal care (approximately 8 weeks gestation). The pre-pandemic period was defined as tests conducted from January 2019 to March 2020, while the pandemic period included tests taken from April through December 2020. Urine samples from 100,005 pregnancies in 95,412 women with a mean age of 31 years were tested. Before the pandemic, prenatal cannabis use was reported in 6.75% of pregnancies; during the pandemic, the rate of prenatal cannabis use increased to 8.14% (95% CI, 7.85 – 8.43%), a 25% increase (95% CI, 12 – 40%)2.

    The American College of Obstetricians and Gynecologists (ACOG), the American Academy of Pediatrics (AAP), and the Academy of Breastfeeding Medicine (ABM) all advise against the use of cannabis during pregnancy and breastfeeding4-6. Cannabis use during pregnancy can lead to a multitude of adverse effects including low birth weight, disruption of normal brain development in the fetus, increased risk of stillbirth, and increased risk of preterm birth3. There was a significantly increased risk of adverse effects such as low birth weight (OR 1.27, 95% CI, 1.05 – 1.54) and small for gestational age (OR 2.14, 95% CI, 1.38 – 3.30) among cannabis users, but not preterm birth. Additionally, a dose-related effect was noted – heavy cannabis users, defined as weekly use or more, had twice the risk of delivering a low birth weight or small for gestational age baby compared to non-cannabis users7. Due to the risk of adverse effects to the fetus, pregnant women who are currently using cannabis to treat anxiety caused or exacerbated by the COVID-19 pandemic should be counselled by their pharmacists and physicians to quit and seek alternative treatment methods that are safer for both mother and baby.

    However, weighing the benefits and risks of taking medication during pregnancy is an age-old conundrum that patients, pharmacists, and physicians have to continually battle. Treating medical conditions during pregnancy involves the patient’s healthcare team taking multiple factors into account, such as the severity of the condition and the risks to mother and baby if the condition goes untreated. Furthermore, health professionals must look at both pharmacologic and non-pharmacologic treatment options and whether there is evidence of detrimental fetal effects of any chosen medication. With rising anxiety levels fueled by the COVID-19 pandemic, it is important for clinicians to have recommendations ready for pregnant women that are safer than cannabis, which has not been extensively studied for safety or efficacy.

    For mild anxiety, non-pharmacologic options may be sufficient for treatment and can ease a pregnant patient’s fear about potential risks medication may have on their unborn baby. Counselling, cognitive behavioral therapy, exercise, and meditation may be appropriate non-pharmacologic strategies to help pregnant women manage their anxiety over cannabis use9. For generalized anxiety disorder, the 2016 Psychopharmacology Algorithm Project at the Harvard South Shore Program recommended selective serotonin reuptake inhibitors (SSRIs) as first line treatment. Various research studies have identified potential areas of concern in the use of SSRIs during pregnancy including a small increase in birth defects such as congenital heart defects, neonatal abstinence syndrome, low birth weight, and preterm delivery9. Other medications such as buspirone and bupropion in particular seem to pose very low risks to the fetus when used for the treatment of anxiety in pregnant women based on current studies9. Since the potential for risk is still present when utilizing medication to treat anxiety during pregnancy, pharmacists and other clinicians must make sure pregnant women have all the facts made available to them. Leaving anxiety untreated also poses its own set of risks, as anxiety can interfere with the woman’s sleep and diet, can negatively impact her relationships with friends and family, or push them to use substances known to be harmful to both mother and baby, such as alcohol, tobacco, or illicit drugs to manage their anxiety8. In studies, moderate to severe maternal anxiety and depression have been linked to adverse effects such as miscarriage, preeclampsia, preterm delivery, and low birthweight.
    This generation’s pregnant women are facing a unique challenge in managing their mental health during the COVID-19 pandemic, and pharmacists play a key role in helping pregnant women make safe, data-driven recommendations when it comes to treating anxiety. Staying up to date on the most current information is vital, and most data points to cannabis being an inappropriate treatment option for pregnant women experiencing anxiety. Non-pharmacologic treatment options remain the safest options for those patients whose symptoms are mild, while patients with more moderate to severe anxiety may find the benefits of medication such as SSRIs, bupropion, or buspirone may outweigh the rare fetal risk.

    Resources

    1. Covid-19 disrupting mental health services in most countries, WHO survey. WHO. 5 Oct 2020. <https://www.who.int/news/item/05-10-2020-covid-19-disrupting-mental-health-services-in-most-countries-who-survey>
    2. Young-Wolff KC, Ray GT, Alexeeff SE, et al. Rates of prenatal cannabis use among pregnant women before and during the Covid-19 pandemic. JAMA. 2021;326(17):1745-1747.
    3. Cannabis and pregnancy. ACOG. Feb 2021. <https://www.acog.org/womens-health/faqs/cannabis-and-pregnancy?utm_source=redirect&utm_medium=web&utm_campaign=int>
    4. Committee Opinion No. 722: Cannabis use during pregnancy and lactation. Obstet Gynecol. Oct 2017;130(4):e205-e209.
    5. Ryan SA, Ammerman SD, O'Connor ME. Cannabis use during pregnancy and breastfeeding: Implications for neonatal and childhood outcomes. Pediatrics. Sep 2018;142(3):e20181889.
    6. Reece-Stremtan S, Marinelli KA. ABM clinical protocol #21: guidelines for breastfeeding and substance use or substance use disorder, revised 2015. Breastfeed Med. Apr 2015;10(3):135-41.
    7. Nguyen VH, Harley KG. Prenatal cannabis use and infant birth outcomes in the Pregnancy Risk Assessment Monitoring System. J Pediatr. Jan 2022;240:87-93.
    8. Conover EH, Forinash AB. How do I weigh the risks and benefits of taking an antidepressant medication during pregnancy? Teratology Primer. Jan 2018. <https://birthdefectsresearch.org/primer/antidepresant-risk.asp>
    9. ACOG Practice Bulletin: Clinical management guidelines for obstetrician-gynecologists. Use of psychiatric medications during pregnancy and lactation. Obstet Gynecol. Apr 2008;111:1001-20 
  • 06 Apr 2022 5:21 PM | Anonymous

    Lumateperone for Treatment of Schizophrenia

    By: Hae Shim, PharmD Candidate 2022, St. Louis College of Pharmacy

    Mentor: Danielle Moses, PharmD, BCPP, SSM Health DePaul Hospital

    Schizophrenia

    Schizophrenia is a chronic psychological disorder that affects 1% of the general population1 and is considered one of the top 15 leading causes of disability worldwide.2 Schizophrenia is characterized by having two symptoms present for a significant portion of one month (less if treated). Symptoms may include delusions, hallucinations, disorganized speech, grossly disorganized or catatonic behavior, negative symptoms. At least one presenting symptom must be a positive symptom of schizophrenia- delusions, hallucinations, or disorganized speech.3 Although the progression of schizophrenia may differ among individuals, it can affect the quality of life if not managed properly.4

    Treatment for schizophrenia requires pharmacological and psychosocial interventions. Pharmacological treatments include first-generation or second-generation antipsychotics. Second-generation antipsychotics are typically preferred due to the lower dopamine-mediated adverse effects.4 Current antipsychotic treatments are effective in reducing symptoms, but many medications are associated with adverse effects such as metabolic disturbances, cardiovascular risks, and hyperprolactinemia.1

    Lumateperone (Caplyta)

    On December 23, 2019, the Food and Drug Administration (FDA) approved lumateperone (Caplyta) for the treatment of schizophrenia.5 Lumateperone has shown to only need 40% striatal D2 receptor occupancy for treatment improvement in schizophrenia compared to other available antipsychotics that need 60-80% occupancy.1 The approved dose of lumateperone is 42 mg by mouth once daily with food. Although lumateperone is a once-daily administered oral medication due to its half-life of 13 to 21 hours, there are strict caloric requirements (at least 350 calories) during administration for its absorption.5

    Efficacy and Safety of Lumateperone for Treatment of Schizophrenia: A Randomized Clinical Trial

    Lumateperone was  studied in a 4 week randomized, double-blinded, phase 3, placebo- controlled study conducted at 12 clinical sites from November 13, 2014, to July 20, 2015.1 Patients experiencing an acute exacerbation of psychosis were eligible to participate in the inpatient study, and were randomized in a 1:1:1 ratio to 42 mg lumateperone, 28 mg lumateperone, or placebo.1 All three groups were given once-daily oral administration in the morning. The study revealed significant improvement in symptoms of schizophrenia beginning at the first week and maintained throughout the 28 day treatment period.1 The study completion rates were 85.3% in the 42 mg lumateperone group, 80.0% in the 28 mg lumateperone group, and 74.0% in the placebo group.1 Overall, 20 participants in the 42 mg lumateperone group, 28 participants in the 28 mg lumateperone group, and 38 participants in the placebo group discontinued the study.1


    Participants treated with 42 mg of lumateperone displayed a statistically significant improvement in the PANSS total score from baseline compared to placebo or treatment with lumateperone 28 mg (Table 1). Common adverse events observed were somnolence, sedation, fatigue, and constipation (Table 2). There was no increase in suicidal ideation or behavior as measured by Columbia Suicide Severity Rating Scale. No extrapyramidal symptoms related to treatment-emergent adverse events occurred in ≥ 5% of any treatment arm. There were no significant mean changes in metabolic parameters (cholesterol, glucose, triglycerides, prolactin, and insulin levels) from baseline to 28 days, and no QTc > 500 milliseconds or a change in QTc > 60 milliseconds from baseline.1

    Conclusion

    Lumateperone 42 mg demonstrated efficacy and safety for treatment of schizophrenia.1 Lumateperone may represent a preferred option for those who desire treatment with minimal cardiac, metabolic, and motor adverse events, though longer-term studies and head-to-head comparison trials are warranted to recommend its use over widely used agents with similar adverse effect profiles (e.g., aripiprazole).

    References

    1. Correll CU, Davis RE, Weingart M, et al. Efficacy and safety of lumateperone for treatment of schizophrenia: a randomized clinical Trial. JAMA Psychiatry. 2020;77(4):349-358.
    2. Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990-2016: a systematic analysis for the global burden of disease study 2016. Lancet. 2017;390(10100):1211-1259.
    3. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Washington D.C.: 2013.
    4. Keepers GA, Fochtmann LJ, Anzia JM, et al. The american psychiatric association practice guideline for the treatment of patients with schizophrenia. Am J Psychiatry. 2020;177(9):868-872.
    5. Lumateperone. In: Lexi-Drugs. Lexi-Comp, Inc. Updated September 30,2021. Accessed October 19, 2021.
  • 06 Apr 2022 5:08 PM | Anonymous

    Magnesium for the Treatment of Postoperative Pain

    Author: Brittany Bush, PharmD Candidate 2022, Xavier University of Louisiana College of Pharmacy

    Mentor: Rachel C. Wolfe, PharmD, MHA, BCCCP, Barnes-Jewish Hospital – Saint Louis, Missouri

    Acute postoperative pain often occurs after surgery with the most severe pain noted within the first 72 hours after intervention.1,2 Systemic opioids are routinely employed to manage postoperative pain. However, they can be associated with significant side effects, including

    long-term use and dependence.3-5 The challenge to reduce reliance on opioids for the treatment of postoperative pain has resulted in a growing interest in utilizing non-opioid analgesics. These medications help achieve pain control, while minimizing adverse effects. Since the perception of pain is a complex phenomenon, a multimodal analgesia approach may be utilized to enhance effectiveness.6 This care model lessens opioid use and drug related adverse effects by capitalizing on mechanistic differences between various analgesic medications, such as acetaminophen,

    non-steroidal anti-inflammatory drugs, dexamethasone, gabapentinoids, local anesthetics, and NMDA antagonists.6

    Literature findings indicate n-methyl-d-aspartate (NMDA) receptor activation is directly associated with pain sensory reception from peripheral tissue and nerve injury. The NMDA receptor is widely located throughout the central nervous system and regulates influx of sodium and calcium and outflow of potassium.7,8 Upon activation, the increased intracellular calcium levels seem to play a role in initiating central sensitization. This is a phenomenon by which repetitive nociceptive inputs eventually results in a prolonged decrease in the pain threshold, leading to hyperalgesia.8 The use of a NMDA receptor antagonist has been shown to significantly decrease pain.7 Magnesium, as an NMDA receptor antagonist, is a pain adjuvant that controls the excitability of the NMDA receptor.8,9

    Although there has been recent interest in preoperative oral magnesium as a pre-emptive analgesic agent, the primary perioperative dosing strategies studied utilize intravenous (IV) magnesium sulfate. Studied doses are typically administered by the way of a bolus dose, continuous infusion, or bolus plus infusion. The bolus dose, infusion rates, and infusion durations have also been variable. At this time, most of the literature supports an intraoperative IV bolus dose followed by a continuous infusion.6,8,9,11,12 The most common and well-studied dose of magnesium sulfate for perioperative pain includes an intraoperative IV loading dose of 30-50 mg/kg administered over 15 to 30 minutes at the start of the surgery followed by a continuous infusion at 6-15 mg/kg/hour until surgery completion.6,8,9,11

    The effectiveness of magnesium in reducing postoperative pain and opioid consumption has been evaluated in several surgical procedure types such as spine, thoracic, major abdominal, and hysterectomy.8-10 A systematic review performed by Albrecht and colleagues included 25 randomized trials, consisting of a total of 1,461 patients, that received perioperative magnesium for the reduction of postoperative pain. Within this review, the primary endpoint assessed was cumulative IV morphine consumption at 24 hours postoperatively. Statistically significant heterogeneity existed in the wide variety of dosing regimens chosen by various trials analyzed. Despite this limitation, magnesium significantly reduced the 24-hour cumulative consumption of IV morphine by 24.4%. A reduction in the amount of analgesics used was observed regardless of the type of surgery performed. For example, morphine consumption decreased by 12.7% in


    gynecological surgery, 37.9% in orthopedic surgeries, and 15% in gastrointestinal surgeries. Time to first analgesic request from patients, however, was not significantly changed with the incorporation of magnesium into the pain regimen. 11

    A more recent systematic review performed by Morel and colleagues provided an in-depth analysis of the literature related to magnesium for pain management. This review

    contained 81 randomized controlled trials, consisting of 5,447 patients, that explored the efficacy of magnesium for the reduction of pain and/or analgesic consumption, 49 of which focused on postoperative pain. Overall, 29 of 44 studies observed a significant decrease in pain as assessed by the visual analog scale. Contrarily, 16 randomized controlled trials displayed no efficacy in pain reduction. An important limitation among the randomized controlled trials in this review is the heterogeneity in dosing strategies. The most commonly studied method of dosing, seen in 33 of the trials reviewed, was the use of an IV bolus followed by a continuous infusion. Thirty-six of the 45 post-operative randomized controlled trials that analyzed analgesia requirements showed a significant decrease in consumption of analgesic agents such as morphine, tramadol, diclofenac, and fentanyl. Contrarily, 11 randomized controlled trials showed no significant different in analgesic consumption in patients.13

    The safety of magnesium in the management of postoperative pain has not been thoroughly evaluated in clinical trials. Side effects of magnesium can be dose or rate related and can present as flushing or hypotension, respectively.14 Monitoring of blood pressure is a useful method to ensure the safety of therapy. 15 Lastly, hypermagnesemia is uncommon in patients with normal renal function; however, due to its significant renal elimination, magnesium doses should be reduced by 50% in patients with renal impairment.12,14

    In conclusion, magnesium may play an important role in the evolution of postoperative pain and therefore could be a valuable analgesic adjunct when incorporated into a multimodal regimen within the perioperative arena. Further research is needed to determine the most effective magnesium regimen that reduces pain and opioid consumption in the immediate postoperative period. Furthermore, it is imperative that we gain insight into the patient populations and procedure types that benefit the most from perioperative NMDA antagonism provided by magnesium.

    References:

    1. Lynch EP, Lazor MA, Gellis JE, et al. Patient experience of pain after elective noncardiac surgery. Anesth Analg 1997;85(1):117-23.
    2. Svensson I, Sjostrom B, Haljamae H. Assessment of pain experiences after elective surgery. J Pain Symptom Manage 2000;20(3):193-201.
    3. Kessler ER, Shah M, Gruschkus SK, et al. Cost and quality implications of opioid-based postsurgical pain control using administrative claims data from a large health system: opioid-related adverse events and their impact on clinical and economic outcomes. Pharmacotherapy 2013;33(4):383-91.
    4. Hill MV, McMahon ML, Stucke RS, et al. Wide variation and excessive dosage of opioid prescriptions for common general surgical procedures. Ann Surg 2017;265(4):709-14.
    5. Gan TJ. Poorly controlled postoperative pain: prevalence, consequences, and prevention. J Pain Res 2017;10:2287-98.
    6. Beckham, T. Perioperative use of intravenous magnesium sulfate to decrease postoperative pain. J Anest & Inten Care Med. 2020; 10(2): 555788.
    7. Petrenko AB, Yamakura T, Baba H, Shimoji K. The role of n-methyl-d-aspartate (NMDA) receptors in pain: a review. Anesth Analg. 2003;97(4):1108-1116.
    8. Shin HJ, Na HS, Do SH. Magnesium and Pain. Nutrients. 2020;12(8):2184.
    9. Na HS, Ryu JH, Do SH. The role of magnesium in pain. Adelaide (AU): University of Adelaide Press; 2011.
    10. De Oliveira GS, Jr., Castro-Alves LJ, Khan JH, McCarthy RJ. Perioperative systemic magnesium to minimize postoperative pain: a meta-analysis of randomized controlled trials. Anesthesiology 2013;119(1):178-90.
    11. Albrecht E, Kirkham KR, Liu SS, Brull R. Peri-operative intravenous administration of magnesium sulphate and postoperative pain: a meta-analysis. Anaesthesia. 2013 Jan;68(1):79-90.
    12. Do SH. Magnesium: a versatile drug for anesthesiologists. Korean J Anesthesiol. 2013;65(1):4-8.
    13. Morel, Véronique et al. “Magnesium for Pain Treatment in 2021? State of the Art.” Nutrients vol. 13,5 1397. 21 Apr. 2021
    14. Magnesium Sulfate. Lexicomp Online. Hudson, OH: Lexi-Comp.
    15. Cascella M, Vaqar S. Hypermagnesemia. StatPearls Publishing; 2021 Jan.
  • 06 Apr 2022 5:02 PM | Anonymous

    Opioid Use Disorder: Identification and Management in the Acute Setting

    Madeline Taylor, BS, PharmD 2022 Candidate & Julianne Yeary, PharmD, BCCCP

    Introduction

    Opioid overdose deaths continue to increase in both urban and rural areas of Missouri, accounting for 1 out of every 56 deaths in 2018.1 The rise in patients suffering from opioid use disorder (OUD) is placing a great burden on the healthcare system. Establishing preventative measures and providing timely recognition and initiation of treatment for patients suffering from OUD is crucial.

     

    Identification of Patients

    In patients presenting with risk factors for OUD (e.g., personal or family history of OUD, related mental health or personality disorder, or a positive urine drug screen), clinicians should keep OUD on their differential diagnosis when particular signs and symptoms are present.2 Signs and symptoms can frequently involve the following domains: mood, physical, psychological, and behavior.2 The DSM-5 criteria should be used to make an official diagnosis in patients suspected to have OUD. Patients must meet at least two of the criteria to be eligible for pharmacological treatment.3

    Acute withdrawal is seen when rebound hyperexcitability occurs after abrupt opioid cessation in opioid dependent patients.2 Opioid withdrawal symptoms (OWS) include anxiety or restlessness, diarrhea, fever, diaphoresis, nausea, vomiting, dilated pupils, tachycardia, and hypertension.4 Onset of withdrawal is dependent on the type of substance being used.5 For example, discontinuation of heroin, a short-acting opioid, will produce OWS in 8-12 hours. Alternatively, methadone, a long-acting opioid, may take up to 36 hours before OWS are apparent.5,6 The Clinical Opioid Withdrawal Scale (COWS) is a scale used in the inpatient setting to score the level of withdrawal as mild, moderate, moderately severe, or severe.5,7 The severity of OWS determined by COWS score guides treatment decisions.

     

    Managing Opioid Use Disorder

    The current Food and Drug Administration approved medications for OUD include methadone, buprenorphine, and naltrexone.2 Methadone and buprenorphine are agents commonly used in the inpatient setting. Naltrexone cannot be initiated until at least seven days since last opioid usage and is therefore not commonly used for the acute management of OUD.2 There are factors that should be considered when selecting optimal pharmacologic intervention for OUD in the hospital including any previous outpatient medication for addiction treatment (MAT), co-morbid conditions, current withdrawal symptoms, willingness to receive OUD treatment, and concomitant medications.

    Opioid Withdrawal Symptom Management

     The opioid agonists buprenorphine and methadone are the primary treatment agents in OUD, while several non-opioid medications focus on OWS. Clonidine, an alpha-2 agonist, is the mainstay of non-opioid treatments for OWS, and is used off-label to manage specific symptoms, such as tachycardia, anxiety, and hypertension.4 Oral hydration, antiemetics, and antidiarrheals are also used for supportive care in OWS.4,5

    Buprenorphine

    Buprenorphine is a partial agonist at the mu opioid receptor which allows for maximal opioid effect with less risk of severe adverse reactions, such as respiratory depression, compared to full opioid agonists.2,5 Sublingual administration is preferred over the oral route to avoid first-pass effect and loss of bioavailability due to intestinal absorption. Peak effect occurs three to four hours after sublingual administration. Buprenorphine is metabolized by the liver, primarily via the cytochrome P450 (CYP) CYP3A4 enzyme, which can lead to drug interactions. Buprenorphine has an extremely high binding affinity and slowly dissociates from the mu opioid receptor providing the sublingual formulation with a long half-life of 38 hours. The only contraindication to its use is a known hypersensitivity to buprenorphine.2,5 Buprenorphine is typically initiated when a patient is in moderate withdrawal or COWS > 11 to avoid precipitating severe OWS (Table 1).2,5 New approaches are emerging to explore buprenorphine initiation strategies prior to OWS, however to date evidence is limited to case reports.15 The drug’s long half-life allows for a “self-taper” effect as it slowly dissociates from the opioid receptors.10,11,12 In two systematic reviews buprenorphine was more effective than clonidine for the management of opioid withdrawal and appeared to be equally effective to methadone.13,14 One systematic review found that buprenorphine may offer advantages over methadone in the inpatient setting for resolution of withdrawal symptoms; however more research is warranted for verification.14

    Buprenorphine is often given in combination with naloxone, a full opioid receptor antagonist. This combination works to reduce adulteration and abuse rates when used for long term management in the outpatient setting and may be restarted when patients present to the acute care setting. Buprenorphine is a Schedule III medication, and prescribers need a waiver to prescribe this medication. Prescribing abilities for a 30-day prescription have also been extended to nurse practitioners and physician assistants, so long as their collaborative practice is with a physician who is waiver certified.16

    Methadone

    Methadone, a long-acting full agonist at the mu opioid receptor, works by dampening the rewarding effects of other opioids through its long-acting effect on the opioid receptors while preventing withdrawal symptoms.2,5 Methadone, which is metabolized in the liver primarily via the CYP2B6 enzyme, carries the risk for drug interactions as well as hypokalemia and QTc interval prolongation.5 Contraindications include current respiratory depression, severe bronchial asthma or hypercapnia, and paralytic ileus.2 A patient with lower opioid tolerance (e.g. re-initiating treatment after relapse) may require a lower initiation dose (Table 1).

    Clonidine

    Clonidine stimulates alpha-2 adrenoceptors in the brain, activating an inhibitory neuron, which results in reduced central nervous system (CNS) sympathetic outflow and ultimately decreases heart rate and blood pressure.8 In a systematic review, clonidine was superior to placebo in reducing withdrawal symptoms.9 Clonidine is metabolized in the liver, however, it does not carry the risk of CYP drug interactions. Patients using clonidine may experience hypotension and bradycardia.2,10 The only contraindication to its use is a known hypersensitivity to clonidine.

    Outpatient MAT

    Both behavioral and medical screening is necessary to determine which patients would be good candidates for MAT at time of discharge. Goals of initial screening include access for crisis intervention, federal and state eligibility requirements, a patient’s ability to understand and accept program responsibilities including benefits and drawbacks of MAT, and recognition of barriers that might hamper a patient’s ability to meet treatment requirements (e.g. lack of transportation, other substance abuse, and commitment concerns).

     

    Conclusion

    The focus of caring for patients with OUD in the inpatient setting should be on both acute treatment as well as prevention. Patients initiated on MAT while inpatient will require follow-up post discharge in the outpatient setting for continued management. Educating clinicians on symptoms of OUD, the importance of providing MAT, and evidence-based treatment options employed to alleviate OWS may improve timely diagnosis and treatment.

    References:

    1. Missouri Department of Health and Senior Services. Missouri Opioids Information. https://health.mo.gov/data/opioids/ (accessed 2021 June 20).
    2. 2020 Focused Update Guideline Committee. The ASAM national practice guideline for the treatment of opioid use disorder: 2020 focused update. J Addict Med. 2020; 14(2S Suppl1):1-91.
    3. American Psychiatric Association. Opioid Use Disorder. https://www.psychiatry.org/patients-families/addiction/opioid-use-disorder (accessed 2021 July 15).
    4. Kosten TR, Baxter LE. Review article: effective management of opioid withdrawal symptoms: a gateway to opioid dependence treatment. Am J Addict. 2019; 28:55-62.
    5. Koehl JL, Zimmerman DE, Bridgeman PJ. Medications for the management of opioid use disorder. Am J Health-Syst Pharm. 2019; 76:1097-1104.
    6. American Addiction Centers. Opiate withdrawal timeline, symptoms, and treatment. (2021). https://americanaddictioncenters.org/withdrawal-timelines-treatments/opiate (accessed 2021 July 16).
    7. Wesson DR, Ling W. The Clinical Opiate Withdrawal Scale (COWS). J Psychoactive Drugs. 2003; 35:253-259.
    8. Catapres (clonidine hydrochloride) package insert. Ridgefield, CT: Boehringer Ingelheim Corporation; 2009 Oct.
    9. Gowing L, Farrell MF, Ali R, White JM. Alpha2-adrenergic agonists for the management of opioid withdrawal. Cochrane Database Syst Rev. 2016; 3:CD002024.
    10. Toce MS, Chai PR, Burns MM, Boyer EW. Pharmacological treatment of opioid use disorder: a review of pharmacotherapy, adjuncts, and toxicity. J Med Toxicol. 2018; 14:306-322.
    11. Sigmon SC, Bisaga A, Nunes EV et al., Opioid detoxification and naltrexone induction strategies: recommendations for clinical practice. Am J Drug Alcohol Abuse. 2012; 38:187-99.
    12. Fishbain DA. Opioid tapering/detoxification protocols, a compendium: narrative review. Pain Med. 2021; 22(7):1676-1697.
    13. Gowing L, Ali R, White JM, Mbewe D. Buprenorphine for managing opioid withdrawal. Cochrane Database Syst Rev. 2017; 2:CD002025.
    14. Gowing L, Ali R, White JM. Buprenorphine for the management of opioid withdrawal. Cochrane Database Syst Rev. 2009; 3:CD002025.
    15. Adams KK, Machnicz M, Sobieraj DM. Initiating buprenorphine to treat opioid use disorder without prerequisite withdrawal: a systematic review. Addict Sci Clin Pract. 2021;16(1):36. Published 2021 Jun 8. doi:10.1186/s13722-021-00244-8
    16. State of Missouri. 630.875 Citation of Law. Missouri Revisor of Statutes - Revised Statutes of Missouri, RSMo, Missouri Law, MO Law, Joint Committee on Legislative Research. https://revisor.mo.gov/main/OneSection.aspx?section=630.875&amp;bid=47957&amp;hl=buprenorphine%25u2044. Accessed March 19, 2022.

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