Safety and Efficacy of Anticoagulation Regimens in COVID-19
By John Love, Pharm.D, MBA
Program Number :
Approved Dates: April 1, 2022-October 1, 2022
Approved Contact Hours: One Hour(s) (1) CE(s) per session
Medically ill patients are at an increased risk of development of venous thromboembolism (VTE). Guidelines have historically made recommendations for prophylactic anticoagulation when patients are acutely ill1 and therapeutic anticoagulation when there is confirmation of deep venous thrombosis or in select situations, such as in atrial fibrillation2. Anticoagulant options include low molecular weight heparin (LMWH), unfractionated heparin (UFH), fondaparinux, direct oral anticoagulants (DOACs) such as apixaban or rivaroxaban, argatroban, or bivalirudin.
In 2019, a novel coronavirus (COVID-19) was discovered which has since become a global pandemic. Early in the pandemic, it was observed that patients acutely ill with COVID-19 were at increased risk of development of VTE. Patients that are hospitalized with COVID-193 are thought to be in a pro-thrombotic state due to increased fibrin deposits, reduced natural anticoagulation (or maximal anticoagulation being reached), an increase in interleukin 1-b and interleukin 18. A recent meta-analysis found that the incidence rate of VTE among COVID positive pateints to be 14.7%4. Unsurprisingly, administration of anticoagulant medications was associated with improved mortality5. However, the optimal regimen for prophylactic anticoagulation was unknown and has since been the objective of many studies.
The International Society of Thrombosis and Hemostasis (ISTH)6, the American Society of Hematologists (ASH)7, and the National Institute of Health (NIH)8 have each produced guidelines that reviewed anticoagulation research in COVID-19. Both ISTH and ASH recommend the use of prophylactic anticoagulation over therapeutic or intermediate dose anticoagulation due to limited data. However, both of these guidelines were published before larger, randomized clinical trials were published that have provided more insight.
The NIH guidelines initially made a similar recommendation but were updated as more data was published. The NIH guidelines currently recommend therapeutic anticoagulation in patients who are hospitalized, require low-flow oxygen, and do not require intensive care unit level of care and have an elevated D-dimer level above the upper limit of normal. Therapy should continue for fourteen days or until discharge, whichever comes first. Based on the results of more recent studies, the NIH recommends against the use of therapeutic anticoagulation in patients requiring intensive care unit level of care or high-flow oxygen. It should be noted that this recommendation is without confirmation of DVT or PE. The NIH does not recommend routine imaging for DVT or PE unless the patient is experiencing symptoms consistent with those conditions. Unless a contraindication exists, the NIH recommends prophylactic dosage anticoagulation in all patients who are not receiving therapeutic anticoagulation.
The NIH identifies contraindications to therapeutic anticoagulation as those with platelet counts < 50 x 109/L, hemoglobin < 8g/dL, requiring dual antiplatelet therapy, major bleeding within 30 days that required a visit to an emergency department or hospitalization, history of a bleeding disorder, or an inherited or active acquired bleeding disorder. This list of contraindications was developed based upon exclusion criteria from the major studies that evaluated the use of therapeutic anticoagulation.
The NIH guidelines also recommend the use of LMWH as first line therapy, UFH as second line, and recommends against the use of direct oral anticoagulants. This recommendation stems from the shorter half-lives of these agents, the relative ease of bleeding reversal, that these agents have intravenous and subcutaneous administration methods (which may be beneficial in patients who are unable to tolerate oral medications due to oxygen requirements), and are noted to have less drug-drug interactions compared to direct oral agents.
The NIH guidelines are based on four randomized trials that together helped identify which patients would benefit most from therapeutic anticoagulation. The ATTACC, ACTIV-4a, and REMAP-CAP investigators combined their results for publication in two of these studies. One study of these studies reviewed non-critically ill patients (defined as those not requiring intensive level care or high-flow oxygen), while the other looked at critically ill patients. The HEP-COVID trial evaluated critical and non-critically ill patients, while the RAPID trial evaluated patients who were started upon anticoagulation shortly after admission.
Therapeutic Anticoagulation with Heparin in Non-Critically Ill Patients with COVID-1910 This is the comparison study published by the ATTACC, ACTIV-4a, and REMAP-CAP investigators that focused on patients who were not yet critically ill. This study included many patients, with a population size of 2219 patients. The included patients were considered non-critically ill, which was defined as being hospitalized without requiring ICU level care (including high-flow oxygen) at enrollment. Again, this study aimed to evaluate the impact on organ support-free days, but also included a stratification based upon D-dimer level at two times the local upper limit of normal for each institution. The primary outcome was designed to analyze the number of days without requiring critical care level organ support.
The final results are included below with a comparison to the data found in critically ill patients, as well as reporting the d-dimer stratification. This study was stopped early due to meeting predefined criterion for superiority for therapeutic anticoagulation, but it is important to note that the pre-defined primary outcome of organ support-free days up to day 21 had to be changed to survival to discharge without requiring intensive care level of organ support as the average organ support-free days in both groups was 22 days (and the outcome was designed to stop counting at 21 days). The authors calculated that for every 1000 patients that received initial treatment with therapeutic anticoagulation, 40 additional patients would not require organ support from addition to discharge. This would come at the expense of 7 additional major bleeds.
The RAPID trial was a multicenter trial that was evaluating the impact of therapeutic dose anticoagulation compared to prophylactic dose when therapy is started early in the disease course, which the study defined as within five days of admission. The RAPID trial only evaluated UFH and LMWH. The primary outcome was a composite outcome defined as death, invasive mechanical ventilation, non-invasive mechanical ventilation, or ICU admission and was not statistically significant. However, this study did not meet power. Unlike the other trials included in this review, this study did not find a benefit in escalation of care but did find a mortality benefit when the composite outcome was broken out into individual components.
“When you can’t find the sunshine, be the sunshine.”- Unknown
“If you do something awesome, you should be proud of yourself.”-Damon Lindelof
“To plant a garden is to believe in tomorrow.” - Audrey Hepburn
Whew, what a year it has been!! As I reflect upon this past year, I cannot help but be overwhelmed by the continued resiliency and dedication displayed by our members.
I am so proud of what we were able to accomplish together as an organization. Throughout the year, there were more educational sessions offered than ever before. As a board, we voted to form two new committees, a Diversity, Equity and Inclusion Committee and a Dues Committee. Both committees will focus on what we can do better as an organization to provide for the needs of our members. In early April, we had a good turnout at Legislative Day. In late April, we had another successful Spring Meeting, providing 20 hours of hours of CE to our members and recognized many of our colleagues for their contributions to the profession.
During my final address at the Spring Meeting, I spoke about thankfulness. Thank you to Laura, Sara and the rest of the Newsletter Committee for the amazing newsletters you continue to put out. Thank you to our Board members for all the time and effort that you have put into this organization over the past year. Thank you to my employer, CoxHealth, for their continued support of my work with MSHP. Thank you to my kids for your understanding about my time away. And thank you to all members of MSHP for trusting in and supporting us as an organization.
A special shout out to Davina for your outstanding run on the presidential team! Best of luck to Nathan as you take the reins this next year! Finally, welcome Sayo to the presidential team!
This will be my last call out to members for you to be on the lookout for opportunities to get more involved with MSHP through committee and board memberships. It takes a small army of willing volunteers to keep this organization successful. Please do not hesitate to reach out to any current board members if you have any interest or questions.
I hope all of you have an amazing summer and am grateful to you all for this opportunity!!
Christina Stafford, PharmD, BCPS
Author: Emily Stock, BS, PharmD Candidate 2023 – St. Louis College of Pharmacy at UHSP
Mentor: Paul Juang, PharmD, BCPS, BCCCP, FASHP, FCCM – Barnes-Jewish Hospital
Of all hospitalizations ending in death, sepsis is present in 30 to 50%. In the US, sepsis accounts for 250,000 deaths annually.1 According to the 2021 Surviving Sepsis Campaign International Guidelines for the Management of Sepsis, sepsis and septic shock are medical emergencies that necessitate immediate resuscitation and treatment.2 While many factors can be optimized in the treatment of sepsis, like use of antibiotics and appropriate monitoring parameters, the best choice of fluids for initial resuscitation has been debated. The 2021 Surviving Sepsis Campaign Guidelines provides an update to the 2016 recommendations on the choice of fluids in resuscitation.2
The Guideline again recommends crystalloid over colloid as the initial fluid of choice.2 Examples of crystalloids include normal saline, lactated ringers, and Plasma-Lyte. Examples of colloid fluids are albumin and, not widely used, hetastarch. Crystalloids are inexpensive and widely available which supports their use in sepsis. In addition, studies have shown there is no clear benefit of colloids over crystalloids.3In 2016, the guideline recommended either saline or balanced salt solutions for choice of crystalloid fluid for initial resuscitation in septic shock. The 2021 update now recommends balanced salt solutions instead of normal saline.2 Balanced salt solutions, like lactated ringers, have electrolytes in concentrations more similar to the serum and the extracellular fluid. This potentially reduces adverse effects related to the disruption of acid-base balance that can be associated with normal saline.4 Potential adverse effects of normal saline include hyperchloremic metabolic acidosis, renal vasoconstriction, increased cytokine secretion, and concern for acute kidney injury (AKI).5In a study evaluating fluid choice in a rat model of sepsis, volume resuscitation with the normal saline resulted in higher rates of kidney injury and acidosis compared to volume resuscitation with Plasma-Lyte.6
The scientific basis of the adverse effects associated with normal saline is related to its chemical makeup. There is 10% more sodium and 50% more chloride in normal saline compared to normal extracellular fluid (see Table 1).5 Based on this higher concentration of chloride, potassium can shift out of the cell in response to the hyperchloremic acidosis. Hyperchloremic acidosis can also increase inflammation via increase in inflammatory mediators. Hyperchloremia can result in renal vasoconstriction and reduced glomerular filtration rate. The acidosis and hyperkalemia that can be induced by normal saline can potentiate existing kidney issues in septic shock patients.
Besides the scientific argument for balanced crystalloids, there is some clinical evidence suggesting the benefit of lactated ringers over normal salinein regards to renal function and possibly mortality. The SMART trial in 2018 showed a lower incidence of major adverse kidney event within 30 days (MAKE30) with balanced crystalloids when compared to saline in critically ill adults. MAKE30 is a composite endpoint of death, new renal replacement therapy, or persistent renal dysfunction.7 Likewise, the SALT-ED trial showed a difference in the secondary outcome of MAKE30 with a statistically significant reduction in the balanced crystalloid group.8 However, the SPLIT trial in 2015 showed no difference in the primary outcome of AKI within 90 days.9 The SMART, SALT-ED, and PLUS trials showed statistically significant lower concentrations of chloride and higher pH levels in patients treated with balanced crystalloids compared to normal saline.7, 8, 10 The most recent trial, the PLUS trial, found no statistically significant difference in the primary outcome of death from any cause.10 The table below (Table 2) highlights pertinent studies comparing balanced crystalloids to saline. In the trials listed, rate and volume of fluid administered was chosen at the discretion of the treating physician. The 2022 New England Journal of Medicine meta-analysis estimates the effect of using balanced crystalloids versus normal saline ranges from 9% reduction to 1% relative increase in death, concluding there is a high probability that balanced crystalloids reduce mortality.11
In regards to fluid choices for initial resuscitation in sepsis, the change to recommend balanced salt solutions over normal saline is weak with a low quality of evidence. This change, in addition to the weakening of the recommendation for 30 mL/kg of fluids to be given, is aimed to improve the care of patients with sepsis.2 While more data are needed to strengthen fluid recommendations, current guidelines and clinical data can guide decision making in the setting of fluid resuscitation in sepsis.
Authors: Eric Johnston, Pharm.D. Candidate1, Justin Alberts, Pharm.D. Candidate1, Shane Austin, Pharm.D., BCPS2, Anastasia L. Armbruster, Pharm.D., FACC, BCPS, BCCP1
1St. Louis College of Pharmacy at the University of Health Sciences and Pharmacy
2Missouri Baptist Medical Center, St. Louis, MO
Heart disease remained the leading cause of death in the United States in 2020 according to the Centers for Disease Control and Prevention.1 In the United States (U.S.), approximately every 40 seconds an individual experiences a heart attack.2 For the management of ST-segment-elevation myocardial infarction (STEMI) and non-ST-segment-elevation myocardial infarction (NSTEMI), the recent 2021 ACC/AHA/SCAI Guidelines for Coronary Artery Revascularization reaffirm the essential role of percutaneous coronary intervention (PCI) in improving clinical outcomes.3Additionally, an extensive array of clinical trials have evaluated antiplatelet therapy in concert with PCI over the past 25 years. Glycoprotein IIb/IIIa inhibitors (GPI) formerly served a critical role in augmenting platelet inhibition surrounding PCI, but in the current paradigm the role of GPIs has largely fallen out of favor. The purpose of this article is to clarify the remaining clinical utility of GPIs available in the U.S. (eptifibatide and tirofiban) through discussing GPI pharmacology and pharmacokinetics, reflecting on historical roles, and evaluating guideline recommendations. This article is intended for pharmacists who verify orders or are integrated into multidisciplinary teams that address patients with acute coronary syndromes (ACS).
Pharmacology and Pharmacokinetics
Two GPIs, eptifibatide (Integrilin®) and tirofiban (Aggrastat®), remain available for use in the U.S., since the last lot of abciximab (ReoPro®) expired in September 2019, and will no longer be manufactured.4 Eptifibatide and tirofiban are both small molecules that exert their pharmacodynamic effect of inhibiting platelet aggregation through reversible inhibition of the glycoprotein IIb/IIIa receptor on platelets5,6 but abciximab was a monoclonal antibody that was thought to utilize steric hindrance to block the glycoprotein IIb/IIIa receptor.7 Further information on the pharmacology of eptifibatide and tirofiban is provided in Table 1.
Historical Guideline and Clinical Trial Considerations
To help clarify the role of GPIs today, it is essential to understand the historical role of GPIs. The history of GPIs revolves around the general concept of platelet inhibition surrounding PCI for ACS. We constructed a timeline (Figure 1) to illustrate advancements in PCI technology, GPI trials, and dual antiplatelet therapy (DAPT) trials to represent the temporal reasoning for why GPIs have fallen out of favor. The origins of PCI are from 1977 when balloon angioplasty was first employed, and a decade passed until FDA approval was granted for the first bare-metal stent (BMS). PCI continued to advance with the utilization of drug-eluting stents (DES), beginning in 2002.8
Landmark GPI trials are the next major element to consider. Specifically, the legacy of the GPIs in question for this article began in 1997 with the IMPACT II and RESTORE clinical trials for eptifibatide and tirofiban, respectively,9,10 and FDA approval followed shortly in May 1998 for both agents. A few more landmark trials for eptifibatide and tirofiban were published before the 2004 ACC/AHA Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction and the two drugs received a class IIb recommendation for use in primary PCI whereas abciximab, benefitting from greater clinical trial experience, received a class IIa recommendation.11 However, a paradigm shift had already begun in 2001 with the results of the CURE trial, which set off a series of trials cementing the case for dual-antiplatelet therapy (DAPT) using aspirin combined with clopidogrel, prasugrel, or ticagrelor.12-14 Upon publication of the 2013 ACCF/AHA Guidelines for the Management of ST-Elevation Myocardial Infarction, the first set of guidelines following the completion of landmark clinical trials for each DAPT option, a Class 1 recommendation to use a loading dose of DAPT at the time of a primary PCI drove the standard for clinical practice firmly in favor of DAPT rather than GPIs. Furthermore, these guidelines narrowed the utility of GPIs to select patients: those with inadequate P2Y12 loading or with a large thrombus burden.15
Finally, there are two time domains which are important to consider: timing of GPI administration and timing of PCI. Timing of GPIs has been a source of debate as to whether any greater benefit could be derived by administering GPIs before proceeding with cardiac catheterization, but evidence strongly suggests that earlier administration of GPIs is not beneficial.16Time to PCI, such as “door-to-balloon” timing, has been another evolution in revascularization from the early 2000’s which significantly reduces in-hospital mortality,15 and may also contribute to the blunted clinical benefit of GPIs.
Current Clinical Roles for GPIs
The appropriateness of GPIs in the present era depends on “large thrombus burden, no-reflow, or slow flow” according to the 2021 ACC/AHA/SCAI Guideline for Coronary Artery Revascularization (Class 2a recommendation).3 This is due to the preeminence of oral DAPT loading strategies as the mainstay of antiplatelet therapy in PCI to reduce mortality and other major clinical outcomes, such as recurrent MI. On the other hand, GPIs seem to only offer benefit in improving procedural success, rather than the aforementioned clinical outcomes.3,17 As described in Table 1, GPIs possess rapid and potent platelet inhibiting properties, hence their utility in complicated or burdensome thromboses of vessels receiving stenting. An important caveat of GPI use is that this is limited to patients presenting with ACS, since stable ischemic heart disease populations do not derive any clinical benefit of GPI therapy for PCI (Class 3 recommendation, no benefit).3,17 Furthermore, patient safety is promoted through discontinuation of GPIs prior to CABG in order to reduce bleeding complications. The optimal timing to discontinue eptifibatide or tirofiban is 4 hours prior to coronary artery bypass graft (CABG) (Class 1 recommendation). Finally, patients who do not have adequate P2Y12 inhibition should most likely be treated with cangrelor (Kengreal), an intravenous P2Y12 inhibitor, rather than a GPI (Class 2b recommendation).3
In summary, the appropriateness of GPIs in the present era should follow four primary traits: only for ACS patients receiving PCI, only be given once coronary anatomy is known (i.e. large thrombus burden), to improve procedural success, and must be discontinued 4 hours before CABG.
By: Destiny Knatt, PharmD Candidate and Gabrielle Gibson, PharmD, BCPS, BCCCP
Addiction is a serious problem that affects millions of Americans of all ages each year. Conversations about addiction and substance use often revolve around recreational drugs and alcohol, but there are many household items that that can be misused or abused. It is important to identify these items that can present problems for those in recovery, struggling with addition, or wanting to experiment. Homes may have a number of substances that are frequently objects of abuse/misuse as they are usually inexpensive, easily accessible, and may feel safer than illicit substances. This newsletter will discuss and bring awareness to management of abuse/misuse due to three of these specific items: loperamide, nutmeg, and cinnamon (Table 1).
Loperamide is an over-the-counter antidiarrheal medication.1 It is a phenylpiperidine opioid that stimulates intestinal mu receptors.2 It has a low bioavailability (0.3%), is hepatically metabolized by CYP3A4 and CYP2C8, is highly protein bound, and has a half-life of 11 hours.2 At recommended doses (2-16 mg/day), loperamide has very little central nervous system activity. However, when taken in large doses (100-400 mg/day), it may be used for its euphoric effects and to alleviate opioid withdrawal symptoms.2 Furthermore, when used with coingestants that can alter loperamide’s metabolism, such as grapefruit juice, cimetidine, black pepper, tonic water, or quinidine, euphoria is increased.1
When patients present with loperamide overdose, they may present with palpitations, nausea/vomiting, anxiety, weakness, presyncope, dyspnea, altered mental status, and/or cardiac arrest.1,2 Workup should include an electrocardiogram as loperamide abuse/misuse can interfere with cardiac conduction, ultimately leading to prolongation of the QTc interval and widened QRS interval.2
Management of loperamide toxicity is largely supportive.1 Patients who experience respiratory depression should receive naloxone 4 to 8 mg intranasally every 2 to 3 minutes in alternating nostrils prior to emergency medical service (EMS) arrival.1-3 During hospitalization, patients should receive 0.4 to 2 mg IV every 2 to 3 minutes as needed. The dose may be titrated to achieve stable respiratory status.1-3 Activated charcoal (25 to 50 grams) may be administered as a one-time dose 2 to 4 hours after ingestion to decrease systemic absorption and increase the clearance of loperamide.1,2 Benzodiazepines (oral or intravenous lorazepam 0.5 to 2 mg every 4 to 6 hours) may be used to manage anxiety.1 Additional management includes correction of potassium, calcium, and magnesium abnormalities to prevent further QT prolongation.1 Importantly, if a patient uses loperamide for its euphoric effects or to manage opioid withdrawal symptoms, they should be referred to an addiction treatment center to address their addiction and prevent further toxicities.1
Nutmeg is a cooking spice derived from the seed of the Myristica gragans tree.4 It can be intentionally used in large doses (~5 teaspoons) to achieve hallucinogenic and euphoric effects at a low cost.4 The active substance in nutmeg, myristicin, has weak monoamine oxidase inhibition and with elemicin (a phenylpropene organic compound found in nutmeg) may be metabolized to an amphetamine-like compound with hallucinogenic effects similar to those experienced with lysergic acid diethylamide (LSD).4
Symptoms of nutmeg intoxication involve central nervous system effects (euphoria, giddiness, anxiety, hallucinations, headache, dizziness, and drowsiness), cardiovascular effects (tachycardia, hypotension, and flushing), gastrointestinal effects (nausea, pain, gagging, and vomiting), and peripheral effects (numbness, blurred vision, hypothermia, and sweating).4 Symptoms appear 3 to 8 hours after ingestion and usually resolve within 1-2 days.4
Treatment is mainly supportive, but benzodiazepines (oral or intravenous lorazepam 0.5 to 2 mg every 4 to 6 hours) may be used to calm the patient and manage the amphetamine-like effects.4,5 One dose of activated charcoal (25 to 50 grams) may help decrease systemic absorption if ingestion was within an hour.4,6,7
The “Cinnamon Challenge” went viral a few years ago when teenagers began posting videos of themselves eating ground cinnamon. The challenge entails swallowing a tablespoon of ground cinnamon in 60 seconds without drinking any fluids. Videos that capture attempts of the challenge reveal contestants immediately beginning to gag, choke, breath heavily, and make sounds of discomfort. Some contestants also experience vomiting and nosebleeds.8
Cinnamon is composed of cellulose fibers, which are bioresistant and biopersistent and they do not dissolve or biodegrade in the lungs.8 Due to this, cinnamon inhalation can cause pulmonary inflammation, which predisposes airways to epithelial lesions and scarring.8 The challenge may pose greater risks to individuals with broncho-pulmonary diseases, such as asthma and chronic obstructive pulmonary disease.8
In most cases the effects of cinnamon toxicity are temporary and resolve on their own, but it could end in an emergency room visit due to the need for ventilator support.8 Treatment is mainly carried out in the form of supportive lung care.8
Ultimately, it is important to be aware of abuse/misuse and overdose potential of items that are commonly found in homes. It is appropriate to keep spices, cleaning supplies, and all medications stored and out of reach of children and pets. Adolescents, who may be easily influenced to attempt social media challenges, should be educated about the potential negative effects that could result as a consequence of performing such challenges. Adults who unintentionally misuse prescription and over-the-counter medications should also be educated about the importance of using medications as directed. Adults who intentionally abuse medications should seek counseling and rehabilitation to help with addiction. Individuals are encouraged to contact the Poison Control Center, 1-800-222-1222, if there is an expected overdose due to drug substances or household products.
By: Katelyn Kennedy, PharmD candidate 2022
Mentor: Kevin Betthauser, PharmD, BCCCP
In the United States each year there are more than 5 million intensive care unit (ICU) admissions.1In the past 30 years, significant progress has been made to improve the outcomes for patients admitted to the ICU. From 1988 to 2012, mortality rates have decreased by 35%, thus creating an overall survival rate of roughly 80%. While encouraging, these positive trends have brought to light new challenges for healthcare providers and survivors of critical illness. In particular, an increasing population of ICU survivors are experiencing complications following their stay, which may manifest as cognitive impairment, mental health conditions, and physical disabilities (Figure 1). These contribute to high rates of readmission, increased risk of mortality, increased healthcare resource utilization, financial hardship, social impairment, and reduced quality of life.1Due to the increasing prevalence of ICU associated complications, the Society of Critical Care Medicine (SCCM) coined the term “Post-Intensive Care Syndrome” (PICS) to help raise awareness and identify the complications in ICU survivors.2PICS is defined as the “new or worsening impairments in physical, cognitive, or mental health status arising after critical illness and persisting beyond acute care hospitalization.”2Since the formal adoption of PICS, initiatives including SCCM’s THRIVE Collaboration and the Critical and Acute Illness Recovery Organization (CAIRO) have been developed to raise awareness and improve care and overall outcomes of ICU patients, their families, and their caregivers.
Management of PICS remains focused on prevention.1-4 For example, implementation of SCCM’s ABCDEF bundle (Figure 2) has been proven to improve PICS-related complications.3,4 The ICU Liberation study was a multicenter, prospective, national quality improvement collaborative cohort study including over 15,000 adult ICU patients. The implementation of the ABCDEF bundle in this study was associated with clinically significant reductions in factors associated with PICS development including a 65% decrease in next day comas, 40% decrease in next day delirium, and 72% decrease in next day mechanical ventilation.4 Physicians, pharmacists, physical and occupational therapists, dietitians, and other healthcare providers are included to foster a holistic, multidisciplinary approach to the inpatient prevention of PICS. By working collectively, healthcare providers can implement and navigate barriers to the ABCDEF bundle at their specific institution(s).
Survivors of critical illness who develop PICS may require extensive care coordination. PICS clinics have emerged as a potential strategy to improve outcomes of patients who experience PICS. In a prospective, single-center, randomized pilot trial, the effect of an interdisciplinary ICU recovery center (ICU-RC) on clinical outcomes and measures was observed.5Patients surviving critical illness were randomized into one of two groups: an ICU-RC group (n = 111) and a usual care group (n =121). Patients in the ICU-RC group received structured, interdisciplinary care and resources including an outpatient ICU recovery clinic visit with a physician, nurse practitioner, pharmacist, psychologist, and case manager. Patients in the usual care group did not receive ICU-RC care and had all aspects of care decided by the treating clinicians. No significant difference was observed in the rate of 30-day readmissions in the ICU-RC group compared to the usual care group (14.4% vs. 21.5%, p = 0.16).5 However, 7-day readmission rates (3.6% vs. 11.6%, p = 0.03) and rates of death or readmission within 30 days (18% vs. 29.8%, p = 0.04) were significantly reduced in patients who received care at an ICU-RC. This study concluded that multidisciplinary ICU-RCs could be beneficial to patients following ICU-discharge.5
Critical care pharmacists have become integral members of PICS clinics across the countrye.1,6-9Pharmacists are uniquely positioned to help manage complex disease states and identify medication-related problems. Through interventions like comprehensive medication reconciliations, pharmacists address problems such as barriers to adherence, administration issues, and adverse effects. Additional opportunities in vaccination screening and administration, healthcare provider and patient education/counseling, and referrals exist for PICS clinic clinical pharmacists as well.1
Stollings et al. prospectively assessed the role and potential impact of critical care clinical pharmacists in a PICS clinic. In total, data from 62 PICS clinic visits were analyzed in which a critical care pharmacist completed a full medication review in 90% of them. The critical care pharmacist made at least 1 intervention in all patients. Thirty-nine percent of patients had medications discontinued and 20% medications initiated. The most common medications discontinued were acid suppressants, steroids, and antibiotics. The most commonly initiated medications included histamine blockers, anti-constipation medications, and non-opioid analgesics. In addition, the critical care clinical pharmacist identified adverse drug events (ADE), implemented ADE preventive measures, and administered influenza vaccinations at over 15% of all visits.6 This study concluded that critical care pharmacists were instrumental in identifying and treating various medication-related problems and suggests a continued role in this setting.
In conclusion, PICS is an increasingly recognized and prevalent complication of ICU survivors. Prevention remains the main goal for PICS; however, management of these patients will likely continue to be required. PICS clinics serve as a potential means of PICS management, and clinical pharmacists serve an integral role in this setting. While initial data is encouraging, it is imperative that more studies are conducted to further illustrate the impact of critical care pharmacists in PICS clinics.
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
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 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 . 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. 
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. 
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. 
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.
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.
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!
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:
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!
Tony Huke, Pharm.D., BCPS
MSHP R&E Executive Director
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:
Creates provisions relating to insurance coverage of pharmacy servicesSponsored by:
HB 1677 (SB 921)Enacts provisions relating to payments for prescription drugs
HB 2452 (SB 1126)
Modifies provisions relating to the administration of medications by pharmacists
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.