By: Colton Frazer, MBA, PharmaD Candidate 2022
Mentor: Dr. Paul Juang, PharmD, BCCCP, BCPS, FAHP, FCCM

The National Transitions of Care Coalition estimated that the United States wastes around 30 to 50 billion dollars in unnecessary medical expenditures to fix transitional care errors each year. Approximately 60% of which are medication related errors. With this in mind, the argument can be made that more emphasis should be placed on pharmacist-led transitions of care (TOC) programs to ensure patients are properly educated on their new medications. Furthermore, this would be a great area for pharmacists to make a positive impact, while expanding our scope of practice. The continuing trend of pharmacists expanding their scope of practice is becoming more and more relevant each year. For example, H.R. 2759/S. 136 is a bill currently in discussion that would add pharmacists to the providers list eligible for Medicare part B service reimbursement. While provider status may continue to elude our profession, pharmacists are the ideal choice to lead TOC programs-- and can successfully implement these programs now. Furthermore, these programs would likely pay for themselves by reducing emergency medical costs paid by health systems.

To begin, what is a transition of care program? A transition of care (TOC) program consists of a healthcare professional that follows up with a patient via phone call after they are discharged from the healthcare facility to return home. The goal of the program is to ensure the accurate communication of all pertinent healthcare information. This can include things such as discussing barriers, medication adherence, and any new developments in their conditions since discharge.

Below is an illustration of a standard TOC program timeline as an example:

The exact process of the TOC program can vary depending on the specific patient and hospital. Despite any difference in TOC follow up protocol, it remains unchanged that transitional follow up is effective for reducing readmission rates among high-risk patients, and reducing overall health care expenditure per patient. By understanding why TOC programs are beneficial, and furthermore, understanding why pharmacists are the ideal candidate to lead these programs, we can advocate for our profession and improve the health outcomes of patients along the way.

One noteworthy case published in the NCBI in 2016 is a great example of small details going unchecked causing big problems for our patients. The case report follows a geriatric patient who was discharged with the medication thiothixene (Navane) by mistake instead of amlodipine (Norvasc). The patient continued to take thiothixene for 3 months and suffered severe mental and behavioral side effects. The patient's untreated hypertension led to severe chest pain and readmission 3 months later. At that time, a different specialist prescribed the patient citalopram and alprazolam to treat these new mental and behavioral side effects that were labeled as depression and anxiety. A few weeks after this, the patient suffered a fall and was taken to the emergency department where the mistake was finally caught many months later. This case report serves as a great illustration as to why TOC programs are crucial for catching and fixing medication errors. Pharmacist-led TOC programs can cater specifically to the new medications that can be overwhelming for patients to sort out by themselves.

As stated previously, many problems during transitions of care arise from medication related problems. There are many notable studies that bolster data to suggest that TOC programs have a significant improvement for the outcome of the patient, while also saving the health system on overall expenditures. One study published in The American Journal of Accountable Care in 2018 contacted 90% of the patients enrolled in the intervention group at 72 hours post discharge. From this group, they found that 86.4% of the 185 patients contacted had a medication related issue. (Fig. 1) These medication related issues ranged from not taking their medication correctly, to discontinuing the medication due to the side effect profile. What’s more, the study found that the readmission rate for patients involved in the TOC program compared to routine care (no follow-up) was significantly lower for patients enrolled in the TOC program. These findings were further amplified by the patients all being categorized as high risk for readmission due to receiving more than 10 medications, having a diagnosis of pneumonia or congestive heart failure, or receiving anticoagulation therapy. The study concluded that a system wide TOC program would save the health system $582 per patient.

Furthermore, a budget impact analysis published in the Journal of Managed Care & Specialty Pharmacy in 2018 set out to determine the impact of regulated pharmacists-led TOC programs for all Medicaid patients. The authors found that pharmacist-led TOC programs could result in a savings of $25 million dollars to Medicaid over a two year time period. This was found by performing a decision tree analysis from the health system payer’s point of view for treatment of high risk patients. (Fig. 2) The main culprit for Medicaid waste was found to be mismanagement of medications leading to costly interventions that could potentially be avoided.

And finally, a study published in the American Journal of Health-System Pharmacy in 2020 found that the 30 and 90 day readmission rates for chronic heart failure patients were significantly lower when enrolled in a pharmacist-led TOC program. This was in comparison to having no follow-up, and had a difference of 13% of patients readmitted from the TOC group versus 28% from the control group. This highlights the ability of pharmacists to improve health outcomes in this setting.

With all of the presented data, and the high prevalence of medication related problems during transitional care, it is clear that medication specialists should lead such a crucial step in a patient's health care. Pharmacists are well equipped to be at the helm of this venture. With such a definitive way for pharmacists to make a dramatic impact on the health outcomes of patients, it is clear that pharmacists-led TOC programs are a great option for all pharmacists to pursue to benefit patient health outcomes, while saving the health system money as well.

References:
Cua, Yvette M, and Sunil Kripalani. “Medication Use in the Transition from Hospital to Home.” Annals of the Academy of Medicine, Singapore, U.S. National Library of Medicine, Feb. 2008, www.ncbi.nlm.nih.gov/pmc/articles/PMC3575742/.

Da Silva, B., & Krishnamurthy, M. (2016, September 7). The alarming reality of medication error: A patient case and review of Pennsylvania and national data. Retrieved August 20, 2021, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5016741/

Tully AP, et al. Evaluation of medication errors at the transition of care from an ICU to non-ICU location. Crit Care Med 2019;47:543-549.

Melody, Karleen T, et al. “Optimizing Care Transitions: The Role of the Community Pharmacist.” Integrated Pharmacy Research & Practice, Dove Medical Press, 22 Apr. 2016, www.ncbi.nlm.nih.gov/pmc/articles/PMC5741037/.

Ni, Weiyi & Colayco, Danielle & Hashimoto, Jonathan & Komoto, Kevin & Gowda, Chandrakala & Wearda, Bruce & McCombs, Jeffrey. (2018). Budget Impact Analysis of a Pharmacist-Provided Transition of Care Program. Journal of managed care & specialty pharmacy. 24. 90-96. 10.18553/jmcp.2018.24.2.90.

By: Sarah Schriewer and Megan Smith, PharmD Candidates 2023; St. Louis College of Pharmacy at University of Health Sciences and Pharmacy in St. Louis

Mentor: Roxane Took, PharmD, BCACP; Assistant Professor, Department of Pharmacy Practice, St. Louis College of Pharmacy at University of Health Sciences and Pharmacy in St. Louis; Gateway Apothecary

Background

The increased prevalence of heart failure readmissions proves costly for both hospital health systems and patients. More than 20% of hospitalized heart failure patients will return for readmission within a 30-day period.¹ Within the last ten years, the Centers for Medicare and Medicaid reduced reimbursement to health systems with excessive 30-day readmission rates in order to curb the climbing occurrence and associated costs of these readmissions.² This was done to remove incentivizing procedures that may lessen the quality of patient care.³ Many hospitals have established transition of care (TOC) teams composed of various healthcare personnel following this reimbursement limitation.⁴ The inclusion of the pharmacy profession on the TOC team remains essential, as confirmed by numerous studies that examined the purpose, involvement, and outcomes related to pharmacy specifically. Through performance and accountability measures, the Joint Commission closely examines the efforts of hospitals to improve heart failure patient outcomes.⁵ Pharmacists play an integral role in improving standards for TOC in heart failure patients.

Clinical Trial Review

A single-center, retrospective, quasi-experimental study regarding the impact of pharmacy involvement in heart failure transitions of care found that 30-day readmission rates significantly decreased with the integration of a pharmacist-led TOC team. These TOC services included medication reconciliation performed by the pharmacist, pharmacy residents, or pharmacy interns upon admission and discharge; and patient education with verbal and written components. The majority of patients transitioned from the hospital setting to home, where the patient and caregivers would greatly benefit from written educational materials provided to patients in the intervention group. The study, conducted at Ascension St John Hospital in Detroit, Michigan, focused on 663 patients admitted to cardiac medical floors with a primary or new diagnosis of heart failure. The 333 patients in the intervention group received the pharmacy-led TOC services, whereas the 330 patients made up the control group received TOC services led by other professions. The most common interventions resulting from medication reconciliation involved addition of a medication, dose titration, treatment discontinuation, and duplication avoidance. A total of 17.3% of control group patients had a heart failure readmission within 30 days following discharge whereas only 10.5% of patients in the intervention group experienced a hospital admission within the 30-day window post-discharge.⁴

Cohort Study Review

A monocenter, retrospective, observational cohort study at the Veterans Administration Tennessee Valley Healthcare System determined the outcomes associated with heart failure patient follow-up interviews performed by a clinical pharmacy specialist (CPS). This study was performed to consider the value of  a CPS, especially during a provider shortage. Cohorts were composed of Advanced Heart Failure Clinic (AHFC) patients within this VA health system. Researchers hypothesized that patients receiving care from a CPS would have similar results in comparison to patients following-up with a “familiar provider.” A novel clinical pharmacy telephone clinic was a valuable component in managing medications and reducing 30-day readmission rates. Patients who received the care provided by the CPS had a 10.9% readmission rate. In contrast, patients without the clinical pharmacy interventions had a 12.9% readmission rate within 30 days. Clinical pharmacy specialists in the Veterans Administration health setting are capable of performing more advanced practitioner care, such as limited prescribing and other patient care authorities. This study provides an interesting outlook on the expanding world of pharmacy practice and the impact pharmacists can make on patient outcomes.¹

Management of Implementation

When implementing TOC teams, it is important to consider the additional time commitments that the pharmacy team will have to make and the best way to spread the added workload out amongst staff. Studies have shown positive results by utilizing pharmacy students in their 3rd and 4th year, PGY1 residents, and paid interns working together.⁴ Other studies emphasize the successfulness of community pharmacists assisting with heart failure TOC encounters via the Centers of Medicare and Medicaid Services Part D Medication Therapy Management programs. These programs allow pharmacists to bill for counseling patients with multiple high-cost medications for various chronic disease states.⁶ Some health systems found success with clinical pharmacists working directly with the patients during discharge.¹ Although there are many ways to set up a pharmacy-led TOC team, it is important to arrange a team best suited to the staffing abilities of different organizations. 

Heart failure remains one of the most prevalent disease states in the United States, and, in individuals over the age of 65 year, heart failure remains the most prevalent disease state that causes hospital admissions.⁷ Data predictions show that more than 8 million adults will be affected, and $69 billion will be spent by 2030 due to the overwhelming amount of hospitalizations.⁶ The benefits of providing pharmacist-led TOC can help improve these outcomes substantially, and this team can look different based on different preferences. Providing medication reconciliation to patients regarding their heart failure medications is one of the best ways to help improve overall quality of life and decrease the amount of money spent on heart failure readmission by catching discrepancies, titrating doses appropriately, and educating patients on proper use of their medications.⁷

Takeaways and Recommendations

• Many patients transition to the home setting where both the patient and any caregivers need proper educational materials
• Pharmacists provide valuable services in reducing 30-day readmission rates for heart failure patients through TOC-related counseling
• Timely follow-up, either in-person or via phone, with a pharmacist is monumentally beneficial

References

1. Benge C, Pouliot J, Muldowney JAS 3rd. Evaluation of a Clinical Pharmacist Specialist Transition of Care Pathway to Manage Heart Failure Readmissions During a Provider Shortage. J Pharm Pract. 2021 Jun 1;1-11.
2. Centers for Medicare and Medicaid Services. Hospital Readmissions Reduction Program (HRRP), 2021. Available from https://www.cms.gov/Medicare/Quality-Initiatives-Patient-Assessment-Instruments/Value-Based-Programs/HRRP/Hospital-Readmission-Reduction-Program [6 August 2021].
3. Cowie MR, Anker SD, Cleland JGF, Felker GM, Filippatos G, Jaarsma T, Jourdain P, Knight E, Massie B, Ponikowski P, López-Sendón J. Improving care for patients with acute heart failure: before, during and after hospitalization. ESC Heart Fail. 2014 Dec;1(2):110-145.
4. Neu R, Leonard MA, Dehoorne ML, Scalia SJ, Kale-Pradhan PB, Giuliano CA. Impact of Pharmacist Involvement in Heart Failure Transition of Care. Ann Pharmacother. 2020 Mar;54(3):239-246.
5. Schmaltz SP, Williams SC, Chassin MR, Loeb JM, Wachter RM. Hospital performance trends on national quality measures and the association with Joint Commission accreditation. J Hosp Med. 2011 Oct;6(8):454-61.
6. Anderson SL, Marrs JC. A Review of the Role of the Pharmacist in Heart Failure Transition of Care. Adv Ther. 2018 Mar;35(3):311-323.
7. Milfred-LaForest SK, Gee JA, Pugacz AM, et al. Heart Failure Transitions of Care: A Pharmacist-Led Post-Discharge Pilot Experience. Progress in Cardiovascular Diseases. 2017;60(2):249-258.

Program Number:  2021-09-04

Approved Dates:   October 1, 2021-April 1, 2022

           

Approved Contact Hours:  One Hour(s) (1) CE(s) per session

Kids Survive: Evidence Based Management of Pediatric Sepsis

Author: Victoria H. Anderson, PharmD; PGY-1 Pharmacy Resident (2020-2021)

Mentor: Jordan E. Anderson, PharmD, BCPS, BCCPS; Pharmacy Clinical Coordinator/PGY-1 Residency Program Director

University of Missouri Women’s and Children’s Hospital – Columbia, MO

Objectives

• 1.      Distinguish features of SIRS, sepsis, severe sepsis, and septic shock.
• 2.      Describe initial management of pediatric sepsis patients.
• 3.      Differentiate medications with and without a routine role in pediatric sepsis management.

Take Assessment Quiz

The Surviving Sepsis Campaign published updated pediatric sepsis guidelines in February 2020. Prior to these guidelines, pediatric recommendations shared a guideline document with adult recommendations in 2004, 2008, and 2012, and the Surviving Sepsis Campaign only published adult guidelines in 2016.

Sepsis Considerations: Definitions and Pharmacokinetics

Early recognition of sepsis and evidence-based care of pediatric sepsis patients are of utmost importance to improve patient outcomes as a study in the UK found that over 50% of pediatric sepsis fatalities occurred in the first 24 hours and approximately half of those fatalities were prior to admission to pediatric intensive care units.¹ Adherence to guidelines can improve outcomes and development of protocols including order sets and standardized education can reduce mortality.¹ A study of emergency department teams found that only 45% correctly adhered to treatment metrics, so there is certainly room for improved implementation of guideline recommended care.¹

Sepsis is defined as systemic inflammatory response syndrome (SIRS) plus suspected or known infection. SIRS criteria include hypo- or hyperthermia, leukopenia or leukocytosis, brady or tachycardia, and tachypnea (see Figure 1).² At least two criteria must be met to diagnose SIRS and at least one of those criteria must be the patient’s temperature or leukocyte count.² Of note, the SIRS criteria and sepsis definitions do not apply to premature infants.² To qualify for severe sepsis, a patient must have cardiovascular or respiratory dysfunction or dysfunction of at least two other organ systems such as neurologic, hematologic, renal, and hepatic.² Septic shock is defined as sepsis with cardiovascular organ dysfunction.² At least 40mL/kg of fluids must be administered over an hour prior to assessing for cardiovascular dysfunction to meet the organ dysfunction criteria.² It is important to recognize that hypotension may not be present with cardiovascular dysfunction until a patient is near collapse, as pediatric patients often have strong compensatory mechanisms.¹ As a result, fluids are very important to management in even normotensive patients as delays can increase ICU and hospital length of stay and increase risk of acute kidney injury(AKI).¹ Rather than titrating to blood pressure goals which is often practiced in adults, fluids should be titrated to increased urine output, improved mental status, and decreased capillary refill time as long as patients remain without hepatomegaly or rales.

Figure 1: 

Organ function changes are important to note not just for diagnosis of SIRS and subsequently sepsis, but because they also can change the pharmacokinetics of medications administered to these children. Critically ill children often have changes in both synthesis and binding affinity of albumin and alpha-1 acid glycoprotein which can impact unbound fraction of medications.³ Changes in pH whether acidosis or alkalosis can also impact drug levels by impacting ionization which can impact both effective concentration and elimination rates of medications.³ Fluid shifts impact volume of distribution which can lead to changes in concentration, particularly of hydrophilic medications such as vancomycin, so it is important when monitoring vancomycin to consider the impact of fluid resuscitation and maintenance fluids on serum concentrations.³ Renal dysfunction can impact enzyme activity, pH, total body water, and drug clearance, but conversely, sepsis can also lead to augmented renal clearance.³ Mild hepatic dysfunction can modify hepatic blood flow, enzyme activity, drug transport, protein binding, and total body water, impacting the disposition of medication.³ More severe hepatic dysfunction is marked by capillary leak, coagulopathy, renal dysfunction, and hypoglycemia.³ Additionally, inflammatory mediators can decrease P450 enzyme metabolism.³ Changes in blood flow to drug clearing organs may decrease elimination of many drugs.³ Cardiovascular changes can also lead to fluid overload and edema, changing volume of distribution, and increases in alpha-1 acid glycoprotein.³ Abdominal venous congestion can also lead to a decrease in enteral absorption of medication.³ Finally, therapies to compensate for dysfunctional organs such as extracorporeal membrane oxygenation (ECMO) and continuous renal replacement therapy (CRRT) also can impact pharmacokinetics.³ The ECMO circuit tubing binds some medications requiring increased dosing initially until binding sites are saturated.³ ECMO also may increase volume of distribution of some medications secondary to added volume required for the circuit.³ The impact of CRRT varies primarily based on the level of protein binding of the medication with lower protein binding leading to increased removal.³

It is also important to consider comorbidities that may impact medication therapy. Forty-nine percent of children with sepsis have a comorbidity making them more vulnerable to infection.¹ A common comorbidity is cancer which both the condition itself and the treatment can impact pharmacokinetics.³ For example, fluconazole trough concentrations have been found to be significantly lower in pediatric cancer patients.³ All of these changes make careful use and monitoring of medications in these patients of utmost importance.

Initial Care: Antibiotic and Hemodynamic Management

Once we have made the presumptive diagnosis of sepsis, rapid protocol-driven treatment is the next important step. Per the Surviving Sepsis Campaign International Guidelines for the Management of Septic Shock and Sepsis-Associated Organ Dysfunction in Children, in patients presenting without shock, antimicrobial therapy should be started within three hours of recognition.⁴ While blood cultures should be obtained prior to initiation of antibiotics if this will not cause delay, it is important to start treatment with antimicrobials as soon as possible, so timing of antibiotics is not dependent upon availability of blood cultures.⁴ The guidelines do not address obtaining multiple blood cultures, however, it is common practice to obtain two blood cultures to enhance our ability to detect causative organisms, and to help determine if bacteria found are pathogenic versus a contaminant. If patients have pre-existing intravenous access devices it is prudent to obtain a set of cultures both from the device and from a peripheral site. In addition to blood cultures, cultures should also be obtained from any suspected non-blood site of infection such as urine, cerebrospinal fluid, or wound drainage.⁴ If a patient presents with shock, guidelines recommend treatment with antimicrobials within one hour of recognition, but for patients without shock, treatment within the first hour has not been found to have a significant impact on mortality as compared to treatment by the end of the third hour.⁴ This is in contrast to the 2016 adult and 2012 pediatric guidelines which recommended antimicrobials within the first hour for all patients with sepsis regardless of the presence of shock, and the 2008 pediatric guidelines which recommended antibiotics within one hour of recognizing severe sepsis, but after inidicated cultures have been taken without the caveat in more recent guidelines not to delay evidence-based treatment while waiting for cultures.^5,6,7 Giving antibiotics sooner than required will clearly not cause harm as long as this is not done at the expense of fully evaluating the patient, so following the older practice of administration within the first hour is not an inappropriate practice when practical.

These initial antimicrobial agents should be broad spectrum to cover all likely pathogens without excess coverage.⁴ A previously health child presenting from home should receive a third-generation cephalosporin such as ceftriaxone.⁴ A child at risk for methicillin-resistant Staphylococcus aureus (MRSA) or presenting from a community with high prevalence of ceftriaxone-resistant pneumococci should additionally receive vancomycin.⁴ In communities where ceftriaxone-resistant gram negative rods are prevalent, addition of aminoglycosides or substitution of a carbapenem in place of the third generation cephalosporin is recommended.⁴ If patients have influenza-like illness and influenza is unable to be ruled out, an anti-viral should additionally be given.⁴ Immunocompromised patients or those with hospital acquired sepsis should receive a beta-lactam covering Pseudomonas aeruginosa.⁴ Patients with suspected intra-abdominal source of sepsis should receive an antibiotic covering anaerobes, and those with toxic shock syndrome or necrotizing fasciitis should receive clindamycin or lincomycin.⁴ Neonates should receive ampicillin and if HSV is suspected should additionally receive acyclovir.⁴ Synergy may be required for device-associated infections, Enterococcal or Staphylococcal endocarditis, group B Streptococcus infections, and carbapenem-resistant Enterobacteriaceaea, but the only patients who should receive double coverage are cancer and transplant patients who are unstable and come from a community with a gram-negative resistance rate of greater than ten percent.⁴ These patents should receive a second agent covering gram-negatives.⁴ This is in contrast to the 2016 adult guidelines which recommended empiric combination therapy for patients in shock with de-escalation within the first few days if the patient is clinically improving regardless of results of cultures, but recommended against routinely double covering any particular pathogen in neutropenic patients unless they were presenting with shock.⁵

The antimicrobials selected should be dosed based on published pharmacokinetic and pharmacodynamic information to ensure safe and effective use.⁴ It is important to note that because vancomycin and beta-lactams have time dependent antimicrobial activity, extended infusion times may enhance therapeutic effect in patients with augmented renal clearance in early sepsis.⁴ Once this initial treatment is selected, it should be re-assessed daily for opportunities to optimize coverage.⁴ Narrowing of therapy should occur based on culture and sensitivity results, or if unavailable, on site of infection and other patient specific factors.⁴ Source control, which is physical removal of infection such as draining an abscess, and site and etiology of infection, as well as the patient’s response to treatment should guide duration of treatment for pediatric sepsis, although the 2016 adult guidelines suggest a duration of 7-10 days unless clinical evidence suggests that a longer or shorter course could be indicated.^4,5

Sepsis can cause an array of physiologic changes which may lead to hemodynamic instability and poor organ perfusion. Fluids are therefore another important component of the initial management of a septic patient. Although caution is required in patients presenting with or developing signs of fluid overload, generally in a health care setting with access to intensive care resources, patients should receive up to 40-60mL/kg in 10-20mL/kg doses over the first hour of treatment.⁴ In settings where intensive care is unavailable, the maximum volume of bolus fluid a child should receive is 40mL/kg in the first hour if hypotension is present, and if hypotension is not present, fluids should be given at a maintenance rate rather than administered as boluses.⁴ Signs to assess for hydration status include blood pressure, capillary refill and heart rate.⁴ Caution is required to avoid fluid overload which may present as pulmonary edema or worsening hepatomegaly.⁴

While most recommendations on selection of fluids for resuscitation are weak, generally balanced buffered crystalloids such as Lactated Ringer’s or PlasmaLyte solutions are recommended over albumin, normal saline, starches, or gelatin-derived fluids.⁴ These recommendations balance both cost and safety with cost being the driving factor in recommending against albumin, and safety being the driver of the only strong recommendation to avoid starches as adult data has shown significant risk of both AKI and mortality with the use of hydroxyethyl starch. The adult guidelines, however, give the option of normal saline in place of balanced crystalloids, and recommend use of albumin if patients are requiring significant crystalloids.⁵ The recommendation to use balanced crystalloids such as Lactated Ringer’s over normal saline in the pediatric guidelines is based on risk of hyperchloremic acidosis, AKI, and coagulopathy with the increased chloride content of normal saline.^4,8 Interestingly, the American Academy of Pediatrics clinical practice guideline for maintenance intravenous fluid in children recommends isotonic fluids for maintenance and specifically mentions normal saline and PlasmaLyte, while excluding Lactated Ringer’s solution from their discussion.⁹ Further studies have evaluated the risks of the supraphysiologic chloride concentrations in normal saline and found that the risk is more significant in bolus fluid administration than slower administration rates, so outside of the bolus phase of treatment switching to normal saline is a reasonable choice although the selection of this fluid for boluses is less clear.⁸ PlasmaLyte is similar though not identical to Lactated Ringer’s, but is used less often secondary to cost. Per the guidelines, albumin is not a preferred fluid in children secondary to evidence that there is not a mortality benefit and there is a significant cost difference between albumin and crystalloids.⁴

For septic shock resistant to fluids or in children who are already at risk of or showing signs of fluid overload, epinephrine and norepinephrine are good first line options recommended over dopamine for blood pressure support.⁴ This is a change from 2008 and 2012 pediatric guidelines when dopamine and inodilators were recommended prior to initiation of norepinephrine or epinephrine.^6,7 While central access is preferred for vasoactive medications, peripheral administration is reasonable during stabilization if central access is not available, and the 2008 and 2012 pediatric guidelines further recommend intra-osseous access if central access is not readily available.^4,6,7 If children are on high doses of catecholamines and still in shock, vasopressin may be added, and if hypoperfusion is still present, addition of an inodilator such as milrinone or dobutamine may be a reasonable option.⁴ This is similar though not identical to the 2016 adult guidelines which recommended norepinephrine first line followed by epinephrine or vasopressin then inodilators.⁵

Some patients may also require hydrocortisone. Hydrocortisone is a corticosteroid that decreases inflammation and reverses capillary permeability. In both the 2016 adult guidelines and the 2020 pediatric guidelines, hydrocortisone is recommended in patients who are still hemodynamically unstable after administration of fluids and vasoactive agents, but not those who are stable on those medications.^4,5 While hydrocortisone can enhance the activity of norepinephrine by decreasing reuptake, steroids have numerous adverse effects including immunosuppression, hyperglycemia, and neuromuscular weakness, so routine use is clearly not benign.⁴ Additionally, while hydrocortisone is an evidence-based treatment for primary adrenal insufficiency, stimulation testing or random cortisol levels in the setting of sepsis are not recommended unless there is evidence to enhance concern for adrenal insufficiency such as significant unexplained hyponatremia and hypoglycemia.⁴

Continued Care: Drugs with and without Routine Indications

Patients with sepsis may also require intubation. In these patients, etomidate is not a recommended induction agent secondary to risk of adrenal insufficiency following etomidate exposure.⁴ The 2008 pediatric guidelines were a bit more specific discouraging etomidate only in meningococcal sepsis.⁷ This recommendation was broadened to address all pediatric sepsis patients in the 2012 guidelines in which a mortality benefit to avoiding etomidate in meningococcal sepsis was mentioned, and avoiding both etomidate and dexmedetomidine in all sepsis patients was recommended secondary to risk of adrenal suppression.⁶ The recommendation to avoid dexmedetomidine was not carried forward into the 2020 pediatric sepsis guidelines.⁴ Future evidence seeks to strengthen recommendations regarding length of neuromuscular blockade for intubated patients which is currently a grey area. Life-threatening Acute Respiratory Failure in Children: to Breathe or Not to Breathe Spontaneously, That’s the Question, is a current study in the Netherlands which started in December 2019 to evaluate rocuronium versus placebo in mechanically ventilated children.¹⁰ This study is expected to be completed in mid-2024.¹⁰

While nutrition is important in recovery from any illness, enteral nutrition, particularly gastric nutrition, is preferred over parenteral nutrition for both adult and pediatric sepsis patients.⁴ The 2008 pediatric guidelines did not address nutrition, but the 2012 pediatric guidelines agree that enteral is preferred if tolerated and additionally address that if not tolerated parenteral feeding with dextrose 10% in a sodium containing solution is recommended.⁶ If patients are not tolerating full enteral feeds, prokinetic agents such as erythromycin or metoclopramide may be tempting options, however this is a practice that is not evidence-based, not risk-free, and not guideline recommended for pediatric patients despite being recommended in the 2016 adult guidelines.^4,5 Even if patients are not tolerating full enteral feeds, total parenteral nutrition (TPN) is not recommended during the first seven days in the PICU.⁴ Delaying initiation of TPN may improve neurocognitive development without negative impacts on survival or health status.⁴ The guidelines are not designed to fully address neonatal sepsis, so neonates expected to be unable to tolerate enteral feeding should be an exception to this seven-day delay in TPN. While the benefit of focusing on enteral nutrition seems clear, blood glucose and calcium goals are less well-defined. A blood glucose goal of less than 140mg/dL is not recommended in order to avoid hypoglycemic events, however the pediatric sepsis guidelines do not define a specific blood glucose target.⁴ American Diabetes Association guidelines for care of hospitalized diabetic patients recommend a blood glucose target of 140-180mg/dL in most critically ill and non-critically ill patients, so this range is a reasonable target.¹¹ This is corroborated with the 2016 adult guidelines which suggest initiating insulin if the blood glucose is greater than 180mg/dL as opposed to more stringent blood glucose targets and the 2012 pediatric guidelines recommending a blood glucose goal less than 180mg/dL.^5,6 Calcium goals are even more poorly defined. The prevalence of hypocalcemia in pediatric sepsis may be as high as 75%, yet calcium supplementation has not been evaluated nor is there consensus in the pediatric healthcare community on the management of hypocalcemia in these patients.⁴ This is further muddied as in the adult critical care population, calcium supplementation has been associated with worsening organ dysfunction, yet in the pediatric population it is known that calcium is associated with improved hemodynamics, particularly in infants with immature cardiomyocytes.^4,12

The pediatric sepsis guidelines specifically recommend against certain nutritional supplements. These include enteral lipid emulsions such as fish oil supplements, selenium, glutamine, arginine, zinc, vitamin C, and thiamine.⁴ Studies have not found benefit to using these supplements, and some studies have even found harm with arginine.⁴ Additionally, acute vitamin D replacement is not recommended despite vitamin D deficiency being associated with organ dysfunction.⁴ While this seems counter-intuitive, vitamin D levels appear falsely low post-resuscitation, and hypervitaminosis D can cause complications leading to death.⁴ If patients are known to be vitamin D deficient prior to onset of sepsis it is recommended to provide supplementation as recommended outside of sepsis, but measuring of levels during sepsis to guide treatment would not be an acceptable standard of care.⁴ The 2016 adult guidelines do not comment on as many supplements, but do agree in recommending against selenium, arginine, and glutamine.⁵ The adult guidelines were unable to make a recommendation for or against carnitine, which is in agreement with pediatric guidelines as carnitine is not mentioned.⁵

There is also limited evidence on temperature management in pediatric sepsis patients. The guidelines discuss use of antipyretics or a permissive strategy for fevers.⁴ Elevated temperature dose have some positive effects on the immune system which are lost if temperature is reduced with antipyretics, however it is not benign, which is most obvious in terms of patient comfort.⁴ Additionally, comparing antipyretics to physical cooling strategies favors antipyretics for early mortality, so it is clear that cooling is generally not a recommended approach in a pediatric sepsis patient.⁴ Acetaminophen and ibuprofen are commonly used antipyretics, but acetaminophen is not recommended in patients less than 3 months of age and ibuprofen in patients less than 6 months of age as the difference between effective and toxic doses is much smaller in these patients leading to heightened risk of adverse events. These are not absolute contraindications, and in fact a study in 2018 found that ibuprofen use in patients less than 6 months of age was not associated with greater adverse events than use in patients over 6 months.¹³ Risk of gastrointestinal and renal adverse events was heightened modestly in patients receiving ibuprofen versus those receiving only acetaminophen, but this risk difference was the same in both age groups.¹³ However, it is still prudent to use these medications cautiously in our youngest patients.

In sepsis patients, T3 and T4 level turnover increases and de-iodination of T4 to T3 decreases.⁴ Additionally, TSH may not be elevated, however, levothyroxine is not recommended for routine use in children with sick euthyroid.⁴ Although theoretically there may be a role for levothyroxine, studies in critically ill children have found no difference in patients treated with levothyroxine as compared to those who did not receive levothyroxine.⁴

Pediatric stress ulcer prophylaxis is a grey area as little research has been published in this area. Hospitals have published protocols, but there are no recent guidelines. A recent observational study found that age, mechanical ventilation, and not receiving enteral nutrition were all independently associated with increased likelihood of the patient receiving stress ulcer prophylaxis.¹⁴ These authors also acknowledged that use of vasopressors, corticosteroids, and NSAIDs, presence of coagulopathy, and higher PRISM III score on admission may also be factors in determining need for stress ulcer prophylaxis, but there was not a uniform prescribing practice.¹⁴ As stress ulcer prophylaxis is not benign, potentially leading to increased risk of pneumonia and Clostridium difficile infections as well as decreased bone mineral density with longer durations of treatment, it is important to consider risks and benefits of stress ulcer prophylaxis in determining which patients require these medications. It is clear that simply being diagnosed with sepsis or even septic shock is not enough to warrant use of stress ulcer prophylaxis.⁴ While there is better data in the adult population, the adult guidelines agree that stress ulcer prophylaxis is only indicated if patients have risk factors that would indicate requiring stress ulcer prophylaxis outside of sepsis.⁵ The 2008 and 2012 pediatric guidelines had no graded recommendations for or against stress ulcer prophylaxis.^6,7 As histamine 2 receptor antagonists are more studied in the pediatric population than proton pump inhibitors and have lower rates of adverse events, choosing histamine 2 receptor antagonists over proton pump inhibitors is a good choice though drug selection is not addressed in the sepsis guidelines.

Venous thromboembolism (VTE) prophylaxis is not routinely indicated in pediatric sepsis patients as VTE is much less common in pediatric patients than it is in adults, but some patients may benefit from VTE prophylaxis.⁴ This is in contrast to the adult guidelines which recommend both mechanical and pharmacologic VTE prophylaxis in sepsis patients.⁵ Pediatric sepsis patients most at risk for VTE and therefore most likely to benefit from VTE prophylaxis are those who are post-pubertal and have a central venous catheter.⁴ As much data on pediatric VTE has been extrapolated from adult data, other risk factors are similar in the two populations including obesity, cancer, use of exogenous estrogens, and renal and cardiac comorbidities.¹⁵ Previous pediatric guidelines had similar grey areas in terms of VTE prophylaxis with the 2008 guidelines stating to use VTE prophylaxis in post-pubertal children and primarily addressing heparin bonded central venous catheters rather than administration of LMWH or UFH, but there was no mention of management of children who have not yet reached puberty.⁷ The 2012 update simply stated no graded recommendations for VTE prophylaxis in pre-pubertal children, again discussed heparin bonded catheters, and did not mention post-pubertal children.⁶ The medication most often used for VTE prophylaxis in pediatric patients is enoxaparin.

Intravenous immune globulin (IVIG) may also be indicated in select patients because it enhances passive immunity but evidence has not supported routine use of IVIG in patients with sepsis.⁴ While IVIG is not routinely recommended for sepsis in pediatric patients, there are a subset of patients for whom IVIG may be a reasonable treatment option.⁴ Patients with streptococcal toxic shock syndrome are likely to benefit from IVIG.⁴ Additionally, it may be beneficial to consider IVIG in immunodeficient or immunocompromised patients with low immunoglobulin levels and patients with necrotizing fasciitis.⁴ While the adult guidelines recommend against IVIG without this caveat of potentially appropriate use, they also suggest that further research may be needed to evaluate the efficacy of IVIG, so with four additional years of research these two guideline statements are essentially in agreement.⁵ The 2012 pediatric guidelines stated that use of IVIG in toxic shock was unclear, which is a bit incongruent with 2008 pediatric guidelines which suggested IVIG in patients with severe sepsis, not just those with toxic shock.^6,7

Medications that no longer appear in the pediatric sepsis guidelines but have previously been recommended against include recombinant human activated protein C in the 2008 guidelines secondary to findings in clinical trials of no difference between patients receiving activated protein C versus placebo.⁷ Based on these findings it would be reasonable to assume that despite not being mentioned, continuing to not utilize activated protein C would be appropriate. The 2012 guidelines recommended against long-term propofol for sedation in patients under three years of age secondary to concerns for metabolic acidosis.⁶ This is another recommendation that while not being mentioned in other iterations of the guidelines continues to seem prudent to follow as it is known that propofol related infusion syndrome is a risk for patients of all ages with extended use of propofol, making propofol a less than ideal agent for patients requiring long-term sedation.

Conclusions

Organ dysfunction is useful not only in differentiating sepsis from severe sepsis, but also in considering changes to medication pharmacokinetics. When shock is present antibiotics should be given within one hour. Fluids are an important component of care even in normotensive patients and balanced buffered crystalloids are recommended. Unless patients require hydrocortisone at baseline, it should only be given if fluids and vasoactive medications are insufficient to maintain hemodynamic stability. Nutrition should be provided enterally if possible, and many supplements including zinc, thiamine, and vitamin C are not routinely indicated. Finally, it is important to carefully consider indications for IVIG, stress ulcer prophylaxis, and VTE prophylaxis.

References

1. Mathias B, Mira JC, Larson SD. Pediatric sepsis. Curr Opin Pediatr. 2016;28(3):380-387.
2. Goldstein B, Giroir B, Randolph A; International consensus conference on pediatric sepsis. international pediatric sepsis consensus conference: definitions for sepsis and organ dysfunction in pediatrics. Pediatr Crit Care Med. 2005;6(1):2-8.
3. Thakkar N, Salerno S, Hornik CP, Gonzalez D. Clinical pharmacology studies in critically ill children. Pharm Res. 2017;34(1):7-24.
4. Weiss SL, Peters MJ, Alhazzani W, et al. Surviving sepsis campaign international guidelines for the management of septic shock and sepsis-associated organ dysfunction in children. Pediatr Crit Care Med. 2020;21(2):e52-e105.
5. Rhodes A, Evans LE, Alhazzani W, et al. Surviving sepsis campaign: international guidelines for management of sepsis and septic shock: 2016. Intensive Care Med. 2017;43:304-377.
6. Dellinger RP, Levy MM, Rhodes A, et al. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock, 2012. Intensive Care Med. 2012;39:165-228.
7. Dellinger RP, Levy MM, Carlet JM, et al. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med. 2008;36(1):296-327.
8. Williams V, Jayashree M, Nallasamy K, Dayal D, Rawat A. 0.9% saline versus Plasma-Lyte as initial fluid in children with diabetic ketoacidosis (SPinK trial): a double-blind randomized controlled trial. Crit Care. 2020;24(1):1.
9. Feld LG, Neuspiel DR, Foster BA, et al. Clinical practice guideline: maintenance intravenous fluids in children. Pediatrics. 2018;142(6):e20183083.
10. Paediatric ards neuromuscular blockade study (PAN). Clinicaltrials.gov identifier: NCT02902055. Updated December 13, 2019.
11. American Diabetes Association. 15. Diabetes care in the hospital. Standards of Medical Care in Diabetes-2020. Diabetes Care. 2020;43(Suppl 1):S193-S202.
12. Averin K, Villa C, Krawczeski CD, et al. Initial observations of the effects of calcium chloride infusions in pediatric patients with low cardiac output. Pediatr Cardiol. 2016;37(3):610-617.
13. Walsh P, Rothenberg SJ, Bang H. Safety of ibuprofen in infants younger than six months: A retrospective cohort study. PLoS One. 2018;13(6):e0199493.
14.  Duffett M, Chan A, Closs J, et al. Stress ulcer prophylaxis in critically ill children: a multicenter observational study. Pediatr Crit Care Med. 2020;21(2):e107-e113.
15. Faustino EV, Raffini LJ. Prevention of hospital-acquired venous thromboembolism in children: a review of published guidelines. Front Pediatr. 2017;5:9.

By: Kelly Williams & Jenny Ohnesorge, Pharm.D. Candidates 2023; UMKC SSHP Chapter Presidents

Despite living and learning in a pandemic, the leadership of UMKC’s SSHP across three campuses (Kansas City, Columbia, and Springfield) persevered by innovating new ways to connect to students and the community. In the Fall of 2020, there were still many unknowns to the pandemic, but the executive teams pushed on and planning was underway for virtual events, a change from previous years. The year kicked off with the New Student Orientation on the lawn of the Health Sciences Building and executive team members were able to talk about what ASHP and SSHP can do for its members. In September, Residency Roundtable was held for the first time ever via Zoom. UMKC’s Residency Roundtable 2020 consisted of discussion-based breakout rooms with the Residency Program Directors and current residents, a keynote presentation, and information about PhorCAS and Midyear. We were able to host a variety of programs from sites that would otherwise be impossible in-person. Many of the programs that attended Residency Roundtable were not from Missouri, but states such as Nebraska, Iowa, Arkansas, Kansas, and Texas. The event was deemed a success from student attendees and the SSHP executive board alike, with talks to continue hosting Residency Roundtable virtually in order to reach a more diverse array of residency programs. Next, in October, we were able to host the Clinical Skills Competition via Zoom as well, where 12 teams of two students competed. The Clinical Skills Competition was held on two separate days, the first day consisting of a written case workup by each team, and the second day consisting of an oral presentation from three semi-finalist teams. Both days were judged by a panel of pharmacy residents. Similar to Residency Roundtable, the Clinical Skills Competition proved to be very successful as it also transitioned to a new virtual structure, with talks to continue this format going forward.

In both the fall and spring, UMKC’s SSHP held monthly general meetings with speakers from health-systems across Missouri. Topics covered included patient cases and general discussion of the day to day activities as a health-system pharmacist. Additionally, we were excited to host MSHP President Dr. Davina Dell as she presented over ASHP’s Practice Advancement Initiative (PAI) 2030. Furthermore, students were encouraged to attend community service events held at the three campuses; such events consisted of volunteering at Harvester’s and Habitat for Humanity and cleaning up trash alongside roads and highways

The Columbia SSHP team was able to coordinate one event with MMSHP in the Fall of 2020, including food trucks, drinks, and trivia at a local eatery. Columbia’s SSHP team was also able to arrange a fundraiser selling embroidered UMKC School of Pharmacy jackets and quarter-zips, a feat that raised over $450 for the UMKC SSHP chapter. We hope to continue this fundraiser in the coming years.

We are excited to once again get creative with our events in the Fall. We look forward to incorporating more virtual events into our schedule, including Residency Roundtable and the Clinical Skills Competition. This summer, the 2021-22 SSHP Executive Team will be hard at work to bring the most valuable experience to its student members. We are very thankful for MSHP’s involvement with SSHP across the three campuses and wish you a restful remainder of your summer!

By: Leah Blocker, PharmD Candidate 2023; SSHP President

At St. Louis College of Pharmacy, our SSHP chapter holds many events that aim to advance and educate pharmacy students. In addition to our ongoing Mentor/Mentee program, some of the events we held this past year included Curriculum Vitae Writing and Review, Resident and Residency Director Roundtables, and a Medical Marijuana Lunch ‘n Learn.

Our Mentor/Mentee Program is an annual matching program we hold that connects undergraduate or P1 students with professional students. Mentors are able to guide their mentees through their transition from the undergraduate program to the professional program at STLCOP. This program helps younger students face the many new challenges that are associated with the professional program, such as a heavier workload and more independent studies. The mentors in our program are there to offer advice.  Not only that, but our mentor-mentee program also opens up discussion about post-graduate opportunities, such as residency, which many younger students have not yet had time to explore.

At our Curriculum Vitae Writing and Review events, we aim to educate students on how to create or improve their professional curriculum vitae (CV). CV’s are one of the most important ways a student can promote themselves to residency programs or future job opportunities. At STLCOP, one of our professors, Dr. Jack Burke, leads the CV Writing event. He plays a key role in educating students on the most important aspects of a CV and how to properly structure a CV. For our CV Review event, students were able to submit their CV to us and receive feedback from one of the pharmacist members of StLSHP. This allowed students the opportunity to have a pharmacist review their CV and make suggestions to help improve their chances of standing out in the future.

Our Resident and Residency Director Roundtable events aim to connect professional students with current pharmacy residents and residency directors in the St. Louis area. The goal is to educate students on the different opportunities available to them after graduation, as well as enlighten them about what residency is like and what to expect. Current residents and residency directors are able to provide students with insight and tips, and students have an open platform to ask questions and receive direct answers.

Lastly, a new event we held this year included a Medical Marijuana Lunch ‘n Learn. With the ever-changing advancements in legislature and medicine, it is important to keep students up to date and educated on significant topics, such as medical marijuana and its uses in the pharmacy field. Students are only briefly exposed to the topic of medical marijuana in our professional studies, so by offering this event, we hoped to expose more students to the topic in order to better prepare them for their future.

By: Elizabeth Nash, St. Louis College of Pharmacy Pharm.D. Candidate 2022 and Morgan Luttschwager Rose, MBA, St. Louis College of Pharmacy Pharm.D. Candidate 2022

Mentor: Michelle Jeon, Pharm.D., BCACP, Assistant Professor of Pharmacy Practice, St. Louis College of Pharmacy at UHSP

Epidemiology
Heparin-induced thrombocytopenia (HIT) is an unusual drug reaction involving heparin exposure. Overall, HIT epidemiology is not well documented; however, reports indicate it will occur in about 0.1-0.5% of patients on heparin therapy including low molecular weight heparin (LMWH) and unfractionated heparin (UF). Based on a population study conducted in 2018, the incidence of HIT diagnosis are relatively low. HIT seems to be more common after cardiac surgeries compared to after orthopedic surgeries.¹

Once HIT occurs, the most common complication is thrombosis, occurring in 30% of cases, with bleeding occurring in 6.2%. In patients that experience bleeding, 25% of patients do not survive regardless of treatment.¹

Pathophysiology
The pathophysiology of HIT (Figure 1) was identified in the early 1970s, nearly 20 years after the first reported case. The prominent players in the pathophysiology of HIT include platelet factor 4, heparin, platelets, monocytes, factors VII, IX, X, and thrombin.

Once heparin is administered, it binds to naturally occurring platelet factor 4 due to ionic forces—this binding halts heparin’s action. The immune system responds by creating IgG antibodies that attack the PF4/heparin complex. The immunocomplex then binds to the surface of platelets and monocytes. This binding triggers their activation through the cross-linking of FcgIIA receptors. Platelet activation then leads to aggregation and stimulation of procoagulant activity. Monocyte activation stimulates tissue factor (TF) generation. TF binds with factor VII to activate factors IX and X, which in turn stimulate thrombin formation. Thrombin leads to known clinical problems associated with HIT, such as pulmonary embolism, mesenteric ischemia, ischemic limb necrosis, acute myocardial infarction, and stroke.² 

Figure 1. Pathophysiology of heparin-induced thrombocytopenia²

Risk Factors
All patients receiving any form of heparin should to be monitored for HIT with routine labs including platelets. However, there are some specific scenarios in which increased risk may be present and extreme caution should be used. Risk factors for HIT include:

Patients under these circumstances may require closer monitoring; however, there is still a risk for HIT in patients who do not have these risk factors.

Diagnosis and Clinical Presentation
Although HIT is rare, patients with suspected signs and symptoms should be evaluated for probability of the disease. As indicated in Figure 2, the 4Ts test considers thrombocytopenia, timeframe of platelet decreasing, thrombosis, and other causes of thrombocytopenia. If these tests reveal intermediate or high probability, an immunoassay, which identifies antibodies against PF4 or heparin should be conducted. If the immunoassay is positive, a functional platelet activation assay (e.g. serotonin release assay) should subsequently be performed, which shows antibodies that specifically induce heparin-dependent platelet activation³. If again positive, HIT is likely and treatment options should be considered. Typical clinical presentation of HIT includes platelet count decreased from baseline by greater than 50% and platelet nadir greater than or equal to 20,000/mm2. Patients with HIT typically have an onset within 5-14 days or less than one day with recent heparin exposure³. These patients may also have a confirmed thrombosis, necrosis of the skin at injection site, adrenal hemorrhage, or anaphylactoid reaction after heparin bolus. Patients with suspected HIT should have no other probable causes of thrombocytopenia.  

Figure 2. Diagnosis for HIT³

Treatment and Management
The most critical information for practicing pharmacists regarding HIT is perhaps the treatment and management. Patients with HIT should be treated with non-heparin anticoagulants. The American Society of Hematology⁵ (ASH) suggests argatroban, bivalirudin, fondaparinux, or a direct-acting oral anticoagulant (DOAC). Patient-specific factors such as comorbidities, ease of administration, cost, route, etc., play a role in helping to select the best medication. If the patient is clinically stable, treatment with fondaparinux or any of the DOACs are best due to the ease of administration and the lack of routine labs required to monitor for safety. In situations where a short-acting anticoagulant is needed – such as in critical illness, increased bleed risk, or the potential for an urgent procedure – argatroban or bivalirudin are ideal. DOACs should be avoided in the case of life or limb-threatening thrombosis because they have not been thoroughly tested in this population. In a matter of such thrombosis, argatroban, bivalirudin, or fondaparinux are recommended for use. If patients also have moderate to severe hepatic dysfunction – defined as Child-Pugh Class B and C – bivalirudin, or fondaparinux are recommended over other options. If necessary, a lowered dose of argatroban may be appropriate in the case of hepatic impairment.³

Monitoring Parameters
HIT requires monitoring for signs and symptoms of thrombosis, bleeding and platelet recovery no matter which therapy option is chosen. Baseline aPTT levels should be drawn, if possible, to establish when thrombin levels have returned to normal. Several treatment options rely on platelet levels to determine duration of therapy. Signs and symptoms of bleeding such as bruising, weakness, and decreased blood pressure should be monitored daily. Patients diagnosed with HIT and a hemorrhage have a poor prognosis, with a 25% mortality rate regardless of treatment. The best chance to counter those odds is to catch the bleed early on with close monitoring.

Drug-specific monitoring parameters can vary, especially between the newer DOACs and older agents. DOACs typically require less laboratory monitoring, which can be favorable for patients.

COVID-19 Considerations
The pathology of heparin-induced thrombocytopenia relies significantly on the platelet factor 4/heparin (PF4/H) complex and the antibodies developed against it. In the case of patients infected with the SARS-CoV-2 virus, the presence of these antibodies is increased.^{4, 5} Once infected, patients develop antibodies against the COVID-19 virus; however, these antibodies resemble the PF4/H antibodies so closely they can activate the B cells associated with HIT. Thrombotic complications associated with COVID-19 infection, therefore, share pathology with HIT. The SARS-CoV-2 infection is strongly related to thromboembolic events, perhaps due to the resemblance of the antibodies, making anticoagulation therapy common in hospitalized patients. When using heparin as anticoagulant therapy in infected patients, extreme caution should be used as the risk for HIT is increased.⁵

Role of a Pharmacist
Pharmacists can significantly impact the treatment of heparin-induced thrombocytopenia; they are on the front line to recognize the drug-induced reaction of HIT. Pharmacists should determine whether or not non-heparin products are an appropriate therapy for anticoagulant use. The risk factors of HIT could guide treatment selection and the level of monitoring needed. Pharmacists can use patient-specific factors to choose the best anticoagulation therapy for a patient. Pharmacists can also recognize when heparin is in lower concentrations in products such as heparin flushes, hematopoietic stem cell products, some total parenteral nutrition products, and prothrombin complex. As the drug experts, pharmacists can be the first to identify someone has HIT by evaluating side effects of the drug. Pharmacists should participate in an interdisciplinary approach to help manage HIT with exemplary patient-centered care.

References:

1. Dhakal B, Kreuziger LB, Rein L, et al. Disease burden, complication rates, and health-care costs of heparin-induced thrombocytopenia in the USA: a population based study. Lancet Haematol. 2018;5(5):e220-e231.
2. Patriarcheas V, Pikoulas A, Kostis M, Charpidou A, Dimakakos E. Heparin-induced thrombocytopenia: pathophysiology, diagnosis and management. Cureus. 2020;12(3):e7385.
3. Pishko AM, Linkins LA, Warkentin TE, Cuker A. Diagnosis and management of heparin-induced thrombocytopenia (HIT) a pocket guide for the clinician. Am Soc of Hematology. 2018;2(22):3226-3256.
4. Zhu W, Zheng Y, Yu M, et al. SARS-CoV-2 receptor binding domain-specific antibodies activate platelets with features resembling the pathogenic antibodies in heparin-induced thrombocytopenia. Research Square. 2021;rs-3.
5. Favaloro EJ, Henry BM, Lippi G. The complicated relationships of heparin-induced thrombocytopenia and platelet factor 4 antibodies with COVID-19. Int J Lab Hematol. 2021;00:1-12.
6. Madala S, Krzyzak M, Dehghani S. Is COVID-19 an independent risk factor for heparin-induced thrombocytopenia. Cureus. 2021;13(2):e13425.
7. Argatroban. Packa a pocketge Insert. LGM Pharma. 2011.
8. Beiderlinden M, Treschan TA, Görlinger K, et al. Argatroban anticoagulation in critically ill patients. Ann Pharmacother. 2007;41(5):749-54.
9. Bivalirudin. Package Insert. International Technidyne Corporation. 2016.
10. Fondaparinux. Package Insert. GlaxoSmithKline. 2010.
11. Agnelli G, Buller HR, Cohen A, et al. AMPLIFY investigators. oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med. 2013;369(9):799-808.
12. Eliquis. Package Insert. Bristol-Myers Squibb Company and Pfizer Inc. 2021.
13. Pradaxa. Package Insert. Boehringer Ingelheim Pharmaceuticals. 2015.
14. Xarelto. Package Insert. Janssen Pharmaceuticals. 2016.

By: Jaynika Patel, PharmD Candidate 2023; University of Health Sciences and Pharmacy at St. Louis College of Pharmacy, Saint Louis, Missouri

Mentor: Priyam Patel, PharmD; Aurora St. Luke’s Medical Center, Milwaukee, Wisconsin

Background
Obesity is a prevalent condition in the United States (U.S.) with nearly one in every three adults being affected.¹ The body mass index (BMI) is utilized to determine the weight classification of an individual and can be calculated by dividing the weight in kilograms by the height in meters squared. Obesity is defined as a BMI of 30.0 kg/m² or above and is further classified into three subcategories: class I (BMI 30-34.9 kg/m²), class II (35-39.9 kg/m²), and class III (≥ 40 kg/m²). Morbidly obese patients are considered Class III based on their BMI.

Obesity presents as a risk factor for venous thromboembolism (VTE).² Venous thromboembolism is a serious, yet preventable medical condition which refers to blood clots in the veins and could lead to a serious illness or death.³ It is estimated that the annual incidence of VTE in the U.S is 1 to 2 per 1000 of the population.³ Due to the high morbidity and mortality risk, the prevention and treatment of VTE have become a growing concern.

Per the American College of Chest Physicians (CHEST) guidelines, the favorable treatment option for patients with VTE and no cancer diagnosis are direct oral anticoagulants (DOACs) over vitamin K antagonist (VKA) therapy.⁴ However, the guideline by the Scientific and Standardization Subcommittee of International Society on Thrombosis and Haemostasis (ISTH) advises that DOACs should not be administered for BMI greater than 40 kg/m² or weight greater than 120 kg due to inadequate drug exposure, short half-lives, and lower peak concentrations in this patient population.⁵ The remainder of this article will evaluate landmark trials and recent studies followed by the key takeaways.

Landmark Trials and Recent Studies
Each DOAC, supported by its landmark trial(s), has been evaluated for its efficacy and safety in the treatment of VTE. The outcomes measured in these trials include, but are not limited to, recurrence of VTE and major bleeding. The results of these studies concluded that DOACs in VTE are as effective for anticoagulation as VKA, such as warfarin.

One limitation, as it pertains to this article, is that these landmark trials were conducted in a general population, which had a low enrollment of morbidly obese patients. The enrollment for the highest weight/BMI categories reported in these trials is summarized in Table 1. Recent studies aim to determine the efficacy and safety of DOAC use in morbidly obese patients.  

Elshafei et al. performed a systematic review followed by a meta-analysis of trials that compared efficacy and safety of DOAC use to warfarin for acute VTE in morbidly obese patients.¹² Four observational studies assessed the efficacy and safety outcomes. The primary efficacy outcome of VTE recurrence rate in morbidly obese patients determined that DOAC use compared to warfarin was non-inferior (OR 1.07, 95% CI 0.93 to 1.23, Q=1.45, I²=0%) with a low I², indicating the results were homogenous. In regard to major bleeding events, the analysis identified a non-significant risk reduction by 20% in the DOAC group (OR 0.80, 95% CI 0.54 to 1.17, Q=0.16, I²=0%). This study provided evidence that DOAC use as an alternative to warfarin in morbidly obese patients is effective and safe.

Spyropoulos et al. conducted a retrospective 1:1 propensity score-matched cohort study that analyzed morbidly obese patients diagnosed with a VTE who received rivaroxaban or warfarin.¹³ Two analyses were conducted in this study to observe continual anticoagulant use: intent-to-treat (ITT) and on-treatment (OT). In the ITT analysis, the risk of recurrent VTE in the rivaroxaban group (16.8%) versus the warfarin group (15.9%) was not significantly different (OR 0.99, 95% CI 0.85 to 1.14, P=0.8443). However, major bleeding events in the treatment group (1.8%) in comparison to the warfarin group (2.5%) were significant lower (OR 0.66, 95% CI 0.45 to 0.98, P = 0.0388). In the OT analysis, the risk of recurrent VTE for rivaroxaban (14.8%) versus warfarin (13.4%) was not statistically significant (OR 1.02, 95% CI, 0.87 to 1.20, P=0.8343). Major bleeding events for rivaroxaban (1.4%) and warfarin (1.8%) also did not occur at a statistically different rate (OT: OR 0.75, 95% CI 0.47 to 1.19, P=0.2266). The two analyses provided consistent results in concluding that rivaroxaban has comparable efficacy to warfarin in this study population.

Coons et al. also performed a retrospective matched cohort study analyzing the effectiveness and safety of DOACs for acute VTE treatment in morbidly obese patients in comparison to warfarin.¹⁴ The primary outcome was the recurrence of VTE within 12 months after the index admission date. Of the patients with a diagnosis of acute VTE and weight threshold of 100 kg to 300 kg, 632 patients had received a DOAC, while 1208 patients had received warfarin. Rivaroxaban was the primary DOAC administered, representing 91.8% of the patient population. The recurrence of VTE occurred in 6.5% of patients in the DOAC group versus the 6.4% of patients in the warfarin group, which was not a statistically significant difference (P=0.93). The incidence of the primary outcome in the apixaban, rivaroxaban, and warfarin groups were 2.1%, 2%, and 1.2%, respectively (P=0.74). Bleeding events in the DOAC group (1.7%) and warfarin group (1.2%) were also not statistically significant (P=0.31). Based on the data, the authors of the study support the treatment of acute VTE in morbidly obese patients with DOACs.

A retrospective single-center cohort study by Patil et al. analyzed the efficacy and safety of DOACs versus warfarin in the morbidly obese Veteran patient population.¹⁵ In the DOAC group, apixaban was administered to 61.68% of the patients, rivaroxaban to 32.71%, and dabigatran to 5.61%. The primary outcome measure was a composite of VTE and stroke/transient ischemic attack. The results of the annual incidence rate of the primary outcome were not statistically significant between the DOAC group (1.61%) and warfarin group (3.91%) (RR 2.436, 95% CI 0.776 to 10.08, P=0.1543). The secondary outcome measuring major bleeding based on the ISTH guidelines had similar annual incidence rates between the two groups (warfarin: 3.13% vs. DOACs: 3.21%, RR 0.97, 95% CI 0.36 to 2.75, P=0.9438). Overall, the study results demonstrated that the administration of DOACs in comparison to warfarin is a viable alternative in morbidly obese patients. 

Conclusion 
The recent studies discussed above suggest that DOAC use in the treatment of VTE in morbidly obese patients may be efficacious in preventing recurrent VTE. The non-inferiority studies still hold warfarin to be a viable treatment option for patients. Regarding safety, DOACs demonstrated similar or slight variations in the rates of bleeding events compared to warfarin which may be contributed from patient-specific factors or inconsistent monitoring. The results of these studies were strengthened by the study design which included a diverse population, relevant subgroup of patients, and large databases for research. 

One major limitation found amongst the retrospective studies was that they relied on accurate documentation that may not have considered other factors at that time, such as specific comorbidities or concomitant use of other high bleeding risk medications. Additionally, the predominance of one DOAC in a study analyzing all DOACs does not provide a balanced comparison. Thus, prospective clinical trials studying the effects of all DOACs for the treatment of VTE in morbidly obese patients are needed to determine which DOAC is superior and most appropriate to recommend. 

References

1. Defining adult overweight & obesity. Centers for Disease Control and Prevention. https://www.cdc.gov/obesity/adult/defining.html. Updated June 7, 2021. Accessed June 9, 2021.
2. Overweight and obesity. National Heart, Lung, and Blood Institute. https://www.nhlbi.nih.gov/health-topics/overweight-and-obesity. Accessed June 3, 2021.
3. What is venous thromboembolism? Centers for Disease Control and Prevention. https://www.cdc.gov/ncbddd/dvt/facts.html. Updated February 7, 2020. Accessed June 1, 2021.
4. Kearon C, Akl EA, Ornelas J, et al. Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report. Chest. 2016;149(2):314-352.
5. Martin K, Beyer-Westendorf J, Davidson BL, Huisman MV, Sandset PM, Moll S. Use of the direct oral anticoagulants in obese patients: guidance from the SSC of the ISTH. J Thromb Haemost. 2016;14(6):1308-1313.
6. Schulman S, Kearon C, Kakkar AK, et al.; RE-COVER Study Group. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med. 2009;361(24):2342-52.
7. Schulman S, Kakkar AK, Goldhaber SZ, et al.; RE-COVER II Trial Investigators. Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis. Circulation. 2014;129(7):764-72. 
8. EINSTEIN Investigators, Bauersachs R, Berkowitz SD, Brenner B, et al. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010;363(26):2499-510. 
9. EINSTEIN–PE Investigators, Büller HR, Prins MH, Lensin AW, et al. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med. 2012;366(14):1287-97.
10. Agnelli G, Buller HR, Cohen A, et al.; AMPLIFY Investigators. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med. 2013;369(9):799-808.
11. Hokusai-VTE Investigators, Büller HR, Décousus H, Grosso MA, et al. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med. 2013;369(15):1406-15.
12. Elshafei MN, Mohamed MFH, El-Bardissy A, et al. Comparative effectiveness and safety of direct oral anticoagulants compared to warfarin in morbidly obese patients with acute venous thromboembolism: systematic review and a meta-analysis. J Thromb Thrombolysis. 2021;51(2):388-396.
13. Spyropoulos AC, Ashton V, Chen YW, et al. Rivaroxaban versus warfarin treatment among morbidly obese patients with venous thromboembolism: Comparative effectiveness, safety, and costs. Thromb Res. 2019;183:159-166.
14. Coons JC, Albert L, Bejjani A, Iasella CJ. Effectiveness and safety of direct oral anticoagulants versus warfarin in obese patients with acute venous thromboembolism. Pharmacotherapy. 2020;40(3):204-210.
15. Patil T, Lebrecht M. A single center retrospective cohort study evaluating use of direct oral anticoagulants (DOACs) in morbidly obese veteran population. Thromb Res. 2020;192:124-130. 

By: Michelle Tulchinskaya, Elena Stroman, and Katherine Nguyen; PharmD. Candidates

Mentor: Anastasia L. Armbruster Pharm.D., FACC, BCPS, BCCP

Since 2017, new therapies for Heart Failure with Reduced Ejection Fraction (HFrEF) have emerged reducing both mortality and hospitalizations for heart failure in this population. In particular, two drug therapies have emerged: angiotensin receptor-neprilysin inhibitors (ARNIs), and sodium-glucose cotransporter-2 inhibitors (SGLT2s). Overall, ARNIs, SGLT2s, and other guideline directed medical therapy (GDMT) are underutilized. CHAMP-HF has exhibited the underutilization of these medications.¹ Specifically sacubitril/valsartan (Entresto®), has been underutilized even after the 2016 ACC/AHA/HFSA Focused Update on HF included it as a Class I recommendation for patients with HFrEF.² In outpatient settings, 86.1% of patients without contraindications did not receive sacubitril/valsartan. Patients with the following characteristics were less likely to receive treatment; older age, Hispanic ethnicity, chronic insufficiency, and higher EF (p ≤ 0.009). Patients with higher systolic blood pressure and a history of hypertension were associated with achieving a ≥50% target dose (all p ≤ 0.037).¹

Traditionally, angiotensin converting enzyme inhibitors (ACE-Is) and angiotensin II receptor blockers (ARBs) have been first line therapies for patients with Stage C HFrEF. The 2021 Update to the 2017 ACC Expert Consensus Decision Pathway for Optimization of Heart Failure Treatment is the first document to prefer the usage of ARNIs for patients with Stage C HFrEF over ACE-Is/ARBs.² Neprilysin, also known as neutral endopeptidase, is a zinc-dependent metalloprotease that inactivates several vasoactive peptides, such as natriuretic peptides, adrenomedullin, bradykinin, and substance P, each of which has an important role in the pathogenesis and progression of HF.² As demonstrated in the PARADIGM-HF trial, sacubitril/valsartan was associated with reduced hospitalizations, morbidity, and mortality in these patients compared to enalapril.³ The composite of death from cardiovascular causes or hospitalization for heart failure occurred in 914 patients (21.8%) in the sacubitril/valsartan group and 1117 patients (26.5%) in the enalapril group (HR in LCZ696 group: 0.80; 95% CI 0.73 - 0.87; P<0.001).⁴ Due to this pivotal trial and following guideline recommendations, the preference is to start patients on an ARNI at the diagnosis of Stage C HFrEF, transition patients from an ACE-I or an ARB, or start patients that have not been given an ARNI, ACE-I, or ARB. Recent data from clinical studies, along with aggregate clinical experience, suggest that directly initiating an ARNI, rather than a pretreatment period ACE-I/ARBs, is a safe and effective strategy.² In the PIONEER-HF trial, it was concluded that sacubitril/valsartan’s efficacy and safety was consistent across dose levels in hemodynamically stable patients with advanced decompensated heart failure. In the randomized, double-blind, active-controlled trial sacubitril/valsartan versus enalapril, there was no heterogeneity across dose levels in the effects of sacubitril/valsartan on the reduction of NT-proBNP, reduction of cardiovascular death, rehospitalization, or pre-specified adverse events.⁵

Although it is recommended to use an ARNI, ideal timing of initiation and rate of titration are frequently discussed. Many providers are concerned that patients will not be able to tolerate target dose due to adverse effects such as hyperkalemia, hypotension, cardiac failure, dizziness, renal impairment, angioedema, and cardiac failure. A randomized, multicenter, open-label study comparing two different treatment initiation regimens of sacubitril/valsartan, concluded that it was feasible for about half of the patients to achieve target dose within 10 weeks. In the TRANSITION trial, about half of the HF patients reached the recommended target dose in 10 weeks (relative RR 0.90; 95% CI 0.79 - 1.02), and over 86% were able to maintain any dose for at least  2 weeks leading to week 10 (relative RR 0.96; 95% CI 0.92 - 1.01).⁶ When obtaining full dose, it was noted that adverse effects of hyperkalemia, hypotension, cardiac failure, dizziness, renal impairment, angioedema, and cardiac failure were low. These adverse events were reasons for patients’ discontinuation of sacubitril/valsartan as well.⁶ It was found that a better tolerability profile was obtained when the uptitration was done gradually and that patient’s tolerability was higher when baseline adverse effects and labs of the patients were taken into account. Another multicenter, randomized, open-label, parallel‐group study found that a more gradual/conservative uptitration can increase the chance of attaining the target dose of sacubitril/valsartan in patients transitioning from lower doses of ACEI/ARBs.⁷ Additionally, it was found that the majority of patients (>80%) with SBP of ≥100 mmHg achieved and maintained the target dose of sacubitril/valsartan if the treatment was titrated gradually.⁸ A gradual dose increase included patients on a low dose of 24 mg/26 mg twice per day, followed by a titration up to 97 mg/103 mg twice per day over a 3 or 6 week period.⁸ These findings suggest that low SBP should not prevent clinicians from considering the initiation of sacubitril/valsartan.

The mortality benefit of sacubitril/valsartan for HFrEF patients is notable as described in the PARADIGM-HF trial, but many patients struggle with access to the life-saving medication due to the high cost. Sacubitril/valsartan is covered by Medicare Part D, but the out-of-pocket cost can be more than $1,600 a year for patients. In a study conducted by DeJong, et al., more than 2,000 Medicare Part D plans were analyzed. While all plans fully covered sacubitril/valsartan, the results concluded that the average cost-sharing for a 30-day supply of an ARNI during the coverage period was $57, as opposed to a range of $2 - 5.00 for other heart failure medications such as ARBs, beta-blockers, and loop diuretics. The study estimated the subjects’ projected annual out-of-pocket costs to be $1,685, of which $1,632 of $1,685 (96.9%) would be attributable to the ARNI.⁹  Although Medicare Part D provides coverage for sacubitril/valsartan, patients would still be left with a considerable amount of out-of-pocket costs.

An additional analysis of the effectiveness and value of sacubitril/valsartan, conducted by Ollendorf, et al., looked at the lifetime cost-effectiveness of sacubitril/valsartan relative to ACE-I therapy. The analysis showed that the ACE-I had averages of 5.56 quality-adjusted life years (QALYs) and total costs of $123,578, while sacubitril/valsartan produced an additional 0.57 QALY and an additional $29,138 in costs.¹⁰ This shows that cost-effectiveness would exceed $100,000 per QALY gained if the benefits of sacubitril/valsartan over enalapril persist for 3.3 years.¹⁰ Another study by Gaziano, et al. examined the cost-effectiveness of sacubitril/valsartan in comparison to enalapril in HFrEF patients. The study estimated that there would be 220 fewer hospital admissions per 1000 patients with heart failure treated with sacubitril/valsartan vs. enalapril over 30 years and calculated sacubitril/valsartan’s incremental cost-effectiveness ratio of US $45,017 per QALY gained.¹¹ These findings concluded that utilization of sacubitril/valsartan could result in more QALYs gained, prevention of premature death, as well as significant cost-savings through avoided hospitalizations.

There is sufficient evidence that exhibits sacubitril/valsartan’s benefit in HFrEF therapy, and updated guidelines now prefer the usage of ARNI. Sacubitril/valsartan has demonstrated a decrease in hospitalizations due to HFrEF in comparison to ACE-I/ARBs, in addition to cost-savings. Though there are concerns for tolerability of sacubitril/valsartan, it can potentially be avoided with a gradual uptitration to target dose. It would be beneficial to use sacubitril/valsartan over ACE-I/ARBs unless limited by contraindications, tolerability or cost limitations.

References:

1. Greene SJ, Butler J, Albert NM, DeVore AD, et al. Medical therapy for heart failure with reduced ejection fraction: The CHAMP-HF Registry. J Am Coll Cardiol. 2018 Jul 24;72(4):351-366.
2. 2021 update to the 2017 ACC expert consensus decision pathway for optimization of heart failure treatment: answers to 10 pivotal issues about heart failure with reduced ejection fraction: a report of the american college of cardiology solution set oversight committee. J Am Coll Cardiol 2021;Jan 11
3. Myhre PL, Vaduganathan M, Claggett B, et al. B-type natriuretic peptide during treatment with sacubitril/valsartan: the PARADIGM-HF trial. J Am Coll Cardiol. 2019;73:1264–72.
4. McMurray JJ, Packer M, Desai AS, et al. PARADIGM-HF Investigators and Committees. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014 Sep 11;371(11):993-1004.
5. Velazquez EJ, Morrow DA, DeVore AD, et al. Angiotensin-neprilysin inhibition in acute decompensated heart failure. N Engl J Med. 2019;380(6):539-548.
6. Wachter R, Senni M, Belohlavek J, et al. Initiation of sacubitril/valsartan in haemodynamically stabilised heart failure patients in hospital or early after discharge: primary results of the randomised TRANSITION study. Eur J Heart Fail. 2019;21(8):998-1007.
7. Senni M, McMurray JJ, Wachter R, et al. Initiating sacubitril/valsartan (LCZ696) in heart failure: results of TITRATION, a double-blind, randomized comparison of two uptitration regimens. Eur J Heart Fail. 2016;18(9):1193-1202.
8. Senni M, McMurray JJV, Wachter R, et al. Impact of systolic blood pressure on the safety and tolerability of initiating and up-titrating sacubitril/valsartan in patients with heart failure and reduced ejection fraction: insights from the TITRATION study. Eur J Heart Fail. 2018;20(3):491-500.
9. DeJong C, Kazi DS, Dudley RA, Chen R, Tseng CW. Assessment of national coverage and out-of-pocket costs for sacubitril/valsartan under Medicare Part D. JAMA Cardiol. 2019;4(8):828-830.
10. Ollendorf DA, Sandhu AT, Pearson SD. Sacubitril-valsartan for the treatment of heart failure: effectiveness and value. JAMA Intern Med. 2016;176(2):249–250.
11. Gaziano TA, Fonarow GC, Claggett B, et al. Cost-effectiveness analysis of sacubitril/valsartan vs enalapril in patients with heart failure and reduced ejection fraction. JAMA Cardiol. 2016;1(6):666–672.

By: Ethan Cowell, PharmD Candidate 2022; University of Health Sciences and Pharmacy in St. Louis

Mentor: Joseph Van Tuyl, PharmD, BCCP; Assistant Professor of Pharmacy Practice/Pharmacy Clinical Specialist – Cardiology; University of Health Sciences and Pharmacy in St. Louis/St. Louis University Hospital

Background:
Heart failure (HF) affected 6 million adults in the United States from 2015 to 2018 and costed approximately $30.7 billion dollars in 2012 alone.¹  Economic estimates predict the total cost of HF will increase to $69.8 billion by 2030.¹  Costs are primarily due to hospitalizations to treat HF and the comorbidities that commonly accompany this disease state. In 2014, the projected mean cost of primary HF hospitalizations was $11 billion (approximately $11,552 per hospitalization).²

HF can be exacerbated by many comorbidities including iron deficiency, which is defined as a serum ferritin <100 mcg/L or serum ferritin 100 to 300 mcg/L with a transferrin saturation (TSAT) <20%.³  Iron deficiency may be prevalent in up to 21% HF patients with anemia, and iron deficiency may be present regardless of the presence of anemia.^{3, 4} Iron deficiency leads to lower iron-sulfur cluster-based complex activity in the mitochondria of cardiomyocytes, thereby, impairing mitochondrial respiration, ATP production, and contractility.⁵ HF patients with comorbid iron deficiency, consequently, are at an increased risk for hospitalizations, decreased quality of life, and exercise intolerance.

Iron stores are regulated by serum hepcidin, an acute phase reactant. Inflammation from HF increases the production of hepcidin. Subsequently, hepcidin binds the ferroportin transporter, which is primarily responsible for gastrointestinal iron absorption and causes its lysosomal destruction.    Consequently, HF patients have a decreased ability to absorb oral iron.³ This was observed in the IRONOUT HF trial, in which clinically insignificant improvements in serum iron and TSAT conferred by oral iron supplementation over a 16-week period demonstrated no significant improvement in the change in peak VO₂ (difference, 21 mL/min; 95% CI, -34 to 76; P-value, 0.46) or 6-minute walk distance (difference, -13 m; 95% CI, -24 to 23; P-value, 0.19) compared to patients receiving placebo.⁶

To overcome the limitations of oral iron supplementation, many clinical trials have assessed the efficacy and safety of intravenous iron therapy to correct iron deficiency in HF. Intravenous iron supplementation may improve clinical outcomes in HF by increasing cardiac mitochondrial function.  

Literature Review:
Intravenous iron supplementation routinely improved functional capacity in randomized controlled trials of chronic HF patients. Study participants were generally characterized as New York Heart Association (NYHA) Class II-III with a left ventricular ejection fraction <45%, and all patients met criteria for iron deficiency (serum ferritin <100 mcg/L or 100-300 mcg/L with a TSAT <20%), regardless of concomitant anemia.^7-10 In the FAIR-HF trial, intravenous ferric carboxymaltose improved self-reported patient global assessment and NYHA functional classification over 24 weeks of follow-up.⁷ Those results were replicated in the CONFIRM-HF trial in which intravenous ferric carboxymaltose improved patient’s 6-minute walk test (difference, 33 ± 11 meters; P=0.002), NYHA functional class, and Kansas City Cardiomyopathy Questionnaire scores when compared to placebo.⁸ Furthermore, the EFFECT-HF trial observed a significant improvement in peak VO₂  with  intravenous ferric carboxymaltose use.⁹  Thus, the 2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure states that it might be reasonable to utilize intravenous iron supplementation in NYHA class II and III HF patients to improve quality of life and functional status (Class IIb; Level of Evidence B-R).¹⁰  Recommendations for intravenous iron supplementation in acute HF, however, are absent from the guidelines.

In a small prospective study, Reed et al. examined the safety and efficacy of intravenous sodium ferric gluconate 250 mg every 12 hours (total dose calculated by the Ganzoni formula, mean dose = 1,269 mg) in patients with NYHA class III-I HF and iron deficiency.  The study showed that intravenous sodium ferric gluconate increased the hemoglobin by 1.2 g/dL (95% CI, 0.45-1.9; P=0.005), ferritin by 364.2 ng/ml (95% CI, 129.7-598.7; P=0.007), and TSAT by 10.5% (95% CI, 6.5-14.6%; P<0.001).  Additionally, iron deficiency was no longer present in eight of the nine patients that followed up in the study.¹¹  Kaminsky et al. further illustrated that patients with acute HF and anemia who received intravenous iron (mean dose = 1,057 mg) had greater improvement in hemoglobin in comparison to a no iron replacement (P=0.0001).¹² The mean difference in hemoglobin from baseline for iron therapy was 0.74 g/dL on day 7 and 2.61 g/dL on day 28, whereas the control group only saw a mean difference of 0.01 g/dL and 0.23 g/dL on days 7 and 28, respectively.¹²  This study also found no statistical difference between iron therapy and the control group in respect to all-cause 30-day readmission rates (P=0.2787), but lack of statistical power precluded a definitive conclusion.¹² In each study, intravenous iron was well-tolerated without significant adverse effects.^{11, 12}

Recently, the AFFIRM-AHF trial assessed the effect of intravenous ferric carboxymaltose on the risk of total HF hospitalizations and cardiovascular death in patients stabilized after acute HF. Patients included were hospitalized with acute HF with a left ventricular ejection fraction <50% and iron deficiency (serum ferritin <100 mcg/L or 100-300 mcg/L with a TSAT <20%).  Ferric carboxymaltose was administered as two repletion doses, up to 1,000 mg prior to discharge and six weeks later, based on patient weight and hemoglobin; subsequent doses were administered at 12 and 24 weeks if iron deficiency persisted upon follow-up. No significant difference in the composite endpoint of total HF hospitalizations and cardiovascular death between the intervention and placebo groups (RR, 0.79; 95% CI, 0.62-1.01; P=0.059). However, a pre-COVID-19 sensitivity analysis was performed and demonstrated a significant decrease in the composite primary outcome (RR, 0.75; 95% CI, 0.59-0.96; P=0.024). Ferric carboxymaltose also decreased in total hospitalizations (RR, 0.74; 95% CI, 0.58-0.94; P=0.013), days lost due to HF hospitalization and cardiovascular death (RR, 0.67; 95% CI, 0.47-0.97; P=0.035), and rate of first hospitalization due to HF or cardiovascular death (HR, 0.80; 95% CI, 0.66-0.98; P=0.030).  Conversely, the trial did not find a significant difference in cardiovascular death between the two groups (HR, 0.96; 95% CI, 0.70-1.32; P=0.81).¹³ Therefore, the trial provided evidence of reduced HF hospitalizations with the use of ferric carboxymaltose in stabilized acute HF patients.

Recommendations:
Intravenous iron supplementation is efficacious in patients with chronic or acute HF and iron deficiency by decreasing hospitalizations and improving exercise intolerance, NYHA functional classification, and quality of life. No major adverse events were observed by intravenous iron replacement. Patients admitted for acute HF should be screened for iron deficiency, and intravenous iron may be administered to decrease the risk of worsening HF symptoms and readmissions.

References

1. Virani SS, Alonso A, Benjamin EJ, et al. Heart disease and stroke statistics-2020 update: a report from the American Heart Association. Circulation. 2020;141(9):e139-e596.
2.  Jackson SL, Tong X, King RJ, Loustalot F, Hong Y, Ritchey MD. National burden of heart failure events in the United States, 2006 to 2014. Circ Heart Fail. 2018;11(12):e004873.
3. von Haehling S, Ebner N, Evertz R, Ponikowski P, Anker SD. Iron deficiency in heart failure: an overview. JACC Heart Fail. 2019;7(1):36-46.
4. Cohen-Solal A, Damy T, Terbah M, et al. High prevalence of iron deficiency in patients with acute decompensated heart failure. Eur J Heart Fail. 2014;16:984-991.
5. Hoes MF, Grote Beverborg N, Kijlstra JD, et al. Iron deficiency impairs contractility of human cardiomyocytes through decreased mitochondrial function. Eur J Heart Fail. 2018;20(5):910-919.
6. Lewis GD, Malhotra R, Hernandez AF, et al. Effect of oral iron repletion on exercise capacity in patients with heart failure with reduced ejection fraction and iron deficiency: the IRONOUT HF randomized clinical trial. JAMA. 2017;317(19):1958-1966.
7. Anker SD, Comin Colet J, Filippatos G, et al. Ferric carboxymaltose in patients with heart failure and iron deficiency. N Engl J Med. 2009;361(25):2436-2448.
8. Ponikowski P, van Veldhuisen DJ, Comin-Colet J, et al. Beneficial effects of long-term intravenous iron therapy with ferric carboxymaltose in patients with symptomatic heart failure and iron deficiency†. Eur Heart J. 2015;36(11):657-668.
9. van Veldhuisen DJ, Ponikowski P, van der Meer P, et al. Effect of ferric carboxymaltose on exercise capacity in patients with chronic heart failure and iron deficiency. Circulation. 2017;136(15):1374-1383.
10. Yancy CW, Jessup M, Bozkurt B, et al. 2017 ACC/AHA/HFSA focused update of the 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. Circulation. 2017;136(6):e137-e161.
11. Reed BN, Blair EA, Thudium EM, et al. Effects of an accelerated intravenous iron regimen in hospitalized patients with advanced heart failure and iron deficiency. Pharmacotherapy. 2015;35(1):64-71.
12. Kaminsky BM, Pogue KT, Hanigan S, Koelling TM, Dorsch MP. Effects of total dose infusion of iron intravenously in patients with acute heart failure and anemia (hemoglobin < 13 g/dl). Am J Cardiol. 2016;117(12):1942-1946.
13. Ponikowski P, Kirwan BA, Anker SD, et al. Ferric carboxymaltose for iron deficiency at discharge after acute heart failure: a multicentre, double-blind, randomised, controlled trial. Lancet. 2020;396(10266):1895-1904.

By: Veeraya White, PharmD Candidate 2022 – University of Health Sciences and Pharmacy in St. Louis

Mentor: Brooke E. Gengler, PharmD, BCCP; Pharmacy Clinical Specialist, Cardiology, SSM Health Saint Louis University Hospital

Introduction
Coronavirus disease 2019 (COVID-19) is a viral respiratory infection caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) which has become a significant threat worldwide. The infection triggers host defense systems resulting in activation of coagulation and thrombin generation, called thromboinflammation.¹ As a result, some patients with COVID-19 encounter complications associated with cytokine overproduction, hypercoagulability, and thrombosis. Thromboinflammation may lead to a life-threatening condition, disseminated intravascular coagulopathy (DIC), a condition in which blood clots throughout the body use up available clotting factors thereby increasing the risk of bleeding.^2,3 Anticoagulants (ACs), such as low molecular weight heparin (LMWH), and unfractionated heparin (UFH), are used to prevent thrombosis.² This article will discuss the appropriate criteria for anticoagulant venous thromboembolism (VTE) prophylaxis in patients with COVID-19. 

Literature Review
Early in the pandemic, clinicians identified that DIC was commonly associated with severe cases of COVID-19 that resulted in death.⁴ Upon closer examination, many of these patients experienced microvascular thrombosis or venous thromboembolism.⁵ As a result, several studies attempted to find an association between various biomarkers such as D-dimer and risk of thrombosis. One retrospective study from Wuhan, China found that patients with sepsis-induced coagulopathy scores (SIC) ≥4 or elevated D-dimers who were given prophylactic doses of LMWH had reduced mortality compared to those without.⁶

Larger, prospective, randomized controlled trials have explored whether prophylactic anticoagulation is enough to prevent thrombosis or if intermediate intensity, doses between prophylactic and therapeutic anticoagulation, should be used instead. The ACTION study evaluated extended duration therapeutic anticoagulation with rivaroxaban or enoxaparin during admission followed by rivaroxaban for 30 days after discharge in acutely ill COVID-19 patients. Compared to standard VTE prophylaxis, therapeutic anticoagulation increased the risk of bleeding without improving clinical outcomes.⁷ In critically ill patients, receipt of early therapeutic anticoagulation within two days of admission was not associated with reduced mortality.⁸ Preliminary data from the multi-platform randomized controlled trial (mpRCT) also indicate that therapeutic anticoagulation did not improve survival or days free from organ support compared to standard pharmacologic prophylaxis. This trial was stopped early due to futility.⁹ Based on currently available evidence, most COVID-19 patients admitted to the hospital should be initiated on standard VTE prophylaxis rather than an intensified regimen.

Application in Practice

Thrombosis prophylaxis in hospitalized COVID-19 patients

• Routine thromboprophylaxis should be used in all hospitalized non-pregnant patients with a standard dose of LMWH or UFH after careful assessment of bleeding risk. LMWH is the preferred agent due to lower frequency of administration.^11,16,17
• VTE prophylaxis regimens should be modified based on body weight, severe thrombocytopenia (i.e. platelet counts <25,000/µL in non-bleeding patients or 50,000/µL in bleeding patients), or declining renal function.^10,13
• In patients with a contraindication to pharmacologic prophylaxis, consistent application of intermittent pneumatic compression devices should be used with regular assessment.¹⁷
• In critically ill patients, thromboprophylaxis should be initiated at standard doses. An intermediate dose may be considered in patients at high risk of thrombosis.¹⁷

Recommended standard prophylaxis doses of anticoagulants (dose adjustments for renal function and obesity not included)^10,12,13

• Enoxaparin 40 mg subcutaneously (SUBQ) daily
• Heparin 5000 units SUBQ every 8 hours (preferred in patients with creatinine clearance (CrCl) <15 mL/min or dialysis)

Recommended intermediate doses of anticoagulants¹⁷

• Enoxaparin 0.5 mg/kg SUBQ twice daily
• Heparin 7500 units SUBQ every 8 hours

Duration of VTE prophylaxis after hospital discharge¹⁰

• Post-hospital VTE prophylaxis may be considered on a case-by-case basis for patients with COVID-19 who are low bleeding risk (e.g. IMPROVE bleed score <7.0) and:
• • Were admitted to the ICU, intubated, sedated, and possibly paralyzed for multiple days
  • Have ongoing VTE risk factors at the discharge (e.g. limited mobility, profound weakness, or not at baseline physical status)

References

1. Connors JM, Levy JH. COVID-19 and its implications for thrombosis and anticoagulation. Blood. 2020;135(23):2033-2040.
2. Moonla C, Sosothikul D, Chiasakul T, Rojnuckarin P, Uaprasert N. Anticoagulation and in-hospital mortality from coronavirus disease 2019: a systematic review and meta-analysis. Clin Appl Thromb Hemost. 2021; 27:10760296211008999.
3. National Heart Lung and Blood Institute. Disseminated intravascular coagulation. Published October 2019. Accessed June 21, 2021.
4. Tang N, Li D, Wang X, Sun Z. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost. 2020;18:844-847.
5. McFadyen JD, Stevens H, Peter K. The emerging threat of (micro)thrombosis in COVID-19 and its therapeutic implications. Circulation Research. 2020;127:571-587.
6. Tang N, Bai H, Chen X, Gong J, Li D, Sun Z. Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy. J Thromb Haemost. 2020;18(5):1094-1099.
7. Lopes RD, de Barros E Silva PGM, Furtado RHM, et al. Therapeutic versus prophylactic anticoagulation for patients admitted to hospital with COVID-19 and elevated D-dimer concentration (ACTION): an open-label, multicentre, randomised, controlled trial. Lancet. 2021;397(10291):2253-2263.
8. Al-Samkari H, Gupta S, Leaf RK, et al. Thrombosis, bleeding, and the observational effect of early therapeutic anticoagulation on survival in critically ill patients with COVID-19 [published correction appears in Ann Intern Med. 2021 Jun;174(6):888]. Ann Intern Med. 2021;174(5):622-632.
9. Zarychanski R. The REMAP-CAP, ACTIV-4a, ATTACC investigators. Therapeutic anticoagulation in critically ill patients with COVID-19 – preliminary report.
10. Benge C, DeWitt K. Anticoagulation Forum. Anticoagulation in COVID-19: summary of societal guidance. Updated December 2020. Accessed June 21, 2021.
11. National Institutes of Health. Antithrombotic therapy in patients with COVID-19. Published February 2021. Accessed June 21, 2021.
12. Bikdeli B, Madhavan MV, Jimenez D, et al. COVID-19 and thrombotic or thromboembolic disease: implications for prevention, antithrombotic therapy, and follow-up: JACC state-of-the-art review. J Am Coll Cardiol. 2020;75(23):2950-2973.
13. Thachil J, Tang N, Gando S, et al. ISTH interim guidance on recognition and management of coagulopathy in COVID-19. J Thromb Haemost. 2020;18(5):1023-1026.
14. Moores LK, Tritschler T, Brosnahan S, et al. Prevention, diagnosis, and treatment of VTE in patients With Coronavirus disease 2019: CHEST guideline and expert panel report. Chest. 2020;158(3):1143-1163.
15. Cuker A, Tseng EK, Nieuwlaat R, et al. American Society of Hematology 2021 guidelines on the use of anticoagulation for thromboprophylaxis in patients with COVID-19. Blood Adv. 2021;5(3):872-888.
16. Spyropoulos AC, Levy JH, Ageno W, et al. Scientific and standardization committee communication: clinical guidance on the diagnosis, prevention, and treatment of venous thromboembolism in hospitalized patients with COVID-19. J Thromb Haemost. 2020;18(8):1859-1865.
17. Barnes GD, Burnett A, Allen A, et al. Thromboembolism and anticoagulant therapy during the COVID-19 pandemic: interim clinical guidance from the anticoagulation forum. J Thromb Thrombolysis. 2020;50(1):72-81.